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Introduction/aims: The degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo., Methods: Data from the NEURO-TTRansform trial on patients with ATTRv-PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor-based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL-Diabetic Neuropathy (Norfolk QoL-DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed., Results: Meaningful improvement in mNIS+7 was estimated as -4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL-DN were -12.8 to -4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were -2.4 to -1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m 2  × g/L and deterioration was -40.9 kg/m 2  × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences., Discussion: Eplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background: The guidelines for Advanced Life Support issued by the European Resuscitation Council recommend considering drug delivery through intraosseous access if intravenous access to the vascular bed is not feasible or unsuccessful. Emergency prehospital intraosseous cannulation may theoretically lead to an increased risk of long-term complications such as osteomyelitis, osteonecrosis, or compartment syndrome. Such complications have previously been reported in case reports or small sample case series. We systematically investigated long-term complications potentially associated with intraosseous cannulation using validated Danish health registries., Methods: Data sources were the nationwide electronic Prehospital Patient Record system, the Danish National Patient Registry, and the Danish Civil Personal Registry. We investigated all patients who were subjected to prehospital intraosseous cannulation in Denmark from January 2016 through December 2019. During a follow-up period of 180 days from the index date we extracted information concerning mortality status and potential long-term complications defined as osteomyelitis, osteonecrosis, or compartment syndrome from the day of prehospital intraosseous cannulation., Results: Of the 5,387 patients receiving intraosseous access, 375 were unidentified and lost to follow-up. Of the 5012 remaining patients, 4,775 were adults, and 237 were children. No children and "less than five" adults had long-term complications. No osteonecrosis, osteomyelitis or compartment syndrome appeared later than 175 days after an intraosseous cannulation., Conclusions: Long-term complications such as osteomyelitis, osteonecrosis, or compartment syndrome following prehospital intraosseous cannulation and drug delivery occurred in less than 0.1% of the cases. Our findings indicate that prehospital intraosseous cannulation may be safe across age groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recently, face mask sampling (FMS) confirmed detection of Mycobacterium tuberculosis DNA from exhaled breath in adults with tuberculosis. To date, no study has evaluated the use of FMS to detect pulmonary tuberculosis in children. We developed a method for FMS of M. tuberculosis-specific DNA in children and performed a clinical exploration to assess feasibility in children., Methods: Face masks were spiked, analyzed on GeneXpert-Ultra, quantitative polymerase chain reaction, and targeted next-generation sequencing. Children with pulmonary tuberculosis were asked to wear 3 modified FFP2 masks for 30 minutes as part of an exploratory clinical study., Results: Experiments with H37Ra M. tuberculosis strain showed a limit of 95% detection of 3.75 colony-forming units (95% confidence interval, 4.85-3.11) on GeneXpert-Ultra. Ten children with pulmonary tuberculosis participated in the clinical study. M. tuberculosis-specific DNA was detected on none of the face masks., Conclusions: Pediatric FMS has a low limit of detection for M. tuberculosis-specific DNA in vitro. However, M. tuberculosis DNA was not detected in any of 30 masks worn by children with pulmonary tuberculosis. This suggests that FMS in this form may not be more effective for detecting M. tuberculosis in children with tuberculosis than existing methods., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Out-of-hospital cardiac arrest (OHCA) remains a critical health concern, where prompt access to automated external defibrillators (AEDs) significantly improves survival. This scoping review broadly investigates the feasibility and impact of dronedelivered AEDs for OHCA response., Methods: PubMed, Cochrane, and Web of Science were searched from inception to August 6, 2024, with eligibility broadly including empirical data. The charting process involved iterative data extraction for thematic analysis., Results: We identified 306 titles and, after duplicate removal, title/abstract screening, and full text review, included 39 studies. These were divided into three categories: 1) Real-world observational studies (n = 3), 2) Test flights/simulation studies and qualitative analyses (n = 15), and 3) Computer/prediction models (n = 21). Real-world studies demonstrated the feasibility of drone AED delivery, with a time advantage of 01:52 - 03:14 min over ambulances observed in 64-67 % of cases. Test flight/simulation and qualitative studies consistently reported feasibility and positive bystander experiences. Computer/prediction models exhibited considerable heterogeneity, yet all indicated significant time savings for AED delivery compared to traditional EMS methods. Moreover, seven studies estimated improved survival rates, with five assessing cost-effectiveness and favouring drone systems. Regional factors such as EMS response times, volunteer responder programmes, terrain, weather, and budget constraints influenced the system's effectiveness., Conclusion: Across all categories, studies confirmed the feasibility of drone-delivered AED systems, with significant potential for reducing time to AED arrival compared to EMS arrival. Prediction models suggested enhanced survival alongside costeffectiveness. Further research, including more extensive real-world studies and regulatory advancements, is imperative to integrate drones effectively into OHCA response systems., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Janet Bray is an Associated Editor and Theresa Mariero Olasveengen an Editorial Board member of Resuscitation Plus. JB and TMO are Editorial Board members of Resuscitation., (© 2024 The Authors.)

This is the eighth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; a more comprehensive review was done in 2020. This latest summary addresses the most recent published resuscitation evidence reviewed by the International Liaison Committee on Resuscitation task force science experts. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, using Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces list priority knowledge gaps for further research.

In 2022, over 1,000,000 people from Ukraine fled to Germany, mostly women and children. The aim of this study was to determine health status and socio-demographic background of Ukrainian refugee minors in Germany and to compare that to German minors. In this study, Ukrainian refugees of all ages, who voluntarily made contact with the study centres via flyers or refugee shelters, were interviewed with the help of trained interpreters from 09-12/2022. We assessed data from minors and their families on socio-economic status, general health perception, current and pre-existing infectious and non-contagious diseases, and vaccination status. The data for the minors were collected by interviewing the accompanying adults. In addition, a physical examination and serological screening for infectious and vaccine-preventable diseases were performed. Overall, 392 minors and accompanying adults (358) were included. Minors' general and mental health were reported as "at least good" in 83% (316) and 80% (304), respectively. In 16% (63), infectious or other underlying diseases were recorded. Tuberculosis infections (7, 1.8%) and hepatitis C (2, 0.5%) were found through the serological tests. HIV could only be detected in one previously known case. Self-reported vaccinations against measles and varicella, for example, did not match serological findings (protection against measles 304; 84%; varicella 230; 64%)., Conclusion: Accompanying adults often rate the general health and well-being of Ukrainian refugee minors as rather poor. Frequently, self-reported vaccinations and preexisting diseases did not match serology results; therefore, Ukrainian refugee minors without formal vaccination certificate should be offered all recommended vaccinations and be generously screened for hepatitis B, C and HIV in addition to tuberculosis., What Is Known: • Infectious diseases (TB, hepatitis B/C, HIV) are more common among Ukrainian minors and vaccine hesitancy is more widespread than in many host countries and require appropriate medical care. • Displacement and war worsen medical care and have negative impact on mental health.., What Is New: • Although intrafamilial spread of infectious diseases was rare (in this cohort), perceived general health of Ukrainian minors is rather poor. • Semi-structured interviews-even with interpreters-are often insufficient to collect valid medical information., Competing Interests: Declarations. Ethics approval: Two different leading ethics committees evaluated the study protocol, the one of the Goethe University in Frankfurt for adult participants (reference number 2022–831) and of Ruhr University in Bochum for the paediatric cohort (“minors”) (registration number 22–7623). Subsequently, the study was approved by all local ethics committees of all study centres. The study was conducted in accordance with the Declaration of Helsinki. Consent to participate: Written informed consent was obtained from all participants included in the study or, in the case of minors, that of the legal guardian. All participants were informed about the publication of anonymized data. No personal data was published, so no separate declaration of consent was obtained for this. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This investigation delineates the evolution and prospective utilisation of an innovative two-blade dermatome, designed for the concurrent harvesting of a conventional split-thickness skin graft (STSG) and an additional dermal graft within the same surgical harvest. Historically, the extraction of dermal grafts has encountered substantial technical impediments, contributing to its limited acceptance and utilisation in clinical practice. The prototype dermatome, introduced in this technical note, offers a solution that could facilitate the more extensive adoption of dermal grafting techniques. The dermal segment of an STSG, obtained as a second graft, confers four notable advancements: First, employing solely the dermal component for grafting and repositioning the uppermost skin flap to the donor site, markedly diminishes donor site morbidity. Second, owing to its elasticity, the dermal graft reduces the need for meshing, thereby enhancing cosmetic outcomes. Third, utilising both the uppermost skin layer and a deeper dermal layer for the recipient site can reduce donor site areas. Fourth, the dermal segment of the graft can serve as a dermal matrix in reconstructive procedures, potentially reducing the need for an allogenic dermal matrix and obviating the subsequent STSG; the dermal graft may heal independently, eliminating the need for an additional conventional STSG. The findings of this study, predicated on the application of a first-generation two-blade dermatome on four cadavers, demonstrate the feasibility of extracting at least two distinct grafts with pre-determined thicknesses in a single, technically less challenging, surgical harvest procedure. In conclusion, this proof-of-concept research elucidates the feasibility of a two-blade dermatome, capable of simultaneously yielding at least one conventional STSG and one dermal graft, thereby simplifying skin graft harvesting. Although these preliminary investigations were conducted on human cadavers, the results hold promise for the development of two-blade dermatomes and represent a significant advancement in skin graft harvesting. Further research is imperative to refine the prototype and to broaden our comprehension of the potential applications of dermal grafting in various clinical scenarios., Competing Interests: Conflict of Interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Fast thawing for emergency situations and reduction of plasma wastage., Background: Evaluation of plasma units, pooled and pathogen reduced (PR) in "maxi-pools" with amotosalen and UVA light, and fast thawing., Methods/materials: Per replicate, 10 WB-derived leukocyte depleted plasma units were frozen within 24 h at ≤ -25°C and stored for 7 days. After thawing, a maxi-pool was constituted from the 10 units. After splitting into 4 sub-pools of 650 mL, the sub-pools were PR treated then split into 3 units resulting in 12 PR plasma units at 200 mL. Hundred and twenty PR plasma units were produced in total. The units were frozen at ≤ -25°C for 1 week, then thawed either in a fast plasma thawer for 5 min or in other control devices (17 to 23 min)., Fviii: C, Fibrinogen, albumin, IgG, protein S and VWF were measured in plasma units, maxi-pools and plasmas after PR treatment and thawing., Results: There was a statistically significant (p < 0.001) but still clinically acceptable (over the recommended levels of ≥0.5 IU/mL and ≥2 g/L) reduction of FVIII:C and Fibrinogen after PR with 69% and 87% recovery, respectively. Other proteins were not significantly affected by the processes., Conclusion: Pooling 10 plasma units before the PR treatment standardises volume and protein content of plasma units. Besides the economic value of generating 12 products for transfusion, this procedure combined with a thawing time of about 5 min is of value in emergency situations and may reduce plasma wastage., (© 2024 The Author(s). Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.)

Background: Humans are subjected to various environmental stressors (bacteria, viruses, pollution) throughout life. As such, an inherent relationship exists between the effect of these exposures with age. The impact of these environmental stressors can manifest through DNA methylation (DNAm). However, whether these epigenetic effects selectively target genes, pathways, and biological regulatory mechanisms remains unclear. Due to the frequency of human rhinovirus (HRV) infections throughout life (particularly in early development), we propose the use of HRV under controlled conditions can model the effect of multiple exposures to environmental stressors., Methods: We generated a prediction model by combining transcriptome and DNAm datasets from human epithelial cells after repeated HRV infections. We applied a novel experimental statistical design and method to systematically explore the multifaceted experimental space (number of infections, multiplicity of infections and duration). Our model included 35 samples, each characterized by the three parameters defining their infection status., Results: Trainable genes were defined by a consistent linear directionality in DNAm and gene expression changes with successive infections. We identified 77 trainable genes which could be further explored in future studies. The identified methylation sites were tracked within a pediatric cohort to determine the relative changes in candidate-trained sites with disease status and age., Conclusions: Repeated viral infections induce an immune training response in bronchial epithelial cells. Training-sensitive DNAm sites indicate alternate divergent associations in asthma compared to healthy individuals. Our novel model presents a robust tool for identifying trainable genes, providing a foundation for future studies., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: Maintaining physical fitness plays an important role in the management of people with cystic fibrosis (pwCF). Longitudinal data on the course of physical fitness and the potential impact of the introduction of highly effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in adult pwCF are scarce. Methods: Health-related and skill-related components of physical fitness were assessed using an incremental cycle test (Wpeak), plus forward bend (FB), prone bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Relevant disease-specific clinical data (body mass index [BMI] and forced expiratory volume in 1 second [FEV1]) were recorded. Results: Twenty-eight adult pwCF (age 26.0 ± 7.8 years) were followed over 5.6 ± 0.9 years; 21 started ETI therapy during this period. Significant improvements from baseline were noted in BMI ( p < 0.001) and health-related fitness components (HE, p = 0.002; PLR, p = < 0.001), whereas Wpeak and FB remained stable over time (all p > 0.05). Skill-related components (SLJ, OLS) showed no change (all p > 0.05). Subgroup analysis revealed significant improvements in BMI, FEV1, and health-related fitness measures of muscular strength and endurance (HE, p = 0.009; PLR, p < 0.001) only in pwCF using ETI. Conclusion: Despite the improvements, the impact of ETI on the individual parameters was small. Other factors than implementation of ETI alone need to be considered on the way to a high level of physical fitness in adult pwCF.

Background: Varicella (chickenpox) caused by varicella-zoster virus (VZV) is a highly contagious pediatric disease. While it typically manifests as a mild disease, complications leading to hospitalization are not uncommon. Knowing the current disease burden, seasonality and risk groups is pivotal for evidence-based decisions on the introduction of a varicella vaccine., Methods: Using the Danish National Patient Register and medical helpline records from the Capital Region, we estimated the burden of VZV infections among children younger than 18 years in Denmark from 2015 to June 2023., Results: We identified 14,443 cases with annual incidence rates of 325/100,000 children for mild-to-moderate varicella cases (helpline calls), 35/100,000 for moderate-to-severe cases (outpatients) and 10/100,000 for severe cases (hospitalized). Mild cases were most prevalent in children 1-4 years old, while moderate-to-severe cases were most prevalent among infants <1 year old. Among hospitalized cases, 23.2% had underlying diseases and 47.3% experienced complications. In April 2022, rapid surge in all types of VZV cases occurred, where admissions surpassed the prepandemic level., Conclusion: This study documents that varicella is highly prevalent among Danish young children. Mild-to-moderately severe cases strain healthcare, causing increased helpline calls and posing a persistent hospitalization risk, especially for infants and children with underlying conditions., Competing Interests: T.K.F. and A.M.E.-C. received funding from the MSD to conduct this study. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The NEURO-TTRansform trial showed that after 66 weeks of treatment, eplontersen significantly reduced neuropathic impairment and improved quality of life (QoL) in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). In this secondary analysis from NEURO-TTRansform, autonomic impairment, and the impact of eplontersen on autonomic impairment progression was evaluated through 85 weeks in patients randomised to eplontersen ( n  = 144) versus external placebo ( n  = 60; through Week 66 from the NEURO-TTR trial)., Methods: Change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, and the Neuropathy Symptoms and Change (NSC) total score was evaluated. Exploratory assessments were change in autonomic components of these instruments, Composite Autonomic Symptom Score-31 (COMPASS-31) total score, and nutritional status (modified body mass index [mBMI])., Results: Patients reported profound autonomic dysfunction at baseline. Improvements with eplontersen versus placebo were observed up to Week 66 in autonomic components of mNIS+7, Norfolk QoL-DN, NSC, and mBMI; eplontersen results were sustained up to Week 85, including improvements in COMPASS-31 (Week 81)., Conclusions: Eplontersen demonstrated benefit across multiple measures of autonomic impairment known to progress rapidly and negatively impact QoL without treatment, without deterioration in nutritional status.

It is not well investigated whether exposure to specific drug classes is associated with COVID-19. We investigated the risk of SARS-CoV-2 infection and severe COVID-19 among healthcare workers according to prescription drug use. We conducted an observational study among Danish healthcare workers. SARS-CoV-2 positivity was defined as a positive PCR/ELISA test throughout 2020 and severe COVID-19 as any above 48-hour hospitalization within 14 days after infection. Patient characteristics came from online surveys while data on SARS-CoV-2, drugs and hospitalizations came from Danish Health Registers. Infected individuals were matched with uninfected controls based on age, sex, and chronic diseases. Drug exposure was defined as any prescription redemption in the past six and one month(s) before infection for each drug class. Models assessing the risk of infection (conditional logistic regression) and severe COVID-19 (logistic regressions) versus drug usage were adjusted for BMI, smoking, alcohol, education, region, and patient contact when possible. We matched 5,710 SARS-CoV-2-infected cases with 57,021 controls. The odds of infection were reduced by calcium channel blocker (adjusted odds ratio (aOR) 0.81, 95% Confidence Interval (CI): 0.66-1.00) and vasoprotective drug (aOR 0.77, CI: 0.62-0.95) usage during the six months before infection compared to no usage. Exposure to antibacterials in the past month increased the odds of infection (aOR 1.27, CI: 1.09-1.48). Among infected participants, the odds of severe COVID-19 were higher with usage of almost any investigated drug, especially, diuretics (crude odds radio (OR) 4.82, CI:2.15-10.83), obstructive airway disease drugs (OR 4.49, CI: 2.49-8.08), and antibacterials (OR 2.74 CI:1.62-4.61). In conclusion, antibacterials were associated with more SARS-CoV-2 infections and calcium channel blockers with less. Once infected, users of prescription drugs had higher odds of developing severe COVID-19. These findings suggest a need for studies to clarify interactions between specific drug groups, behaviour, known risk factors, and disease susceptibility/severity., Competing Interests: S.B.’s research salary was sponsored by Sygesikring Danmark and the Capital Region of Denmark’s Research Foundation. K.I. received grants from Lundbeck Foundation to his institution [grant number R349-2020-731]. A.D.K has received a grant from The Danish Heart Foundation and a grant from the European Commission (EU 7th Framework [grant number 603266]). C.T-P. has received grants from Bayer and Novo- Nordisk for studies not related to the current study. F.F. has received research grant from the Novo Nordisk Foundation and an unrestricted research grant from the Laerdal Foundation to the Copenhagen EMS. S.D.N received an unrestricted research grants from the Novo Nordic Foundation, Augustinus Foundation, Kirsten and Freddy Johansen’s Foundation. U.F.R.’s research salary was sponsored by a grant from Kirsten and Freddy Johansen’s Foundation. A.E., M.V., H.B., J.R., R.B.H., J.H.K., P.B.N., M.M.P-H., K.F., J.B.N., O.A., T.K.F., R.B.D., S.R.O., S.B.D., M.G-B., E.S., L.H.H., T.B., F.N.E., H.E.P., H.U., and J.R. have no conflicts of interest to declare., (Copyright: © 2024 Eiken et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In 2017 the Swedish public insurance company Löf published national guidelines for in-hospital trauma team activation (TTA), which are now widely adopted in Sweden. No studies have examined triage accuracy at non-trauma-center hospitals in the Stockholm trauma system since the implementation of the new TTA criteria., Aim: To assess trauma triage accuracy at one non-trauma-center hospital in Stockholm., Methods: 3528 trauma patients treated at Södersjukhuset during 2019-2022 were acquired from the Swedish Trauma Registry (SweTrau) to calculate TTA triage accuracy. Undertriage was defined in accordance with national guidelines as patients with a New Injury Severity Score > 15 who did not prompt level 1 TTA on arrival to hospital., Results: In total there were 849 severely injured patients during the study period, of which 2.2% (n = 19) prompted TTA level 1, corresponding to an undertriage of 98% (n = 830). Of the 849 severely injured patients, 41% (n = 348) prompted TTA level 2 whereas the remaining 57% (n = 482) prompted no TTA on arrival to hospital. There were a total of 3046 patients prompting TTA during the study period, but only 19% (n = 19) of level 1 and 12% (n = 348) of level 2 patients were severely injured, and 45% had a NISS ≤ 3., Conclusion: Undertriage of severely injured trauma patients was 98% according to the definition specified by Swedish trauma triage guidelines, higher than reasonably acceptable. There is considerable overtriage with non-severely injured patients prompting TTA. However, the suitability of using NISS > 15 to retrospectively define the need for TTA is debatable as this does not always correlate with the fulfillment of the TTA criteria. Further investigation of adherence to trauma triage guidelines in clinical practice may be of value to improve triage accuracy in organized regional trauma systems., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethical Review Authority in Sweden who also waived the need for informed consent (2022-06727-01). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Wearable accelerometers allow continuous assessment of physical activity during normal living conditions and may be useful in evaluating the effects of treatment for heart failure. We explored the relationships between accelerometer measures of physical activity and 6-minute walk distance and patient-reported measures of functional limitation in participants across the entire spectrum of left ventricular ejection fraction in the DETERMINE (Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE walk test in patients with heart failure) trials., Methods: A subgroup of patients in the DETERMINE trials wore a waist-based accelerometer during 7-day periods at 3 points during the trial: between screening and randomization and during weeks 8 and 14. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) at baseline and at weeks 8 and 16., Results: Of the 817 patients randomized, 319 (39%) had adequate baseline accelerometer data. Patients with lower levels of physical activity had lower (ie, worse) KCCQ scores and 6MWD, higher NT-proBNP levels and BMIs, worse kidney function, and a greater likelihood of diabetes and atrial fibrillation. Baseline accelerometer values had weak correlations with KCCQ summary scores (Pearson r = 0.06-0.21) and weak to moderate correlations with 6MWD (Pearson r = 0.20-0.31). The change from baseline to 16 weeks in accelerometer-measured physical activity correlated weakly with the change in KCCQ summary scores (Pearson r = 0-0.18) and 6MWD (r = 0.01-0.10)., Conclusions: In the DETERMINE trials, accelerometer-based measures of physical activity correlated modestly with KCCQ summary scores and 6MWD. Accelerometer-based assessments of physical activity may provide additional information complementing that obtained from standard measures of functional limitation in patients with heart failure., Competing Interests: Disclosures KFD reports that his employer, the University of Glasgow, has been remunerated by AstraZeneca for work relating to clinical trials. He has received speaker's honoraria from AstraZeneca, Pharmacosmos, Boehringer Ingelheim, Translational Medicine Academy and Radcliffe Cardiology, has served on an advisory board for Us2.ai and holds equity in the company, has served on an advisory board and served on a clinical endpoint committee for Bayer AG, and has received grant support from Boehringer Ingelheim, Roche Diagnostics and AstraZeneca (paid to his institution). RBL, FF, JC, AH, AML, BR, UW and MRC are employees of AstraZeneca and may own stock or stock options. RAB has had speaker engagements with and/or received fees from and/or served on advisory boards for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals, NovoNordisk, and Roche, and has received travel support from Abbott, Cardior Cardior Pharmaceuticals, and NovoNordisk. The institution of RAB has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals, Novo Nordisk, and Roche. DWK has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer-Ingleheim, NovoNorDisk, Rivus, and St. Luke's Medical Center, has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo NorDisk, Rivus, and St. Luke's Medical Center, and owns stock in Gilead Sciences. MNK has received research grant support from AstraZeneca and Boehringer Ingelheim‚ has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma‚ has received other research support from AstraZeneca‚ and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. MS has received honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving grants and/or research support and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, and Sanofi. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart‚ Lung‚ and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. JJVM reports receiving support from a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; has received payments through Glasgow University for work on clinical trials, consulting and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, SunPharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of targeted therapies for atopic diseases, urticaria, and angioedema with biologics is progressing rapidly: New "targets" of clinical-therapeutic relevance have been identified, the corresponding targeted antibodies developed, tested in clinical trials, and approved for therapy. These include the anti-IgE antibody omalizumab (also effective and approved for the treatment of urticaria), the anti-IL-4/13 receptor-specific antibody dupilumab, the two anti-IL-13 antibodies lebrikizumab and tralokinumab, the anti-TSLP antibody tezepelumab, the two anti-IL-5 antibodies mepolizumab and reslizumab, and the anti-IL5 receptor-specific antibody benralizumab for the treatment of atopic diseases. For the treatment of hereditary angioedema, C1 inhibitor and the antibody lanadelumab (directed against kallikrein) have also long been approved as biologics in addition to low-molecular substances. Other therapeutic antibodies are in various stages of development. Furthermore, the range of indications for some very effective biologics has been successfully expanded to include additional diseases. In this context, the first results on biologic therapy of food allergy and eosinophilic esophagitis are interesting. Biologics that address different target structures are also increasingly being administered in combination, either simultaneously or sequentially, in order to achieve optimal efficacy. A developing area is the use of biologics in children and the observation of immunological and non-immunological side effects. In some cases, new unexpected side effects and hypersensitivity reactions have emerged, which in turn raise pathomechanistic questions, such as conjunctivitis with dupilumab therapy, which only appears to occur in the treatment of atopic dermatitis but not in the treatment of other atopic diseases. In dermatology, paradoxical reactions have been described under therapy with some biologics. And immune reactions of type alpha to epsilon to biologics (hypersensitivity reactions) continue to be a clinically relevant problem, whereby the selection of an alternative therapeutic agent is a challenge and the diagnostics that support this have not yet been sufficiently incorporated into routine work., Competing Interests: CT, AG, VF, KCB, and FB have no conflict of interest. UJ received hotel accommodation and meals for a lecture and for leading a workshop organized by ALK Abello. The fee went to her organization, the RCB. In addition, another hotel night and dinner were recently provided by ALK Abello. Her research on molecular allergology is funded by the Federal Ministry of Education and Science, the Federal Ministry of Food and Agriculture (BMEL), the German Research Foundation and the Kanert Foundation: all outside the topic of this article. The Federal Ministry of Technology, Economics and Technology has funded their research on assays for the detection of anti-drug antibodies via the AiF-ZIM program. ST reports support for consultancy, lectures, and other scientific activities from AbbVie, Janssen/ JNJ, Leo Pharma, Lilly, Novartis, and Regeneron/Sanofi outside the submitted work, memberships: DGAKI, DDG, EAACI. RT received research support from Sanofi-Genzyme and the Hautnetz Leipzig/Westsachsen e.V. as well as fees for lectures and consultations from ALK-Abello, Takeda, Novartis, Sanofi-Genzyme, Abbvie, and support for congress visits from Takeda. LK reports grants and/or personal fees from Allergopharma, MEDA / Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk and Cassela med outside the submitted work; and memberships: AeDA, DGHNO, German Academy of Allergology and Clinical Immunology, HNO-BV, GPA, EAACI. MWo reports support for consultancies, lectures and other scientific activities from ALK-Abelló Arzneimittel GmbH, Abbvie, Eli Lilly, Mylan Germany GmbH, Bencard Allergie GmbH, Novartis AG, Biotest AG, Sanofi-Aventis Deutschland GmbH, HAL Allergie GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Stallergenes GmbH. S. Seurig reports support for consultations, lectures, and other scientific activities by Allergopharma, ALK-Abelló Arzneimittel GmbH, AstraZeneca, Takeda outside the submitted work, memberships: DGAKI, DGP, EAACI TZ reports support for consultations, lectures and other scientific activities by AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, Lofarma, L’Oreal, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Sanoflore, Stallergenes, Takeda, Teva, UCB as well as responsible participation in the following organizations: Committee member, WHO initiative “Allergic Rhinitis and its Impact on Asthma” (ARIA), Member of the Board, German Society for Allergy and Clinical Immunology (DGAKI), Head, European Centre for Allergy Research Foundation (ECARF), Secretary General, Global Allergy and Asthma European Network (GA2LEN), Member, Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). TW reports support for consultancy, lectures, and other scientific activities from AbbVie, ALK Abello, Almirall, Astellas, Bencard, Galderma, Janssen/JNJ, Leo Pharma, Leti, Lilly, Novartis, Pfizer, Regeneron/Sanofi, Stallergen. MWa has received fees for consulting, lectures or research support from the following companies in the past 3 years: Allergopharma, ALK-Abelló, AstraZeneca, CSL Behring, Genzyme, GSK, HAL Allergie, Infectopharm, LETI Pharma, Novartis, Regeneron, Sanofi, Stallergenes, Takeda. HR: Co-Founder STERNA Biologicals and SECARNA Pharmaceuticals. Table 1.Frequency of hypersensitivity reaction to biologics. BiologicTargetAuthorYearHSR %IR %ISR %Urticaria %Anaphylaxis %AdalimumabTNF-αPuxeddu et al. [243]20123.5–1.51.50Tarkiainen et al. [244]201518.117.0––EMA [245]20231.0 – 10.012.91.0 – 10.00.01 – 0.1FDA [246]20236.05.0 – 20.06.0–BenralizumabIL-5RCastro et al. [247]2014–16.0––Park et al. [248]2019–00 – 2.0–Liu et al. [249]2019–2.6–17.5––FDA [250]20193.02.23.03.0Bourdin et al. [251]20190 – 3.23.2 – 6.5––EMA [252]2023up to 10.02.2up to 10.0–Yamaguchi et al. [253]20240.3––0.3BrodalumabIL-17RAFDA [254]2017–1.51.0–Iznardo et al. [255]2020< 1.01.8––Kim et al. [256]2023–1.3––EMA [257]2023–1.0 – 10.0–0.01 – 0.1CertolizumabTNFαFDA [258]2022–1.7 – 3.2––EMA [259]2023–1.0 – 10.0–0.01 – 0.1Kim et al. [256]2023–3.9––DupilumabIL-4RαOu et al. [260]2018–13.2––Halling et al [261]2021–5.3––EMA [262]2023–1.0 – 10.0–0.01 – 0.1Kim et al. [256]2023–11.3––FDA [263]2024< 1.06.0 – 38.0< 1.0< 1.0Simpson et al. [264]2024–3.0––Yew et al. [265]2024–2.05.9–EtanerceptTNF-α-RIIPuxeddu et. al. [243]20125.3–1.62.00.8Tarkiainen et al. [244]201511.37.5––Girolomoni et al. [266]2018–10 – 49.0––Codreanu et al. [267]2019–0.8–0.8FDA [268]2023< 1.015 – 43.0< 2.0< 2.0EMA [269]2024–13.6 – 36.00.1 – 1.00.01 – 0.1EtokimabIL-33Chen et al. [270]2019––25.016.7–Chinthrajah et al. [271]2019––26.76.70NCT03614923 - Eclipse [272]2022––2.8 – 5.7––FezakinumabIL-22–––––––GaradacimabFXIIaCraigh et al. [273]20230–5.0–0GuselkumabIL-23Langley et al. [274]201801.10FDA [275]2020–4.5< 1.0–European Comission [276]20200.1 – 1.01.0 – 10.00.1 – 1.00.1 – 1.0Coates et al. [277]2021–1.80.40McInnes et al. [278]2022–2.5 – 2.7-0Danese et al. [279]202404.0-0InfliximabTNF-αMaggi et al. [280]2011–1.0 – 27.0–––Puxeddu et al. [243]201213.8–04.49.3Tarkiainen et al. [244]201534.1–1.9–1.9Lichtenstein et al. [281]2015–5.0 – 23.0–4.0–Panés et al. [282]2019–13.0–––FDA [283]2023–< 20.0–< 1.0< 1.0EMA [284]2024–> 10.01.0 – 10.01.0 – 10.00.1 – 1.0IxekizumabIL-17AFDA [285]2022≤ 0.117.0≤ 0.1≤ 0.1EMA [286]2023–> 10.00.1 – 1.00.01 – 0.1Kim et al. [256]2023–11.2––Mastorino et al. [287]2023–3.1––Ying et al. [288]20230.33.0 – 9.73.3–LanadelumabPlasma kallikreinFDA [289]20181.045.0 – 57.0––Craig et al. [290]2021–5.1 – 62.5––Hide et al. [291]2023–50.0––EMA [292]20241.252.4––LebrikizumabIL-13Hanania et al. [293]20150 – 0.911.1 – 20.5–0 – 0.9Hanania et al. [294]2016–6.0 – 10.0–< 1.0Simpson et al. [295]2018–1.3–0Korenblat et al. [296]2018–2.9–1.0Austin [297]202007.0–0EMA [289]2023–2.6––Paller et al. [299]2023–2.42.90Stein Gold et al. [300]202302.6–0LigelizumabCε3 domain of IgEGauvreau et al. [301]2016–12.5 – 25.000Maurer et al. [302]2019–4.0 – 7.0–0Wood et al. [239]2022––17.00.4Maurer et al. [303]20246.0 – 11.04.0 – 11.0–< 1.0MepolizumabIL-5Pavord et al. [304]2012≤ 1.05.0–12.0––0Lugogo et al. [305]2016< 1.0<1.03.0–0Leung et al. [306]20170 – 1.05.0 – 12.03.0 – 9.04.0 – 16.00.002Khatri et al. [307]20192.0–12.0–0Chapman et al. [308]2019< 1.0–3.0< 1.00EMA [309]20221.9 – 3.0–6.0 – 7.0–0FDA [310]20231.0 – 4.02.0 – 15.0––Ishii et al. [311]2023< 1.0––< 1.0NemolizumabIL-31RαNemoto et al. [312]2016–––0Kabashima et al. [313]2018–2.02.0 – 6.0–Silverberg et al. [314]2020–1.8 – 3.5––Ständer et al. [315]2020–3.0––Kabashima et al. [185]2022–< 1.0––Igarashi et al. [316]2023–2.2––OmalizumabIgECox et al. [317]2007< 0.2––0.09Di Bona et al. [318]2017–3.41.00FDA [319]a2023–12.0 – 45.00.20.1FDA [319]b2023–0.6 – 2.7––EMA [320]2023–2.70.1–1.00.2Kim et al. [256]2023–4.5––ReslizumabIL-5Castro et al. [321]2015––1.0 – 2.0–< 1.0Murphy et al. [322]2017< 1.0< 1.0< 1.0< 1.00FDA [323]2019––––0.3Virschow et al. [324]2020––––< 1.0Bernstein et al. [325]20200–6.0 – 11.0––EMA [326]20230.190.19––0.19RituximabCD20Terrier et al. [327]2010–9.0––1.4Maggi et al. [280]2011–10 – 77.0–––FDA (s.c.) [328]2021––13–26.0––FDA (i.v.) [329]2021–≥ 25.0–2.0 – 8.0< 2.0BCCA [330]20241.0 – 10.014 – 77.020.07.0–EMA [331]20241.0 – 10.0> 10.0< 20.01.0 – 10.00.01 – 0.1Riveiro-Barciela et al. [332]2024–9.0––2.8SecukinumabIL-17ABlauvelt [333]2016–0.7––Deodhar et al. [334]20192.40.8–1.3––Grace et al. [335]2020–25.0––Asawanonda et al. [336]2022–0.6––Li et al. [337]2022–2.3––FDA [338]20230.01 – 0.1–0.6 – 1.2–EMA [339]2023––0.1 – 1.00.01 – 0.1Kim et al. [256]2023–1.9––TezepelumabAnti-TSLPMenzies-Gow et al. [340]2021–3.6–0Corren et al. [341]2023–4.0–0EMA [342]2024–3.8––TralokinumabIL-13Wollenberg et al. [343]2019–5.2––Panettieri et al. [344]2018–4.0–5.4–0Busse et al. [345]2019–15.7–0Carlsson et al. [346]201913.2 – 25.9–< 1.00Silverberg et al. [347]20216.7FDA [348]2023–7.4 – 11.1––EMA [349]2023–7.2––Paller et al. [40]2023–2.1 – 9.2–0UpadacitinibJAK inhibitorFDA [350]20232.0 – 3.0–2.0 – 3.02.0 – 3.0EMA [351]20230.1 – 1.01.0 – 10.00.1 – 1.0UstekinumabIL-12 / IL-23Ghosh et al. [352]2019<1.00.1–< 1.00FDA [353]20230.08–1.0 – 5.0–0.1EMA [354]20230.1 – 1.01.90.1 – 10.00.080.01 – 0.1Kim et al. [256]2023––2.80.1 – 1.0– aResults of clinical studies with asthma in FDA 2023 label. bResults of pooled chronic idiopathic urticaria trials in FDA 2023 label. JAK = Janus kinase; TSLP = thymic stromal lymphopoietin; HSR = hypersensitivity reaction; IR = infusion reaction, substance-specific; ISR = injection-site reaction. Figure 1The incidence of anaphylaxis (%).Figure 2The incidence of hypersensitivity reactions (%).Figure 3The incidence of injection-site reactions (%). Figure 4The incidence of urticaria (%). Table 2.Laboratory tests before administration of immunosuppressive or immunomodulating drugs [1]. Infectious agentsTestHepatitis B virus– anti-HBS quantified – HBs Antigen, anti-HBs and – anti-HBc Hepatitis C virus(anti-Hepatitis C)Hepatitis A virus(anti-HAV IgG)Epstein-Barr virusanti-EBVCytomegalovirusanti-CMV IgG and IgMHerpes virusanti-HSV q and 2: IgG and IgMVaricella zoster virusAnti-VZ IgGSyphilis VDRL or TPPA Table 4.Biologics investigated in ongoing studies for the indication of eosinophilic esophagitis. NameTargetPhaseBarzolvolimabKIT-TKIPhase II [228]EtrasimodSphingosine 1P-R modulatorPhase II [229]CendakimabIL-13 inhibitorPhase III [230]TezepelumabAnti-TSLP antibodyPhase III [231] Table 3.Biologics investigated in ongoing studies for the indication of chronic spontaneous urticaria.NameTargetPhaseUB-221IgER antagonistsPhase II [221]LirentelimabSiglec-8 agonistPhase II [222]BarzolvolimabKIT-TKIPhase II [223]RilzabrutinibBruton-TKIPhase II [224]TAS-5315Bruton-TKIPhase II [225], (© Dustri-Verlag Dr. K. Feistle.)

Background: Little is known about specific safety aspects in children with significant comorbidities receiving the mRNA vaccine BNT162b2, as approval studies did not address this population. This study's purpose is to evaluate safety and adverse events in these children compared to healthy children., Methods: In this prospective, multicentre, industry-independent cohort study, caregivers whose children received BNT162b2 were asked to participate in an online questionnaire. Potential side effects were evaluated in ten organ related categories. Frequency of symptoms was compared in both cohorts by bivariate analysis., Results: From a total of 1,294 responses to the questionnaire, 793 data sets were included into the analysis (179 children with comorbidities and 614 healthy children). Responses were given at a median of 17 days after vaccination. Overall, safety of BNT162b2 was high in both cohorts. Psychological (OR: 3.56, [95% CI: 1.461 to 8.629]), pulmonary (OR: 7.14, [95% CI: 2.039 to 21.48]), gastrointestinal (OR: 2.35, [95% CI: 1.231 to 4.665]), neurological (OR: 1.74, [95% CI: 1.078 to 2.796]) and dermatological (OR: 2.28, [95% CI: 1.220 to 4.172]) side effects were increased in children with comorbidities over healthy controls., Conclusion: The higher rate of reported post-vaccination symptoms could either be due to a higher susceptibility for symptomatic effects following immune stimulation, or due to a trained awareness to health-related symptoms. The data emphasizes the importance to evaluate safety of the new mRNA COVID-19 vaccines not only in healthy children but also in children with comorbidities. To perform such evaluation should be made mandatory for pharmaceutical enterprises., Competing Interests: Declarations Competing interests Prof. Schmitt reports institutional grants for investigator-initiated research from the German Federal Joint Committee, German Ministry of Health, German Ministry of Research, European Union, German Federal State of Saxony, Novartis, Sanofi, ALK, and Pfizer. He participated in advisory board meetings as a paid consultant for Sanofi, Lilly, and ALK. Prof. Schmitt serves the German Ministry of Health as a member of the German National Council for Health and Care. 2427Conflict of interest The other authors have no conflicts of interest relevant to this article to disclose., (© 2024. The Author(s).)

Background: Following international guidelines, communities have deployed automated external defibrillators at train stations without substantive evidence., Methods and Results: We geocoded public out-of-hospital cardiac arrests (OHCAs) (2016-2020), automated external defibrillators, and train stations. The stations were divided into the following groups according to passenger flow: 1 (0-499), 2 (500-4999), 3 (5000-9999), and 4 (>10 000) passengers per day. Risk ratios (RRs) were calculated using Poisson regression of rates, and odds ratios (ORs) were analyzed through logistic regression. OHCAs at train stations accounted for 102 (2.3%) of 4467 public OHCAs. The incidence rate (IR) and RR for OHCAs were for group 1: IR, 0.02 OHCA per station per year, RR, 1.0 (reference); group 2: IR, 0.07, RR, 4.1 (95% CI, 2.3-7.3); group 3: IR, 0.25, RR, 12.7 (95% CI, 6.2-25.9); and group 4: IR, 0.34, RR, 16.3 (95% CI, 8.6-30.9). Compared with other public OHCAs, OHCAs at train stations were just as likely to receive bystander cardiopulmonary resuscitation (OR, 1.13 [95% CI, 0.60-2.12]). However, they had higher odds of bystander defibrillation (OR, 1.66 [95% CI, 1.06-2.58]), were more likely to achieve return of spontaneous circulation (OR, 1.88 [95% CI, 1.24-2.85]), and survive 30 days (OR, 2.37 [95% CI, 1.57-3.59])., Conclusions: The incidence of OHCAs at train stations was associated with passenger flow, with the busiest stations having a 16-fold higher risk of OHCAs than the lowest. OHCAs at train stations had better outcomes compared with other public OHCAs.

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cardiovascular outcomes in patients with type 2 diabetes, but few studies have studied the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether GLP-1 RA use reduce OHCA risk in type 2 diabetes when compared to dipeptidyl peptidase-4 inhibitor (DPP-4i) use., Methods: We identified all patients having a redeemed prescription of a glucose-lowering drug between 1995 and 2019 and excluded patients with a first-time redeemed prescription consisting of insulin. Within this cohort, we nested a case-control population comprising all OHCA-cases from presumed cardiac causes between 2013 and 2019. OHCA-cases were matched 1:5 to non-OHCA controls of the same sex and age on the date of OHCA. The odds ratios (ORs) and corresponding 95% confidence intervals (95%-CIs) of OHCA were reported comparing GLP-1 RAs versus DPP-4is., Results: We identified 3,618 OHCA-cases from presumed cardiac causes and matched them to 18,090 non-OHCA controls. GLP-1 RAs were used by 269 (7.44%) cases and 1297 (7.17%) controls, and conferred no increase in the overall odds of OHCA compared with DPP-4i use (OR:0.89, 95%-CI 0.74-1.07). However, stratification according to sex revealed that OHCA risk was significantly reduced in women (OR:0.59, 95%-CI 0.40-0.86) but not in men (OR:1.01, 95%-CI 0.82-1.26, P-value interaction:0.0093). The OR of OHCA did not vary significantly when stratifying for age, duration of diabetes, chronic kidney disease, or presence of cardiovascular disease., Conclusion: Our findings indicate that GLP-1 RA use is not associated with a reduced risk of OHCA in Danish individuals with type 2 diabetes when compared to DPP-4is., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Objectives: Call-takers face a complex situation when assessing medical problems in emergency medical services calls. Patients with myocardial infarction experiencing atypical symptoms risk misinterpretation. We examined development in call-takers' decision-making process in telephone consultations with patients having imminent myocardial infarction., Methods: Recording of 38 calls among 19 patients (two per patient) who contacted Copenhagen Emergency Medical Services (Denmark) at least twice within one week before myocardial infarction diagnosis. The penultimate and last call were compared using qualitative content analysis., Results: Call-takers' assessment of the condition changed from unclear symptom picture and dismissal of heart disease in penultimate call to severe condition, not heart-related, and possible heart disease in last call. Call-takers recommended watchful waiting in the penultimate call. Both calls involved response negotiation, while caution regarding misinterpretation was only seen in the penultimate call., Conclusion: Call-takers used different decision-making approaches when the caller's symptom descriptions appeared unclear and not corresponding with the medical understanding of severe conditions. Call-takers did not negotiate the condition's assessment but engaged in discussions about the response choice., Practice Implications: A protocol to negotiate response choice with callers having unclear clinical conditions should be developed. Clarifying watchful waiting as a recommendation may assist call-takers' decision-making., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Filip Gnesin has received a joint grant from Novo Nordisk Foundation and Danish Heart Foundation, unrelated to this study. Dr. Zylyftari has received funding from the European Union’s Horizon 2020 Research and Innovation Program European Sudden Cardiac Arrest Network Towards Prevention, Education, New Effective Treatment supported by European Cooperation in Science and Technology, and Helsefonden, unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chest pain is a frequent cause of health care contacts. We examined the prehospital management, in-hospital discharge diagnoses, and mortality of patients calling a non-emergency and emergency medical service with chest pain., Methods: The Copenhagen Emergency Medical Services (EMS) consists of a non-emergency medical helpline (calls to 1813) and emergency medical service (1-1-2 calls). We included all calls to the Copenhagen EMS with a primary complaint of chest pain from 2014 to 2018 in Copenhagen, Denmark. The outcomes were: emergency response (ambulance dispatch, other transports/self-transport/home visits, self-care, and unknown/cancelled response), in-hospital diagnosis within 7 days after the call (cardiovascular, pulmonary, or other non-cardiovascular/pulmonary) and 30-day mortality., Results: Among 4,834,071 calls, 91,671 were registered with chest pain at the Copenhagen EMS. The first call for each patient was kept for analysis (n = 66,762). In total, 91.4% were referred to the hospital, 75.8% (n = 50,627) received an ambulance and 15.6% (n = 10,383) received other transport/self-transport/home visits. Overall, 26.9% (n = 17,937) were diagnosed with a cardiovascular disease, 5.2% (n = 3,490) a pulmonary disease, 52.8% (n = 35.242) other non-cardiovascular/pulmonary disease, and 15.1% (n = 10,093) received no diagnosis. Among ambulance-transported patients, the prevalence of cardiovascular discharge diagnoses was higher (32.1%) and fewer received no diagnosis (11.0%). Cardiovascular disease was less prevalent among patients not transported by ambulance and patients not referred to hospital at all (2-13.4%) and in patients ≤ 40 years of age (< 10%). The 30-day mortality was below 5% regardless of diagnosis (0.6-4%), and 65,704 (98.4%) were still alive 30 days later., Conclusion: Nearly all patients calling with chest pain were referred for treatment. Among ambulance-transported patients, around half of the patients did not have a cardiovascular/pulmonary disease. While current practices appear reasonable, improved differentiation of chest pain patients in telephone consultations could potentially both improve the treatment and management of these patients and reduce the in-hospital burden of non-acute chest pain consultations., (© 2024. The Author(s).)

Background: Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations., Methods: In a voluntary substudy of the DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure), patients wore a waist-worn triaxial accelerometer for as long as possible (ideally for 24 h/d for 7 days) at 3 points during the trial, between the screening visit and randomization (baseline data), and during weeks 8 and 14 to 16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity, time spent in moderate-to-vigorous physical activity, movement intensity during walking, number of vector magnitude units' and total activity counts., Results: Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as ≥10 hours of wear time for ≥3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference, 778 [95% CI, 240-1315]), time spent in moderate-to-vigorous physical activity (0.16 [95% CI, 0.03-0.29] hours), and in the mean vector magnitude units (25 [95% CI, 0.1-49] counts per minute). There were no between-group differences in the other accelerometer outcomes of interest., Conclusions: In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with heart failure across the entire left ventricular ejection fraction spectrum, yet did not improve 6-minute walk distance, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6-minute walk distance and identify beneficial effects of treatment not detected by 6-minute walk distance., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224., Competing Interests: Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials; he has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosmos, Translational Medical Academy, and Radcliffe Cardiology; has served on Advisory Boards for Us2.ai and holds stock in the company; has served on an advisory board and served on a clinical end point committee for Bayer AG; has performed consultancy for FIRE-1; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis, and Boehringer Ingelheim. Drs Buendia Lopez, Cowie, Hammarstedt, Langkilde, and Reicher and F. Folkvaljon are employees of AstraZeneca and may own stock or stock options. The institution of Dr de Boer has received research grants or fees from AstraZeneca, Abbott, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche; he has had speaker engagements with or received fees from or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche; and has received travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingelheim, Novo Nordisk, Rivus, and St. Luke’s Medical Center; has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. Dr Senni has received honoraria or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr Shah was supported by research grants from the US National Institutes of Health (NIH; U54 HL160273; R01 HL140731; and R01 HL149423); has received research funding from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cytokinetics, Edwards Lifesciences, Eli Lilly, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Merck, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving grants or research support or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management Inc, and Sanofi. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/National Heart‚ Lung‚ and Blood Institute (NHLBI), Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr McMurray reports receiving support from British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline and Novartis, British Heart Foundation, NIH/NHLBI, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; personal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; and on the Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc. He is a director of Global Clinical Trial Partners Ltd.

Importance: In patients with ST-segment elevation myocardial infarction (STEMI), acute inflammation is related to the extent of myocardial damage and may increase infarct size. Thus, administration of pulse-dose glucocorticoid in the very early phase of infarction may reduce infarct size., Objective: To determine the cardioprotective effect of prehospital pulse-dose glucocorticoid in patients with STEMI., Design, Setting, and Participants: This was a 1:1 investigator-initiated, blinded, placebo-controlled, randomized clinical trial conducted between November 14, 2022, and October 17, 2023, with last follow-up on January 17, 2024. Patients 18 years and older with less than 12 hours of acute chest pain and STEMI were included in the prehospital setting throughout the Region Zealand and Capital Region of Denmark and transferred to Rigshospitalet, Denmark., Intervention: Patients were randomly allocated to intravenous glucocorticoid (methylprednisolone, 250 mg) or placebo in the prehospital setting., Main Outcomes and Measures: The primary outcome was final infarct size on cardiac magnetic resonance (CMR) at 3 months. The power calculation was based on an anticipated final infarct size of 13%. Secondary outcomes included CMR outcomes on acute scan and at 3 months, peak of cardiac biomarkers, clinical end points at 3 months, and adverse events., Results: Of 530 included patients (median [IQR] age, 65 [56-75] years; 418 male [78.9%]) with STEMI, 401 (76%) were assessed for the primary outcome, with 198 patients treated with glucocorticoid and 203 with placebo. Median final infarct size was similar in the treatment groups (glucocorticoid, 5%; IQR, 2%-11% vs placebo, 6%; IQR, 2%-13%; P = .24). Compared with placebo, the glucocorticoid group had smaller acute infarct size (odds ratio, 0.78; 95% CI, 0.61-1.00), less microvascular obstruction (relative risk ratio, 0.83; 95% CI, 0.71-0.99), and greater acute left ventricular ejection fraction (mean difference, 4.44%; 95% CI, 2.01%-6.87%). Other secondary outcomes were similar in both groups., Conclusions and Relevance: In patients with STEMI, treatment with prehospital pulse-dose glucocorticoid did not reduce final infarct size after 3 months. However, the trial was likely underpowered as the final infarct size was smaller than anticipated. The glucocorticoid group had improved acute parameters compared with placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT05462730.

Background: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults., Methods: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732)., Findings: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events., Interpretation: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20., Funding: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD)., Competing Interests: Declaration of interests CB, LM, DF, WX, MW, JL, UKB, and HLP are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD) and may hold stock in Merck & Co, Rahway, NJ, USA. CGG reports serving on an advisory board for MSD and grants or contracts from the National Institutes of Health, the US Centers for Disease Control, Agency for Healthcare and Research Quality, the US Food and Drug Administration, and Syneos Health. JYS reports serving as a principal investigator for this study, and a grant for the investigator-initiated trial from MSD: non-randomized clinical trial to compare the immunogenicity of revaccination with 23-valent pneumococcal polysaccharide vaccine between healthy elderly and those with diabetes in Korea. EB reports clinical trial agreements with MSD, Astra-Zeneca, Janssen, GSK, Clover, and Moderna. DG-H reports serving as a principal investigator for this study. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Ongoing opioid treatment can potentially modify symptoms of myocardial infarction (MI) and cause a lack of recognition and treatment delay., Objectives: The purpose of this study was to examine MI symptoms and the time to hospitalization for patients in ongoing opioid treatment compared to patients without ongoing opioid treatment., Methods: We evaluated calls to the Copenhagen Emergency Medical Services in Denmark from 2014 to 2018. Calls were included when followed by hospitalization and a diagnosis of MI. Symptoms of MI and the time from call to hospitalization in patients in ongoing opioid treatment initiated prior to the onset of MI were compared to a control group of MI patients without opioid treatment., Results: In total, 6,633 calls were included; 552 calls from patients in opioid treatment and 6,081 calls from controls. Patients in opioid treatment were older and had more comorbidities than controls. Chest pain was less prevalent in MI patients in opioid treatment compared to controls (adjOR: 0.70; 95% CI: 0.57-0.85). The median time from the call to hospitalization was longer in patients in opioid treatment than in controls (50 vs 47 minutes; P  = 0.006)., Conclusions: In calls to the Emergency Medical Services, opioid treatment initiated prior to the onset of MI was associated with less frequent chest pain in MI. Therefore, awareness of ongoing opioid treatment may improve telephone triage of patients with MI, as symptom presentation in opioid-treated patients may differ and potentially challenge and delay the emergency response., Competing Interests: This work was supported by The Danish Heart Foundation (grant number 18-R122-A8403). Dr Torp-Pedersen has received grants from 10.13039/501100004191Novo Nordisk and 10.13039/100004326Bayer. Dr Bang is employed at Novo Nordisk, Denmark. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: During the COVID-19 pandemic, disturbing images of ambulances unable to respond to the demands for prehospital assistance appeared from several parts of the world. In Denmark, however, a notion occurred that the demands for emergency medical assistance declined. The purpose of this study was to compare the patients' use of the Danish Emergency Medical Services (EMS) before and during the COVID-19 pandemic. Furthermore, we investigated the overall mortality of the ambulance population, the main reason for calling the emergency medical dispatch centre, and the diagnosis assigned to the admitted patients., Methods: The study was a nationwide registry-based cohort study based on the national prehospital medical records and the Danish National Patient Registry. The primary outcome was the requested number of ambulances. Secondary outcomes included the primary reason for contact with the dispatch centre (reflected by the dispatch criteria), patient mortality, and the diagnoses assigned to the patients transported to the hospital by ambulance during the COVID-19 pandemic in Denmark in March-December 2020. Comparisons were made using a similar period in 2019 before the pandemic., Results: In comparison with the baseline values before the pandemic, the total number of patients treated by the EMS was reduced by 4.5% during the COVID-19 pandemic. The number of patients transported to the hospital during the pandemic was similarly reduced by 3.5%. Compared with baseline values, fewer were patients hospitalised with respiratory diseases during the pandemic (a reduction of 53.3% from April 2019 to April 2020). Compared to the baseline period, there were significant increases in both the 48-h mortality (from 1.4% to 1.5%) and the 30-day mortality (from 4.9% to 5.4%) (p < 0.03 and p < 0.001, respectively), in patients hospitalised during the pandemic., Conclusion: During the first wave of the COVID-19 pandemic, the Danish EMS experienced an overall reduction in the requests for and the use of ambulances and, especially, in the number of patients admitted to hospitals for respiratory diseases. Despite the overall reduction in EMS requests, the mortality of the ambulance population increased, indicating that despite the reduced ambulance use, the prehospital population was more severely ill during the pandemic., (© 2024. The Author(s).)

Although our understanding of frailty has evolved and multiple indices have been developed, the impact of burn injuries on long-term health has been overlooked. With over 11 million annual cases globally, burns affect all demographics, although socioeconomic disparities are evident. With survival rates improved, morbidity among survivors is becoming more evident, and shows similarity to predictors of frailty. Some of the chronic effects of burns, including mental health issues and increased risks of disease, mirror frailty markers. Studies show burn survivors have lower life expectancy, independent of burn severity. Integrating burn history into frailty assessments and establishing specialized long-term care can mitigate this frailty risk. Improved interdisciplinary follow-up and research are vital for enhancing burn survivors' quality of life and longevity., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The post-cardiac arrest syndrome (PCAS) after out-of-hospital cardiac arrest (OHCA) is characterized by a series of pathological events, including inflammation. In the randomized "STERoid for OHCA" (STEROHCA) trial, prehospital high-dose glucocorticoid decreased interleukin (IL) 6 and C-reactive protein levels following resuscitated OHCA. The aim of this predefined sub-study was to assess the inflammatory response the first three days of admission., Methods: The STEROHCA trial enrolled 137 OHCA patients randomized to either a single prehospital injection of methylprednisolone 250 mg or placebo. Inflammatory markers, including pro- and anti-inflammatory cytokines, were analyzed in plasma samples, from 0-, 24-, 48-, and 72 h post-admission. Mixed-model analyses were applied using log-transformed data to assess group differences., Results: The 137 patients included in this sub-study had a median age of 67 years (57 to 74), and the 180-day survival rates were 75% (n = 51/68) and 64% (n = 44/69) in the glucocorticoid and placebo group, respectively. A total of 130 (95%) patients had at least one plasma sample available. The anti-inflammatory cytokine IL-10 was increased at hospital admission in the glucocorticoid group (ratio 2.74 (1.49-5.05), p = 0.006), but the intervention showed the strongest effect after 24 h, decreasing pro-inflammatory levels of IL-6 (ratio 0.06 (0.03-0.10), p < 0.001), IL-8 (ratio 0.53 (0.38-0.75), p < 0.001), macrophage chemokine protein-1 (MCP-1, ratio 0.02 (0.13-0.31), p < 0.001), macrophage inflammatory protein-1-beta (MIP-1b, ratio 0.28 (0.18-0.45), p < 0.001), and tumor necrosis factor-α (TNF-α, ratio 0.6 (0.4-0.8), p = 0.01)., Conclusion: Administering high-dose glucocorticoid treatment promptly after resuscitation from OHCA influenced the inflammatory response with a reduction in several systemic proinflammatory cytokines after 24 h., Trial Registration: EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www., Clinicaltrials: gov; Unique Identifier: NCT04624776., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The corresponding author (LERO) received salary support from a grant provided by the Research Foundation of Rigshospitalet (E-22652-04). The study, including the salary of RPB, received backing from a grant from the Novo Nordisk Foundation (NNF20OC0064043) under the supervision of CH. Additionally, CH benefits from an unrestricted grant from the Lundbeck Foundation (R186-2015–2132), received a speaker honorarium from Abiomed during the study, and holds positions as a board member of the European Society of Cardiology and chair of the Danish Heart Foundation. JK is supported by an unrestricted grant from the Novo Nordisk Foundation (NNF17OC0028706) and serves on two Data Safety Monitoring Boards for the IVIO trial (as chair) and the COCA trial without financial compensation. JEM received research grants from Abiomed and the Novo Nordisk Foundation outside the current study, speaker honorariums from Abiomed, Abbott, and Boehringer Ingelheim, and attended meetings with support from Abiomed. FF is backed by a research grant from the Novo Nordisk Foundation (NNF19OC0055142). RFS received grants from the Lundbeck Foundation, Danish Heart Foundation, and Sygeforsikringen Danmark Research Fund, all unrelated to the present study. The remaining authors have no disclosures to report.]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Breast reconstruction after mastectomy helps women with breast cancer feel better about their bodies and lives. There is debate about the best time and type of reconstruction (immediate versus delayed, and using own tissue versus implants). Long-term studies are rare., Aim: This study looked at long-term results of different breast reconstruction methods and timings in Swedish women who had mastectomies in 2000, 2005 or 2010. It focused on how satisfied the women were with their surgeries and their quality of life., Method: The study included 5853 women from the Swedish National Breast Cancer Registry who had mastectomies in 2000, 2005 or 2010. Of these, 2904 women answered the survey, and 895 had breast reconstruction. Satisfaction and quality of life were measured using two surveys: EORTC QLQ-BRECON23 and BREAST-Q., Results: Of the women who answered the survey, 895 (31%) had breast reconstruction. Of these, 176 (20%) had immediate reconstruction, and 719 (80%) had delayed reconstruction; 58% had implant-based reconstructions, 31% had reconstructions using their own tissue, 2% had both types and 9% did not report the type of reconstruction. There were no major differences in satisfaction between immediate and delayed reconstruction. Women who used their own tissue were more satisfied with their results and breast appearance than those with implants., Conclusion: Autologous reconstruction leads to better satisfaction and outcomes than implants. The timing of reconstruction (immediate versus delayed) was less of an influence on quality of life., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Primary ciliary dyskinesia (PCD) is a rare genetical disease with malfunction of the motile cilia leading to impaired muco-ciliary clearance in the respiratory tract. There is no cure for PCD, only supportive therapy aimed at minimizing the progression of the disease and improving the patient's quality of life (QoL). Physical activity (PA) is one of these recommended supportive therapies for people with PCD (pwPCD). However, there is no scientific evidence to support this recommendation. In addition, regular medical advice to increase PA remains largely ineffective in pwPCD., Methods: To test the main hypothesis, that an individualized and supported PA program leads to a better QoL 6 months after randomization (QoL-PCD questionnaire) compared to usual recommendation in pwPCD, 158 pwPCD aged 7 to 55 years are to be included in this multi-center randomized controlled trial (RCT). After the screening visit, a 1:1 randomization stratified by age group and FEV1 will be performed. A QoL-PCD questionnaire, motor test, and lung function will be carried out at regular intervals in both groups. PA is recorded in both groups using activity trackers during the study period. The main aim of the trial is to estimate the difference in the change of QoL between the groups after 6 months. Therefore, our full analysis set consists of all randomized patients and analysis is performed using the intention-to-treat principle. Statistical software R ( http://www.r-project.org ) is used. Ethical approvement without any reservations: RUB Bochum Ethics Committee (No. 23-7938; December 4, 2023). Recruitment start: March 2024., Discussion: Limitations result from the rarity of PCD with its broad disease spectrum and the large age range. These are reduced by stratified randomization and the measurement of the individual change in QoL as primary endpoint. In our view, only a PA program tailored to individual needs with close contact to trainers offers the chance to meet personal needs of pwPCD and to establish PA as a pillar of therapy in the long term. The study protocol explains all procedures and methods of recruitment, implementation of the study visits and intervention, measures for patient and data safety, and for minimizing risks and bias., Trial Registration: German Clinical Trials Register (DRKS) 00033030. Registered on December 7, 2023. Update 10 July 2024. STUDY PROTOCOL VERSION 10: Version 1.2; 12 June 2024., (© 2024. The Author(s).)

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)

Background: As several recent studies have shown low mortality rates in burn injury induced ARDS early (≤7 days) after the burn, the Berlin criteria for the ARDS diagnosis in this setting may be disputed. Related to this issue, the present study investigated the incidence, trajectory and risk factors of early Acute Respiratory Distress Syndrome (ARDS) and outcome in burn patients, as per the Berlin criteria, along with the concurrent prevalence and influence of inhalation injury, and ventilator-acquired pneumonia (VAP)., Methods: Over a 2.5-year period, burn patients with Total Burn Surface Area (TBSA) exceeding 10% admitted to a national burn center were included. The subgroup of interest comprised patients with more than 48 h of ventilatory support. This group was assessed for ARDS, inhalation injury, and VAP., Results: Out of 292 admissions, 62 sustained burns > 10% TBSA. Of these, 28 (45%) underwent ventilatory support for over 48 h, almost all, 24 out of 28, meeting the criteria for ARDS early, within 7 days post-injury and with a P a O 2 /F i O 2 (PF) rat i o nadir at day 5. The mortality rate for this early ARDS group was under 10%, regardless of PF ratios (mean TBSA% 34,8%). Patients with concurrent inhalation injury and early ARDS showed significantly lower PF ratios (p < 0.001), and higher SOFA scores (p = 0.004) but without impact on mortality. Organ failure, indicated by SOFA scores, peaked early (day 3) and declined in the first week, mirroring PF ratio trends (p < 0.001)., Conclusions: The low mortality associated with early ARDS in burn patients in this study challenges the Berlin criteria's for the early ARDS diagnosis, which for its validity relies on that higher mortality is linked to worsening PF ratios. The finding suggests alternative mechanisms, leading to the early ARDS diagnosis, such as the significant impact of inhalation injury on early PF ratios and organ failure, as seen in this study. The concurrence of early organ failure with declining PF ratios, supports, as expected, the hypothesis of trauma-induced inflammation/multi-organ failure mechanisms contributing to early ARDS. The study highlights the complexity in differentiating between the contributions of inhalation injury to early ARDS and the related organ dysfunction early in the burn care trajectory. The Berlin criteria for the ARDS diagnosis may not be fully applicable in the burn care setting, where the low mortality significantly deviates from that described in the original Berlin ARDS criteria publication but is as expected when considering the actual not very extensive burn injury sizes/Baux scores as in the present study., Competing Interests: Declaration of Competing Interest On behalf of all co-authors, I hereby affirm no conflicts of interest associated with this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The epidemiology, care, and outcomes of perineal and genital burns (PG) in high-income countries have been previously described, but an analysis of this topic in LMICs has yet to be performed. We use the World Health Organization's Global Burn Registry to fill this gap., Methods: The GBR was searched from inception to November 2023 to identify all burn patients, excluding cases from high-income countries. Demographics and mechanism of injury were retrieved. Primary outcomes were length of hospital stay (LOHS), surgical intervention, discharge with physical impairment, and mortality. A multivariate regression analysis was performed controlling for burnt total body surface area (TBSA), age, sex, inhalation injury, mechanism of burn and care center characteristics., Results: Of 9041 patients identified, 1213 (13.4 %) had PG burns with 136 (1.6 %) isolated to the PG region. PG patients had higher TBSA (p < 0.001) and more inhalation injury (p < 0.001). They had better access to rehabilitation and lower access to theater space for burns (p < 0.001). Multivariable analysis showed that PG patients had longer LOHS (p = 0.001), greater mortality (p < 0.001), were less likely to undergo surgery (p = 0.01) or be discharged home with physical impairment (p = 0.03)., Conclusion: Similarities and differences exist between high- and low/middle-income countries in terms of the patterns of injury, care, and recovery in patients with PG burns. The longer LOHS and higher mortality among PG patients, previously reported in high-income countries, are verified. This highlights the importance of greater vigilance when caring for such patients., (Copyright © 2024. Published by Elsevier Ltd.)

With the emergence of SARS-CoV-2, various non-pharmaceutical interventions were adopted to control virus transmission, including school closures. Subsequently, the introduction of vaccines mitigated not only disease severity but also the spread of SARS-CoV-2. This study leveraged an adapted SIR model and non-linear mixed-effects modeling to quantify the impact of remote learning, school holidays, the emergence of Variants of Concern (VOCs), and the role of vaccinations in controlling SARS-CoV-2 spread across 16 German federal states with an age-stratified approach. Findings highlight a significant inverse correlation (Spearman's ρ = -0.92, p < 0.001) between vaccination rates and peak incidence rates across all age groups. Model-parameter estimation using the observed number of cases stratified by federal state and age allowed to assess the effects of school closure and holidays, considering adjustments for vaccinations and spread of VOCs over time. Here, modeling revealed significant (p < 0.001) differences in the virus's spread among pre-school children (0-4), children (5-11), adolescents (12-17), adults (18-59), and the elderly (60+). The transition to remote learning emerged as a critical measure in significantly reducing infection rates among children and adolescents (p < 0.001), whereas an increased infection risk was noted among the elderly during these periods, suggesting a shift in infection networks due to altered caregiving roles. Conversely, during school holiday periods, infection rates among adolescents mirrored those observed when schools were open. Simulation exercises based on the model provided evidence that COVID-19 vaccinations might serve a dual purpose: they protect the vaccinated individuals and contribute to the broader community's safety., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: In high-resource settings, the survival of children with immunocompromise (IC) has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools, and outcome of IC children with tuberculosis (TB) in Europe., Methods: Multicenter, matched case-control study within the Pediatric Tuberculosis Network European Trials Group, capturing TB cases <18 years diagnosed 2000-2020., Results: A total of 417 TB cases were included, comprising 139 children who are IC (human immunodeficiency virus, inborn errors of immunity, drug-induced immunosuppression, and other immunocompromising conditions) and 278 non-IC children as controls. Nonrespiratory TB was more frequent among cases than controls (32.4% vs 21.2%; P = .013). Patients with IC had an increased likelihood of presenting with severe disease (57.6% vs 38.5%; P < .001; odds ratio [95% confidence interval], 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs 6.0%; P < .001) and QuantiFERON-TB Gold assay (30.0% vs 7.3%; P < .001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs 49.3%; P = .083). Although the mortality in children with IC was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs 6.1%; P = .004)., Conclusions: Children with IC and TB in Europe have increased rates of nonrespiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in patients with IC, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies., Competing Interests: Potential conflicts of interest . B. S. G. and M. T. have received support from Cepheid for a project on molecular tuberculosis diagnostics unrelated to the study reported here. M. T. has received QuantiFERON-TB assays at reduced pricing or free of charge for tuberculosis diagnostics projects from Cellestis/Qiagen in the past and has received support for conference attendance from Cepheid. The manufacturers had no influence on the study design, data collection, analysis or interpretation, writing of the manuscript, or the decision to submit the data for publication. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Health-related quality of life (HRQoL) is one of the most important outcome variables for assessing the effectiveness of intensive care, together with mortality and survival, where comorbidity is suggested to have high impact. However, studies are lacking that examine to what extent HRQoL is affected after a general ICU period, beyond that of the effects that may be claimed to be due to comorbidities., Design: Purpose-specific literature review including literature searches in PubMed, Cinahl, Scopus, and Cochrane library between 2010 and 2021., Measurements and Results: This Purpose-specific, i.e., task focused review examines HRQoL (assessed by either SF-36 or EQ-5D, > 30 days after leaving the hospital) in adult patients (≥ 18 years) having an ICU length of stay > 24 h. Further, the HRQoL comparisons were adjusted for age or comorbidity. A total of 11 publications were found. A majority comprised observational, prospective cohort studies, except three that were either case-control, cross-sectional comparison, or retrospective cohort studies. A total of 18,566 critically ill patients were included, and the response rate ranged from 16 to 94%. In all studies, a recurrent relevant finding was that HRQoL after ICU care was affected by pre-ICU comorbidities. In three studies (n = 3), which included a comorbidity adjusted control group, there were no effect of the critical care period itself on the registered HRQoL after the critical care period., Conclusion: Health-Related Quality of Life (HRQoL) in former ICU patients appears to be primarily influenced by comorbidity. A notable limitation in this field of research is the high heterogeneity observed in the studies reviewed, particularly in terms of the HRQoL measurement tool employed, the duration of follow-up, the methodology for comorbidity assessment, and the adjustments for age and sex. Despite these variations and the limited number of studies in the review, the findings suggest a minimal HRQoL impact beyond the effects of comorbidity. Given the significant dearth of comprehensive studies in this domain, there is an escalating call for more thorough and detailed research endeavours., (© 2024. The Author(s).)

Background: Early percutaneous coronary intervention (PCI) is recommended for ST-segment elevation myocardial infarction (STEMI) treatment. Delays in time-to-PCI, kept within guideline recommendations, have seldom been investigated., Objectives: The purpose of this study was to investigate the consequences of delay, due to system factors or hospital distance, for the time between last patient distress call and PCI., Methods: Registry-based cohort study including times of first call to medical services, admission and PCI for patients admitted with STEMI in Copenhagen, Denmark (2014-2018). The main combined outcome included death, recurrent myocardial infarction, or heart failure estimated at 30 days and 1 year from event. Outcomes according to time from call to PCI (system delay) and door-to-balloon time were standardized to the STEMI population using multivariate logistic regression., Results: In total, 1,822 STEMI patients (73.5% male, median age 63.3 years [Q1-Q3: 54.6-72.9 years]) called the emergency services ≤72 hours before PCI (1,735, ≤12 hours). The combined endpoint of 1-year cumulative incidence was 13.9% (166/1,196) for patients treated within 120 minutes of the call and 21.2% (89/420) for patients treated later. Standardized 30-day outcomes were 7.33% (95% CI: 5.41%-9.63%) for patients treated <60 minutes, and 11.1% (95% CI: 8.39%-14.2%) for patients treated >120 minutes., Conclusions: The risk of recurrent myocardial infarction, death, and heart failure following PCI treatment of STEMI increases rapidly when delay exceeds 1 hour. This indicates a particular advantage of minimizing time from first contact to PCI., Competing Interests: The work was supported by the 10.13039/100007405Danish Heart Foundation. This organization had no influence on the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. Dr Møller has received funding from Sygeforsikringen “danmark”. Dr Engstrøm received speaker’s fee from and is on advisory board of Abbott. Dr Folke has received NovoNordisk Research Grant NNF19OC0055142, Unrestricted Research Grant Laerdal Foundation; and teaches general practitioners resuscitation paid by AstraZeneca. Dr Køber has received speaker honorarium from AstraZeneca, Bayer, Boehringer, and Novartis. Dr Gnesin has a relationship with Danish Cardiovascular Academy-Novo Nordisk Foundation and Danish Heart Foundation. Dr Zylyftari has received funding from the European Union’s Horizon 2020 Research and Innovation Program European Sudden Cardiac Arrest Network Towards Prevention, Education, New Effective Treatment, the COST Action PARQ supported by European Cooperation in Science and Technology, and Helsefonden. Dr Kragholm has received grants from The Laerdal Foundation. Dr Lippert has received unrestricted research grants from the Danish TrygFoundation, Laerdal Foundation, and Novo Nordic Foundation. Dr Christensen has received funding from TrygFoundation, Laerdal, and Region Zealand Research fund. Dr Torp-Pedersen has received grants for randomized study and epidemiological study from Bayer and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Strategies to reach out-of-hospital cardiac arrests (called cardiac arrest) in residential areas and reduce disparities in care and outcomes are warranted. This study investigated incidences of cardiac arrests in public housing areas., Methods: This register-based cohort study included cardiac arrest patients from Amsterdam (the Netherlands) from 2016 to 2021, Copenhagen (Denmark) from 2016 to 2021, and Vienna (Austria) from 2018 to 2021. Using Poisson regression adjusted for spatial correlation and city, we compared cardiac arrest incidence rates (number per square kilometer per year and number per 100 000 inhabitants per year) in public housing and other residential areas and examined the proportion of cardiac arrests within public housing and adjacent areas (100-m radius)., Results: Overall, 9152 patients were included of which 3038 (33.2%) cardiac arrests occurred in public housing areas and 2685 (29.3%) in adjacent areas. In Amsterdam, 635/1801 (35.3%) cardiac arrests occurred in public housing areas; in Copenhagen, 1036/3077 (33.7%); and in Vienna, 1367/4274 (32.0%). Public housing areas covered 42.4 (12.6%) of 336.7 km 2 and 1 024 470 (24.6%) of 4 164 700 inhabitants. Across the capitals, we observed a lower probability of 30-day survival in public housing versus other residential areas (244/2803 [8.7%] versus 783/5532 [14.2%]). The incidence rates and rate ratio of cardiac arrest in public housing versus other residential areas were incidence rate, 16.5 versus 4.1 n/km 2 per year; rate ratio, 3.46 (95% CI, 3.31-3.62) and incidence rate, 56.1 versus 36.8 n/100 000 inhabitants per year; rate ratio, 1.48 (95% CI, 1.42-1.55). The incidence rates and rate ratios in public housing versus other residential areas were consistent across the 3 capitals., Conclusions: Across 3 European capitals, one-third of cardiac arrests occurred in public housing areas, with an additional third in adjacent areas. Public housing areas exhibited consistently higher cardiac arrest incidences per square kilometer and 100 000 inhabitants and lower survival than other residential areas. Public housing areas could be a key target to improve cardiac arrest survival in countries with a public housing sector., Competing Interests: Disclosures Dr Juul Grabmayr has received research grants from Trygfonden and Helsefonden. Dr Hansen has received grants from the Independent Research Fund Denmark, TrygFonden, Laerdal Foundation, Helsefonden, and the Capital Region of Denmark Research Fund. Dr Krychtiuk has received speaker fees from Zoll Medical and Daiichi Sankyo and consulting fees from Novartis and Amgen, unrelated to this article’s topic. Christian Torp-Pedersen has received grants from Bayer and Novo Nordisk unrelated to the current study. Dr Tan has received funding from the European Union’s Horizon 2020 research and innovation program under the acronym ESCAPE-NET, registered under grant agreement number 733381, and the COST Action PARQ (grant agreement No. CA19137) supported by COST (European Cooperation in Science and Technology), not related to the current study. Drs Andelius and Kjoelbye were supported by a research grant from TrygFonden, unrelated to the current study. The other authors report no conflicts.

Introduction: Eosinophil-derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non-invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma., Methods: We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)-adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression., Results: uEDN/uCr values were higher in atopic versus non-atopic preschool-aged subjects (p = .035) and associated with the sum of allergen-specific IgE in younger (r = 0.24, p = .003), and older subjects (r = 0.23, p = .043). uEDN/uCr was marginally a good determinant for atopy (p = .078, for subjects aged <6 years, and p = .058 for subjects ≥6 years). Children with the T2-high phenotype had higher uEDN/uCr (p < .001) versus T2-low-irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV 1 z-scores: r = -0.30, p = .007, and FEV 1 /FVC z-scores: r = -0.24, p = .038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV 1 (p = .038), and to a lesser extent, FEV 1 /FVC (p = .080)., Conclusions: uEDN/uCr may serve as a non-invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

This study used demographic data in a novel prediction model to identify areas with high risk of out-of-hospital cardiac arrest (OHCA) in order to target prehospital preparedness. We combined data from the nationwide Danish Cardiac Arrest Registry with geographical- and demographic data on a hectare level. Hectares were classified in a hierarchy according to characteristics and pooled to square kilometers (km2). Historical OHCA incidence of each hectare group was supplemented with a predicted annual risk of at least 1 OHCA to ensure future applicability. We recorded 19,090 valid OHCAs during 2016 to 2019. The mean annual OHCA rate was highest in residential areas with no point of public interest and 100 to 1000 residents per hectare (9.7/year/km2) followed by pedestrian streets with multiple shops (5.8/year/km2), areas with no point of public interest and 50 to 100 residents (5.5/year/km2), and malls with a mean annual incidence per km2 of 4.6. Other high incidence areas were public transport stations, schools and areas without a point of public interest and 10 to 50 residents. These areas combined constitute 1496 km2 annually corresponding to 3.4% of the total area of Denmark and account for 65% of the OHCA incidence. Our prediction model confirms these areas to be of high risk and outperforms simple previous incidence in identifying future risk-sites. Two thirds of out-of-hospital cardiac arrests were identified in only 3.4% of the area of Denmark. This area was easily identified as having multiple residents or having airports, malls, pedestrian shopping streets or schools. This result has important implications for targeted intervention such as automatic defibrillators available to the public. Further, demographic information should be considered when implementing such interventions., Competing Interests: KBR received research grants from TrygFonden and the Danish Heart Foundation outside this work. KHK received research grants from the Laerdal Foundation outside this work. CMH received unrestricted research grants from TrygFonden, Helsefonden and Laerdal Foundation outside this work. CT-P reports grants from Bayer and Novo Nordisk outside the submitted work. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Estimation of the effects that drugs or other interventions have on patients' symptoms and functions is crucial in heart failure trials. Traditional symptoms and functions clinical outcome assessments have important limitations. Actigraphy may help to overcome these limitations due to its objective nature and the potential for continuous recording of data. However, actigraphy is not currently accepted as clinically relevant by key stakeholders., Methods and Results: In this state-of-the-art study, the key aspects to consider when implementing actigraphy in heart failure trials are discussed. They include which actigraphy-derived measures should be considered, how to build endpoints using them, how to measure and analyze them, and how to handle the patients' and sites' logistics of integrating devices into trials. A comprehensive recommendation based on the current evidence is provided., Conclusion: Actigraphy is technically feasible in clinical trials involving heart failure, but successful implementation and use to demonstrate clinically important differences in physical functioning with drug or other interventions require careful consideration of many design choices., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with sleep apnea (SA) are at increased cardiovascular risk. However, little is known about the risk of out-of-hospital cardiac arrest (OHCA) in patients with SA. Therefore, we studied the relation between SA patients who did and did not receive continuous positive airway pressure (CPAP) therapy with OHCA in the general population., Methods: Using nationwide databases, we conducted a nested case-control study with OHCA-cases of presumed cardiac causes and age/sex/OHCA-date matched non-OHCA-controls from the general population. Conditional logistic regression models with adjustments for well-known OHCA risk factors were performed to generate odds ratio (OR) of OHCA comparing patients with SA receiving and not receiving CPAP therapy with individuals without SA., Results: We identified 46,578 OHCA-cases and 232,890 matched non-OHCA-controls [mean: 71 years, 68.8% men]. Compared to subjects without SA, having SA without CPAP therapy was associated with increased odds of OHCA after controlling for relevant confounders (OR:1.20, 95%-Cl:1.06-1.36), while having SA with CPAP therapy was not associated with OHCA (OR:1.04, 95%-Cl:0.93-1.36). Regardless of CPAP therapy, age and sex did not significantly influence our findings. Our findings were confirmed in: (I) patients with neither ischemic heart disease nor heart failure (untreated SA, OR:1.24, 95%-CI:1.04-1.47; SA with CPAP, OR:1.08, 95%-CI:0.93-1.25); and (II) in patients without cardiovascular disease (untreated SA, OR:1.33, 95%-CI:1.07-1.65; SA with CPAP, OR:1.14, 95%-CI:0.94-1.39)., Conclusion: SA not treated with CPAP was associated with OHCA, while no increased risk of OHCA was found for SA patients treated with CPAP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

E-cigarettes are primarily used by teenagers and young adults. Flavors in e-cigarettes increase their attractiveness and encourage young people and adults to start using them. This exposes young people in particular to the risk of nicotine addiction and various toxic substances from the aerosol of e-cigarettes. There are indications that various flavors in e-cigarettes are harmful to health, although toxicological studies are still lacking for the majority of flavors. There is a need for independent scientific investigations in this area. The scientific societies involved are calling for a ban on flavors in e-cigarettes, a ban on disposable e-cigarettes, effective regulation of the sale of e-cigarettes and effective control and implementation of the provisions for the protection of minors., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891 ). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels. Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature ( IFNG , CXCL9 , CXCL10 , KLRC1 , CD8A , GZMA ). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels. Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB -related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

Background: Defibrillation is essential for achieving return of spontaneous circulation (ROSC) following out-of-hospital cardiac arrest (OHCA) with shockable rhythms. This study aimed to investigate if the type of defibrillator used was associated with ROSC in OHCA., Methods and Results: This study included adult patients with OHCA from the Danish Cardiac Arrest Registry from 2016 to 2021 with at least 1 defibrillation by the emergency medical services. We used multivariable logistic regression and a difference-in-difference analysis, including all patients with or without emergency medical services shock to assess the causal inference of using the different defibrillator models (LIFEPAK or ZOLL) for OHCA defibrillation. Among 6516 patients, 77% were male, the median age (quartile 1; quartile 3) was 70 (59; 79), and 57% achieved ROSC. In total, 5514 patients (85%) were defibrillated using LIFEPAK (ROSC: 56%) and 1002 patients (15%) were defibrillated using ZOLL (ROSC: 63%). Patients defibrillated using ZOLL had an increased adjusted odds ratio (aOR) for ROSC compared with LIFEPAK (aOR, 1.22 [95% CI, 1.04-1.43]). There was no significant difference in 30-day mortality (aOR, 1.11 [95% CI, 0.95-1.30]). Patients without emergency medical services defibrillation, but treated by ZOLL-equipped emergency medical services, had a nonsignificant aOR for ROSC compared with LIFEPAK (aOR, 1.10 [95% CI, 0.99-1.23]) and the difference-in-difference analysis was not statistically significant (OR, 1.10 [95% CI, 0.91-1.34])., Conclusions: Defibrillation using ZOLL X Series was associated with increased odds for ROSC compared with defibrillation using LIFEPAK 15 for patients with OHCA. However, a difference-in-difference analysis suggested that other factors may be responsible for the observed association.

Background: Out-of-hospital cardiac arrest (OHCA) is a frequent and lethal condition with a yearly incidence of approximately 5000 in Denmark. Thirty-day survival is associated with the patient's prodromal complaints prior to cardiac arrest. This paper examines the odds of 30-day survival dependent on the reported prodromal complaints among OHCAs witnessed by the emergency medical services (EMS)., Methods: EMS-witnessed OHCAs in the Capital Region of Denmark from 2016-2018 were included. Calls to the emergency number 1-1-2 and the medical helpline for out-of-hours were analyzed according to the Danish Index; data regarding the OHCA was collected from the Danish Cardiac Arrest Registry. We performed multiple logistic regression to calculate the odds ratio (OR) of 30-day survival with adjustment for sex and age., Results: We identified 311 eligible OHCAs of which 79 (25.4%) survived. The most commonly reported complaints were dyspnea (n = 209, OR 0.79 [95% CI 0.46: 1.36]) and 'feeling generally unwell' (n = 185, OR 1.07 [95% CI 0.63: 1.81]). Chest pain (OR 9.16 [95% CI 5.09:16.9]) and heart palpitations (OR 3.15 [95% CI 1.07:9.46]) had the highest ORs, indicating favorable odds for 30-day survival, while unresponsiveness (OR 0.22 [95% CI 0.11:0.43]) and blue skin or lips (OR 0.30, 95% CI 0.09, 0.81) had the lowest, indicating lesser odds of 30-day survival., Conclusion: Experiencing chest pain or heart palpitations prior to EMS-witnessed OHCA was associated with higher 30-day survival. Conversely, complaints of unresponsiveness or having blue skin or lips implied reduced odds of 30-day survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022., Methods: Using different media, we recruited Ukrainian refugees at 13 sites between 9-12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration., Results: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children. Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B., Conclusions: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This review summarizes current knowledge on post-acute sequelae of COVID-19 (PASC) and post-COVID-19 condition (PCC) in children and adolescents. A literature review was performed to synthesize information from clinical studies, expert opinions, and guidelines. PASC also termed Long COVID - at any age comprise a plethora of unspecific symptoms present later than 4 weeks after confirmed or probable infection with severe respiratory syndrome corona virus type 2 (SARS-CoV-2), without another medical explanation. PCC in children and adolescents was defined by the WHO as PASC occurring within 3 months of acute coronavirus disease 2019 (COVID-19), lasting at least 2 months, and limiting daily activities. Pediatric PASC mostly manifest after mild courses of COVID-19 and in the majority of cases remit after few months. However, symptoms can last for more than 1 year and may result in significant disability. Frequent symptoms include fatigue, exertion intolerance, and anxiety. Some patients present with postural tachycardia syndrome (PoTS), and a small number of cases fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, no diagnostic marker has been established, and differential diagnostics remains challenging. Therapeutic approaches include appropriate self-management as well as the palliation of symptoms by non-pharmaceutical and pharmaceutical strategies.    Conclusion: PASC in pediatrics present with heterogenous severity and duration. A stepped, interdisciplinary, and individualized approach is essential for appropriate clinical management. Current health care structures have to be adapted, and research was extended to meet the medical and psychosocial needs of young people with PASC or similar conditions. What is Known: • Post-acute sequelae of coronavirus 2019 (COVID-19) (PASC) - also termed Long COVID - in children and adolescents can lead to activity limitation and reduced quality of life. • PASC belongs to a large group of similar post-acute infection syndromes (PAIS). Specific biomarkers and causal treatment options are not yet available. What is New: • In February 2023, a case definition for post COVID-19 condition (PCC) in children and adolescents was provided by the World Health Organization (WHO), indicating PASC with duration of at least 2 months and limitation of daily activities. PCC can present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). • Interdisciplinary collaborations are necessary and have been established worldwide to offer harmonized, multimodal approaches to diagnosis and management of PASC/PCC in children and adolescents., (© 2024. The Author(s).)

Background: The influence of habitual physical activity and exercise capacity on health-related quality of life (HRQoL) in people with cystic fibrosis (pwCF) is poorly characterized. This study investigated the influence of habitual physical activity, exercise capacity, lung function, and body mass index (BMI) on HRQoL in adolescent and adult pwCF., Method: Subjects were fitted with an accelerometer to determine habitual physical activity (steps/day), including time spent at different intensities, for up to 4 weeks. Then bicycle ergometry (maximal exercise capacity; Wpeak), lung function (percent predicted forced expiratory volume in 1 s, ppFEV 1 ), BMI, and response to the Cystic Fibrosis Questionnaire-Revised (CFQ-R) were determined., Results: Sixty-five pwCF participated in the study. Physically active pwCF had significantly higher ppFEV 1 (p < .001) and exercise capacity (p < .001) than inactive pwCF, and had significantly higher scores on the CFQ-R physical (p = .006), emotional (p = .015), role (p = .008), health (p = .006), and weight (p = .004) subscales. On multiple linear regression analysis, ppFEV 1 and, to a lesser extent, exercise capacity, were the most important determinants of HRQoL in pwCF. Time spent in moderate-to-vigorous intensity physical activity did not influence any of the CFQ-R subscales, whereas time spent in vigorous-intensity influenced CFQ-R scores for role (p = .007), body (p = .001), health (p = .009), and weight (p = .01)., Conclusion: HRQoL in adolescent and adult pwCF was influenced by several factors. Avoiding sedentary behavior and spending time in vigorous-intensity levels positively influenced HRQoL, whereas the total number of steps per day played only a minor role in determining HRQoL. Both ppFEV 1 and exercise capacity markedly influenced HRQoL., (© 2024 Wiley Periodicals LLC.)