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BackgroundDiabetes distress refers to the negative emotional reaction to living with the demands of diabetes; it occurs in >40% of adults with type 1 diabetes (T1D). However, no interventions to reduce diabetes distress are specifically designed to be an integral part of diabetes care. ObjectiveThis study aims to modify and adapt existing evidence-based methods into a nurse-led group intervention to reduce diabetes distress among adults with T1D and moderate to severe diabetes distress. MethodsThe overall framework of this study was informed by the initial phase of the Medical Research Council’s complex intervention framework that focused on undertaking intervention identification and development to guide the adaptation of the intervention. This study took place at 2 specialized diabetes centers in Denmark from November 2019 to June 2021. A total of 36 adults with T1D participated in 10 parallel workshops. A total of 12 diabetes-specialized nurses were interviewed and participated in 1 cocreation workshop; 12 multidisciplinary specialists, including psychologists, educational specialists, and researchers, participated in 4 cocreation workshops and 14 feedback meetings. Data were analyzed by applying a deductive analytic approach. ResultsThe intervention included 5 biweekly 2.5-hour small group sessions involving adults with T1D and diabetes distress. Guided by a detailed step-by-step manual, the intervention was delivered by 2 trained diabetes specialist nurses. The intervention material included visual conversation tools covering seven diabetes-specific sources derived from the 28-item Type 1 Diabetes Distress Scale for measuring diabetes distress: (1) powerlessness, (2) self-management, (3) fear of hypoglycemia, (4) food and eating, (5) friends and family, (6) negative social perception, and (7) physician distress. The tools are designed to kick-start awareness and sharing of diabetes-specific challenges and strengths, individual reflections, as well as plenary and peer-to-peer discussions about strategies to manage diabetes distress, providing new perspectives on diabetes worries and strategies to overcome negative emotions. Diabetes specialist nurses expressed a need for a manual with descriptions of methods and detailed guidelines for using the tools. To deliver the intervention, nurses need increased knowledge about diabetes distress, how to support diabetes distress reduction, and training and supervision to improve skills. ConclusionsThis co-design study describes the adaptation of a complex intervention with a strong evidence base, including detailed reporting of the theoretical underpinnings and core mechanisms.

BackgroundDespite the extensive use of antibiotics and the growing challenge of antimicrobial resistance, there has been a lack of substantial initiatives aimed at diminishing the prevalence of infections in nursing homes and enhancing the detection of urinary tract infections (UTIs). ObjectiveThis study aims to systematize and enhance efforts to prevent health care–associated infections, mainly UTIs and reduce antibiotic inappropriateness by implementing a multifaceted intervention targeting health care professionals in nursing homes. MethodsA before-and-after intervention study carried out in a minimum of 10 nursing homes in each of the 8 European participating countries (Denmark, Greece, Hungary, Lithuania, Poland, Slovakia, Slovenia, and Spain). A team of 4 professionals consisting of nurses, doctors, health care assistants, or health care helpers are actively involved in each nursing home. Over the initial 3-month period, professionals in each nursing home are registering information on UTIs as well as infection and prevention control measures by means of the Audit Project Odense method. The audit will be repeated after implementing a multifaceted intervention. The intervention will consist of feedback and discussion of the results from the first registration, training on the implementation of infection and prevention control techniques provided by experts, appropriateness of the diagnostic approach and antibiotic prescribing for UTIs, and provision of information materials on infection control and antimicrobial stewardship targeted to staff, residents, and relatives. We will compare the pre- and postintervention audit results using chi-square test for prescription appropriateness and Student t test for implemented hygiene elements. ResultsA total of 109 nursing homes have participated in the pilot study and the first registration audit. The results of the first audit registration are expected to be published in autumn of 2024. The final results will be published by the end of 2025. ConclusionsThis is a European Union–funded project aimed at contributing to the battle against antimicrobial resistance through improvement of the quality of management of common infections based on evidence-based interventions tailored to the nursing home setting and a diverse range of professionals. We expect the intervention to result in a significant increase in the number of hygiene activities implemented by health care providers and residents. Additionally, we anticipate a marked reduction in the number of inappropriately managed UTIs, as well as a substantial decrease in the overall incidence of infections following the intervention. International Registered Report Identifier (IRRID)DERR1-10.2196/60099

Abstract Labelling of nucleic acid amplicons during polymerase chain reaction (PCR) or isothermal techniques is possible by using both labelled primers and labelled nucleotides. While the former is the widely used method, the latter can offer significant advantages in terms of signal enhancement and improving the detection limit of an assay. Advantages and disadvantages of both methods depend on different factors, including amplification method, detection method and amplicon length. In this study, both methods for labelling PCR products for lateral flow assay (LFA) analysis (LFA-PCR) were analysed and compared. It was shown that labelling by means of nucleotides results in an increase in label incorporation rates. Nonetheless, this advantage is negated by the need for post-processing and competitive interactions. In the end, it was possible to achieve a detection limit of 3 cell equivalents for the detection of the Legionella-DNA used here via primer labelling. Labelling via nucleotides required genomic DNA of at least 3000 cell equivalents as starting material as well as an increased personnel and experimental effort.

Abstract Aims To investigate parent's knowledge and beliefs of common infections and antibiotics in children before and after an educational intervention provided by maternal and child health nurses. Second, to investigate sociodemographic differences in parent's knowledge before and following the intervention. Design A prospective pre‐post intervention study. The intervention consisted of a booklet with information about childhood infections delivered by maternal and child health nurses. Methods The study population included 344 parents with a child born during 2017 and residing in three Danish municipalities. Knowledge about infections and antibiotics were collected quantitatively through an online questionnaire before and after the intervention (August 2017–November 2018) and analysed using linear mixed models. Results Parental knowledge increased after the intervention. Parents with lower education and born in Denmark compared to parents with higher education and born in other countries experienced a higher increase in knowledge from baseline to follow‐up.

Registries are an important platform to which persons with dementia and other cognitive impairments can contribute to research studies. Registries also provide an opportunity for patients to stay informed about current studies. Engaging patients in registry development can increase sustainability of a registry and patient retention in clinical registries. We sought the perspective of persons with dementia and their accompanying family members about their registry participation experiences, barriers and facilitators to participation, and potential avenues for improvement of registry processes such as recruitment, data collection, and knowledge translation. Two semi-structured focus groups with persons with dementia and their family members (n = 18) were conducted and analyzed using thematic content analysis. Participants were recruited from an existing patient registry made up of patients currently being seen in a dementia assessment clinic. The main themes identified included altruistic motives with regards to registry participation; and access to and privacy of personal health information. As electronic health records are becoming more common, understanding barriers and facilitators from the perspectives of people with dementia is essential to inform the future development of cognitive condition-related registries. The results from our focus groups identified engagement strategies and solutions to overcome perceived barriers for individuals experiencing progressive cognitive decline to participate in longitudinal registry projects. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic β-cells have an extraordinary ability to adapt to acute fluctuations in glucose levels by rapid changing insulin production to meet metabolic needs. Although acute changes have been characterised, effects of prolonged metabolic stress on β-cell dynamics are still unclear. Here, the aim was to investigate pancreatic β-cell dynamics and function during and after prolonged hypoglycaemia. Hypoglycaemia was induced in male and female rats by infusion of human insulin for 8 weeks, followed by a 4-week infusion-free recovery period. Animals were euthanized after 4 or 8 weeks of infusion, and either 2 days and 4 weeks after infusion-stop. Total volumes of pancreatic islets and β-cell nuclei, islet insulin and glucagon content, and plasma c-peptide levels were quantified. Prolonged hypoglycaemia reduced c-peptide levels, islet volume and almost depleted islet insulin. Relative β-cell nuclei: total pancreas volume decreased, while being unchanged relative to islet volume. Glucagon: total pancreas volume decreased during hypoglycaemia, whereas glucagon: islet volume increased. Within two days after infusion-stop, plasma glucose and c-peptide levels normalised and all remaining parameters were fully reversed after 4 weeks. In conclusion, our findings indicate that prolonged hypoglycaemia inactivates β-cells, which can rapidly be reactivated when needed, demonstrating the high plasticity of β-cells even following prolonged suppression.

Objective This study aimed to describe prescription of antibiotics to the elderly population in general practice in Denmark from 2010–2017. Design This is a national register-based observational study. Setting General practice, Denmark Main outcome measure The main outcome measure was prescriptions/1,000 inhabitants/day (PrID) in relation to year, age and sex, indication, and antibiotic agent. Subjects In this study, we included inhabitants of Denmark, ≥65 years of age between 01st July 2010–30th June 2017. Results A total of 5,168,878 prescriptions were included in the study. Antibiotic prescriptions decreased from 2.2 PrID to 1.7 (-26.9%, CI95% [-31.1;-22.4]) PrID during the study. The decrease in PrID was most noticeable among 65–74-year-olds (-25%). The ≥85-year-olds were exposed to twice as many PrID than the 65–74-year-olds, but only accounted for 20% of the total use. Urinary tract infection (UTI) was the most common indication for antibiotic prescription and increased with advancing age. The most commonly prescribed antibiotics were pivmecillinam and phenoxymethylpenicillin. Prescribing with no informative indication was present in one third of all cases. Conclusion The prescription of antibiotics in the elderly population in general practice decreased from 2010 to 2017. The oldest age group was exposed twice as frequently to antibiotic prescriptions as the 65–74-year-olds. The smallest reduction was observed for the ≥85-year-olds, suggesting targeting interventions at this group.Key Points High antibiotic use among elderly is well known and studies indicate mis- and overuse within this population. Our study shows. The prescription rate is decreasing within all age groups of the elderly population. The ≥85-year-olds receive twice as many prescriptions/1000/day as the 65–74-years-olds.

Background To curb future antibiotic resistance it is important to monitor and investigate current prescription patterns of antibiotics. Objectives To examine trends in antibiotic prescription to children aged 0–6 years old and the association with socioeconomic status of municipalities in the Capital region of Denmark between 2009 and 2018. Methods This is a register-based study combining data on antibiotic treatments from 2009 to 2018, inhabitant-data and socioeconomic municipality scores. Subjects were children aged 0–6 years, residing in the Capital Region of Denmark. The study quantifies the use of antibiotics as number of antibiotic treatments/1000 inhabitants/year (TIY), inhabitants defined as children aged 0–6. Socioeconomic status of the municipalities is evaluated by a score from 3 to 12. Results The average TIY of the municipalities decreased from 741.2 [95%CI 689.3–793.2] in 2009 to 348.9 [329.4–368.4] in 2018. The difference between the highest and lowest prescribing municipalities was reduced from 648.3 TIY in 2009–212.5 TIY in 2018. The average increase in TIY per unit increase in socioeconomic municipality score changed from 20.05 [7.69–31.06] in 2009 to −4.58 [-16.02–5.60] in 2018, representing a decreasing association between socioeconomic municipality score and use of antibiotic in the respective municipalities. Conclusion The trend in antibiotic prescription to children aged 0–6 years old decreased substantially in all the investigated municipalities in the 10-year study period. Local differences in prescription rates declined towards a more uniform prescription pattern across municipalities and association with socioeconomic status of the municipalities was reduced.

Abstract Background When CO2 escapes from plasma, the pH of the plasma increases. In samples left open or kept in long‐term storage, the pH may increase considerably. Assays in which the ratio of plasma sample relative to the total volume including reagents is high may be sensitive to the pH of the plasma sample. Objective The aim was to investigate the effect of the pH of plasma samples used in the calibrated automated thrombin generation (CAT) assay in which the ratio (plasma sample) / (total volume) is high. Methods Plasma pH was increased by allowing CO2 to escape in open beakers before the CAT analysis. The effect of pH was also investigated by mixing plasma with buffers with different pH levels. Results At a pH close to 8.0, endogenous thrombin potential (ETP) and peak decreased considerably, whereas lagtime and time‐to‐peak were modestly increased. Mixtures of plasma and buffer with pH levels between 7 and 8 showed that ETP and peak decreased at alkaline pH; lagtime and time‐to‐peak were higher at acidic pH levels but were shortened, partly in contrast to first results, at alkaline pH levels. The addition of 4‐(2‐hydroxyethyl)‐1‐piperazineethanesulfonic acid buffer to plasma with a high pH attenuated the effects; however, the effect was most significant if added before the CO2 escaped. Conclusion Modifications of plasma pH can significantly alter thrombin generation. In alkaline samples, for example, after lengthy storage in a freezer where pH can increase considerably, thrombin generation is lowered. To minimize this effect, plasma should be stored in tubes filled to the maximum volume.

Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.

Abstract Background The thrombin generation (TG) assay, which measures global coagulation, has mainly been used as a research tool to investigate thrombotic and bleeding disorders. Recently, Diagnostica Stago launched the ST Genesia, a fully automated system to perform “routine version” of this assay. The objectives of this study were to evaluate the imprecision compared with the previous method, Thrombinoscope CAT, and to establish reference intervals. Methods Thrombin generation was measured in platelet‐poor citrated plasma from 20 normal controls (fresh and after freezing at −80°C up to 12–13 weeks) on CAT and ST Genesia in duplicate to estimate the total variation, and within and between variations. The reference intervals were estimated nonparametrically in 30 men, 30 women taking combined oral contraceptives (COCs), and 30 women not taking COCs. These were sampled in both Vacutainer and Monovette tubes (i.e., tubes with a high and minimal contact activation, respectively). Results Freezing had minimal effects. Imprecision was comparable between the ST Genesia and CAT, with a strong correlation between the two methods. TG was higher when sampled in Vacutainer than in Monovette. We observed a distinct difference between women taking and not taking COCs, whereas men and women not taking COC were quite similar. Conclusions Thrombin generation on ST Genesia showed an analytical variation similar to that of CAT. The results depended on the type of sample tubes; thus, reference intervals must be established for the collection tubes used in each laboratory. Furthermore, a considerable difference was observed between women using and not using COCs.

Background: Overprescribing antibiotics for common or inaccurately diagnosed childhood infections is a frequent problem in primary healthcare in most countries. Delayed antibiotic prescriptions have been shown to reduce the use of antibiotics in primary healthcare. Objective: The aim was to examine primary care physicians’ views on delayed antibiotic prescriptions to preschool children with symptoms of upper respiratory tract infections (URTIs). Methods: A questionnaire was sent to 1180 physicians working in general practice in the Capital Region of Denmark, between January and March 2015. The questions focused on physicians’ attitude and use of delayed antibiotic prescriptions to children with URTIs. Results: The response rate was 49% (n = 574). Seven per cent of the physicians often used delayed prescriptions to children with symptoms of URTI, but 46% believed that delayed prescription could reduce antibiotic use. The physicians’ views on delayed antibiotic prescription were significantly associated with their number of years working in general practice. Parents’ willingness to wait-and-see, need for reassurance, and knowledge about antibiotics influenced the physicians’ views. Also, clinical symptoms and signs, parents’ willingness to shoulder the responsibility, the capability of observation without antibiotic treatment, and structural factors like out-of-hour services were relevant factors in the decision. Conclusions: Most physicians, especially those with fewer years of practice, had a positive attitude towards delayed antibiotic prescription. Several factors influence the views of the physicians—from perceptions of parents to larger structural elements and years of experience.

Background It is unclear whether nonvitamin K antagonist oral anticoagulants (NOACs) can mitigate dementia development in atrial fibrillation. We compared dementia development among users of NOACs or warfarin in patients with atrial fibrillation with no prior neurological diagnoses. Methods and Results We conducted a Danish nationwide cohort study including 33 617 new oral anticoagulant users with nonvalvular atrial fibrillation, of which 11 052 were aged 60 to 69 years, 13 237 were aged 70 to 79 years, and 9238 were aged 80 years and older. To exclude prevalent non‐oral anticoagulants–associated dementia, we considered the at‐risk population of patients alive and free of dementia at 180 days following inclusion. We compared rates of new‐onset dementia by age and treatment regimen using inverse probability of treatment weighting to account for confounding. Approximately 60% of patients were NOAC users and 40% were warfarin users. Mean follow‐up was 3.4 years. Dementia occurred in 41 patients aged 60 to 69 years, 276 patients aged 70 to 79 years, and 441 patients aged 80 years and older. Relative to warfarin users, dementia rates were nonsignificantly lower among NOAC users aged 60 to 69 years (0.11 events/100 person‐years versus 0.12 events/100 person‐years; weighted hazard ratio, 0.92 [95% CI, 0.48–1.72]) and NOAC users aged 70 to 79 years (0.64 events/100 person‐years versus 0.78 events/100 person‐years; weighted hazard ratio, 0.86 [95% CI, 0.68–1.09]), whereas NOACs were associated with significantly higher dementia rates (2.16 events/100 person‐years versus 1.70 events/100 person‐years; weighted hazard ratio, 1.31 [95% CI, 1.07–1.59]) in patients 80 years and older. Conclusions This nationwide cohort of patients with atrial fibrillation revealed no clinically meaningful difference in dementia development between users of NOACs or warfarin apart from a higher risk in NOAC users 80 years and older, which may relate to residual confounding from selective prescribing and unobserved comorbidities.

Objective: To investigate the distribution of antibiotic prescriptions in primary health care among children aged 0–6 years and its association with socioeconomic factors. Design: A cross-sectional study describing antibiotic prescriptions and socioeconomic factors, using different population-based registers from Statistics Denmark. Setting: Antibiotic prescriptions in 2012 from primary health care in the Capital Region of Denmark. Subjects: The population of children aged 0–6 years (n = 139,398) in the Capital Region of Denmark. Main outcome measures: High use of antibiotics identified by number of antibiotic prescriptions (≥ 3 prescriptions per year) and defined daily doses (DDD). A multinomial logistic regression analysis estimating the association between high antibiotic use and parents’ education, employment status, income, child’s sex, and ethnic background. Results: Ten percent of children accounted for 25% of the total use DDD. There was a clear tendency that the risk for high antibiotic use increased as parental educational level decreased. The risk for high use was the highest among children of mothers and fathers with basic schooling ≤10 years (OR 1.60, 95% CI 1.29–1.98, and OR 1.60, 95% CI 1.34–1.91, respectively). Low income and unemployment were not associated with high antibiotic use. Conclusion: Socioeconomic factors can only partially explain differences in antibiotic use. Further research is needed to clarify the unequal distribution of antibiotic prescribing and the association between high antibiotic use and low educational level. This would provide valuable information in the planning of strategies to promote rational use of antibiotics among children.KEY POINTS The Capital Region of Denmark has the highest rate of antibiotic prescribing in Denmark. Preschool children are among the age groups with the highest use. Ten percent of the children accounted for 25% of the total antibiotic use. Low parental educational level was associated with increased antibiotic use. Parents’ income or employment status was not found to be associated with high antibiotic use.

Background: Inappropriate antibiotic treatments for urinary tract infections (UTIs) in nursing homes cause the development of resistant bacteria. Nonspecific symptoms and asymptomatic bacteriuria are drivers of overtreatment. Nursing home staff provide general practice with information about ailing residents; therefore, their knowledge and communication skills influence prescribing. This paper describes the development of a tailored, complex intervention for a cluster-randomised trial that targets the knowledge of UTI and communication skills in nursing home staff to reduce antibiotic prescriptions. Methods: A dialogue tool was drafted, drawing on participatory observations in nursing homes, interviews with stakeholders, and a survey in general practice. The tool was tailored through a five-phase process that included stakeholders. Finally, the tool and a case-based educational session were tested in a pilot study. Results: The main barriers were that complex patients were evaluated by healthcare staff with limited knowledge about disease and clinical reasoning; findings reported to general practice were insignificant and included vague descriptions; there was evidence of previous opinion bias; nonspecific symptoms were interpreted as UTI; intuitive reasoning led to the inappropriate suspicion of UTI. Conclusion: Sustainable change in antibiotic-prescribing behaviour in nursing homes requires a change in nursing home staff’s beliefs about and management of UTIs.

BackgroundSepsis may adversely affect bleeding risk in anticoagulated patients with atrial fibrillation (AF), but the impact of warfarin treatment in such patients is poorly described. This registry‐based nationwide cohort study examined safety of oral anticoagulant treatment (OAC) in patients with preexisting AF who were hospitalized because of incident sepsis in the period 2000–2015. Methods and ResultsWe identified 3030 AF patients who were warfarin users at the time of sepsis diagnosis, and we used inverse probability of treatment weighting to compare the rates of bleeding, thromboembolic events, and death within 90 days after sepsis diagnosis with a comparable cohort of 55721 patients without warfarin treatment and known AF. Weighted 90‐day bleeding rates were slightly higher among warfarin users compared with nonusers (0.14 versus 0.12 per 100 person‐years), yielding a weighted hazard ratio of 1.19 (95% confidence interval, 1.00–1.41). Thromboembolic event rates during the 90‐days after sepsis were marginally higher among warfarin users versus nonusers (0.04 versus 0.03; hazard ratio: 1.25, 95% confidence interval, 0.89–1.76), while the 90‐day all‐cause mortality was substantially lower among warfarin users (hazard ratio: 0.64, 95% confidence interval, 0.58–0.69). Various sensitivity analyses conducted to challenge the robustness these findings yielded results that were consistent with the main findings. ConclusionsAF patients who are on warfarin therapy at sepsis diagnosis experienced an increase in bleeding rates within the 3 months following sepsis. Warfarin use was associated with lower mortality, despite virtually comparable thromboembolic event rates.

Turoctocog alfa pegol (N8-GP) is a glycoPEGylated human recombinant factor VIII for the treatment of hemophilia A. The safety profile of rFVIII, and polyethylene glycols (PEG) technology, is well-established. Conducting long-term toxicity studies in animals using human proteins can be complicated by anti-drug antibody (ADA) development. To evaluate long-term safety of N8-GP, 26- and 52-week toxicity studies were conducted in immune-deficient rats dosed intravenously every fourth day with 0, 50, 150, 500, or 1200 IU/kg N8-GP. Observations included clinical observations, body weight, ophthalmoscopy, hematology, chemistry, coagulation, urinalysis, toxicokinetics, antibody analysis, and macroscopic/microscopic organ examination. Immunohistochemical staining examined the distribution of PEG in the brain. No adverse test item-related findings were seen and PEG was not detected in the brain. Exposure was confirmed for ~75% of the animals dosed with 500 and 1200 IU/kg N8-GP; the high lower limit of quantification of the bioanalysis assay prevented confirmation of exposure in the lower doses. A small number of animals developed ADAs, and the proportion of animals surviving until scheduled termination was >80%. N8-GP was well tolerated, and the immune-deficient rat proved suitable for testing long-term toxicity of human proteins that are immunogenic in animals.