Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Primary weight loss failure after Roux-en-Y gastric bypass is characterized by impaired gut-hormone mediated regulation of food intake.

BACKGROUND/OBJECTIVES: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure. SUBJECTS/METHODS: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting. RESULTS: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]). CONCLUSIONS: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.

CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology. OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. METHODS: We sequenced GLP1R in 8642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cyclic adenosine monophosphate (cAMP) formation and ß-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330 566 unrelated White exome-sequenced participants in the UK Biobank cohort. RESULTS: We identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1-induced cAMP signaling compared to wild-type. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on glycated hemoglobin A1c. CONCLUSION: Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

Physical Activity and Insulin Sensitivity Independently Attenuate the Effect of FTO rs9939609 on Obesity.

OBJECTIVE: The association between FTO rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, to assess whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms. RESEARCH DESIGN AND METHODS: Genetic association analyses comprised up to 19,585 individuals. PA was self-reported, and IS was defined based on inverted HOMA insulin resistance index. Functional analyses were performed in muscle biopsies from 140 men and in cultured muscle cells. RESULTS: The BMI-increasing effect of the FTO rs9939609 A allele was attenuated by 47% with high PA (ß [SE], -0.32 [0.10] kg/m2, P = 0.0013) and by 51% with high IS (-0.31 [0.09] kg/m2, P = 0.00028). Interestingly, these interactions were essentially independent (PA, -0.20 [0.09] kg/m2, P = 0.023; IS, -0.28 [0.09] kg/m2, P = 0.0011). The rs9939609 A allele was also associated with higher all-cause mortality and certain cardiometabolic outcomes (hazard ratio, 1.07-1.20, P > 0.04), and these effects tended to be weakened by greater PA and IS. Moreover, the rs9939609 A allele was associated with higher expression of FTO in skeletal muscle tissue (0.03 [0.01], P = 0.011), and in skeletal muscle cells, we identified a physical interaction between the FTO promoter and an enhancer region encompassing rs9939609. CONCLUSIONS: Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of FTO in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract FTO-related genetic predisposition to obesity.

Postpartum pelvic floor muscle training, levator ani avulsion and levator hiatus area: a randomized trial.

INTRODUCTION AND HYPOTHESIS: Vaginal delivery may lead to tearing of the levator ani (LA) muscle from its bony insertions (complete LA avulsion) and increased levator hiatus (LH) area, both risk factors for pelvic floor dysfunctions. Early active rehabilitation is standard treatment after musculo-skeletal injury. We hypothesized that pelvic floor muscle training (PFMT) early postpartum would reduce the presence of LA avulsions and reduce LH area. METHODS: We carried out a planned secondary analysis from a randomized controlled study. Primiparous women (n=175) giving birth vaginally were included 6 weeks postpartum, stratified on complete LA avulsion, and thereafter randomized to PFMT or control. The training participants (n=87) attended a supervised PFMT class once a week and performed home-based PFMT daily for 16 weeks. The control participants (n=88) received no intervention. Presence of complete LA avulsion, LH area at rest, maximal contraction, and maximal Valsalva maneuver were assessed by transperineal ultrasound. Between-group comparisons were analyzed by analysis of covariance for continuous data, and relative risk (RR) for categorical data. RESULTS: Six months postpartum, the number of women who had complete LA avulsion was reduced from 27 to 14 within the PFMT group (44% reduction) and from 28 to 17 within the control group (39% reduction). The between-group difference was not significant, RR 0.85 (95% CI 0.53 to 1.37). Further, no significant between-group differences were found for LH area at rest, during contraction, or Valsalva. CONCLUSIONS: Supervised PFMT class combined with home exercise early postpartum did not reduce the presence of complete LA avulsion or LH area more than natural remission.

A pre-post intervention study: Knowledge among parents about child infections and antibiotic use facilitated by maternal and child health nurses.

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.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Sociodemographic characterisation of antibiotic heavy users in the Danish elderly population.

AIMS: The development of effective interventions to reduce inappropriate use of antibiotics in the elderly population requires knowledge on who can benefit from such interventions. Thus, we aimed to identify and characterise antibiotic heavy users among elderly patients in general practice with respect to sociodemographic variables. METHODS: We conducted a retrospective nationwide register-based study on all Danish elderly citizens (⩾65 years) who redeemed an antibiotic prescription in 2017. Heavy users were defined as the 10% with the highest excess use, that is, their recorded use minus the average use for their sex, age group and comorbidity level as estimated from a linear regression model. Comparative analyses of sociodemographic characteristics (civil status, employment status, urbanity, educational level and country of origin) of heavy users and non-heavy users were performed using logistic regression models. RESULTS: The study population consisted of 251,733 elderly individuals, who in total redeemed 573,265 prescriptions of antibiotics. Heavy users accounted for 68% of all excess use of antibiotics. In multivariable analyses, individuals with an educational level above basic schooling, non-retired, residing in an urban municipality and being born in a country outside Scandinavia all had lower odds of being a heavy user. Widowed, divorced or single individuals had higher odds of being a heavy user compared with married individuals. Relative importance analyses showed that civil status and educational level contributed considerably to the explained variance. CONCLUSIONS: This study found an association between sociodemographic characteristics and risk of being a heavy user, indicating that sociodemographic variation exists with regard to antibiotic prescribing.

Recovery of pelvic floor muscle strength and endurance 6 and 12 months postpartum in primiparous women-a prospective cohort study.

INTRODUCTION AND HYPOTHESIS: To date there has been scant knowledge on the natural recovery of the pelvic floor muscles (PFMs) after childbirth. The aims of the present study were to investigate whether PFM variables at 6 and 12 months postpartum had returned to mid-pregnancy levels and assess risk factors for reduced recovery at 12 months postpartum. METHODS: This was a prospective cohort study following 235 nulliparous pregnant women from mid-pregnancy to 12 months postpartum. Vaginal resting pressure (VRP), PFM strength and endurance were assessed by manometry at 22 weeks, 6 and 12 months postpartum. Multiple linear regression was used to address factors influencing PFM variables beyond birth mode. RESULTS: Cesarean section was protective for change in PFM variables. From mid-pregnancy to 12 months postpartum there was a 20% reduction in VRP (p<0.001) and a 7.5 % reduction in PFM strength (p=0.007), and an increase of 9% in PFM endurance (p=0.002) in the normal vaginal birth. The instrumental vaginal group had a decline in VRP of 21% (p<0.001) and PFM strength of 15% (p=0.011), but no significant change in PFM endurance. Higher BMI at 12 months postpartum, longer second stage of labor, and major tears of the levator ani muscle had a negative influence on the PFM recovery beyond delivery mode. CONCLUSIONS: At 12 months postpartum following vaginal delivery, the PFMs are not fully recovered compared with mid-pregnancy values. More follow-up physical therapy may be warranted in the postpartum period, especially for women with complicated vaginal births and higher BMI.

Pelvic floor symptoms from first pregnancy up to 8 years after the first delivery: a longitudinal study.

BACKGROUND: Despite the strong association between vaginal childbirth and pelvic floor dysfunction, genetic factors, pregnancy, advancing age, and lifestyle also play a role. The pelvic floor undergoes substantial changes during pregnancy, which may contribute to pelvic floor dysfunction. Conversely, these changes may be favorable for vaginal delivery. However, there is a lack of studies assessing pelvic floor symptoms over time according to delivery mode and including predelivery assessment. OBJECTIVE: This study aimed to describe urinary incontinence, vaginal symptoms, and bowel control symptoms from 21 weeks of gestation in the first pregnancy up to 8 years after the first delivery, stratified by delivery mode. STUDY DESIGN: This was a longitudinal observational cohort study. A total of 300 nulliparous women were recruited during their first pregnancy. Pelvic floor symptoms were assessed at 21 and 37 weeks of gestation, and at 6 weeks, 6 months, 12 months, and 8 years after first delivery using the International Consultation on Incontinence Questionnaire modules: the urinary incontinence sum score, the weighted vaginal symptom sum score, the vaginal-associated quality of life score, the bowel control sum score, and the bowel-associated quality of life sum score. Delivery mode at first delivery defined delivery groups as: normal vaginal, operative vaginal, and cesarean delivery. A linear mixed-model analysis was used to assess symptom scores over time and differences in symptom scores between the delivery groups. RESULTS: Of the 300 women included in the study, 193 attended the 8-year follow-up. Pelvic floor symptoms differed between women who had vaginal delivery and those who had cesarean delivery. The symptom scores showed a nonlinear statistically significant trend. In women who delivered vaginally, there was an increase of urinary incontinence and vaginal symptom scores already during pregnancy. In women who later delivered by cesarean, there was a decrease of symptom scores during pregnancy, and overall lower symptom scores relative to women who had vaginal delivery at 12 months after the first delivery. Pelvic floor symptom scores increased from 12 months to 8 years after the first delivery and exceeded pregnancy levels in all delivery groups; however, overall symptom scores were low. Differences between delivery groups were not statistically significant. CONCLUSION: Pelvic floor symptoms differed between women who had vaginal delivery and those who had cesarean delivery from the first pregnancy up to 8 years after the first delivery. These differences were already recognizable before the first delivery.

Health alliance for prudent prescribing and yield of antibiotics in a patient-centred perspective (HAPPY PATIENT): a before-and-after intervention and implementation study protocol.

BACKGROUND: Excessive and inappropriate use of antibiotics is the most important driver of antimicrobial resistance. The aim of the HAPPY PATIENT project is to evaluate the adaptation of European Union (EU) recommendations on the prudent use of antimicrobials in human health by evaluating the impact of a multifaceted intervention targeting different categories of healthcare professionals (HCPs) on common community-acquired infectious diseases, especially respiratory and urinary tract infections. METHODS/DESIGN: HAPPY PATIENT was initiated in January 2021 and is planned to end in December 2023. The partners of this project include 15 organizations from 9 countries. Diverse HCPs (doctors, nurses, pharmacists, and pharmacy technicians) will be audited by the Audit Project Odense (APO) method before and after an intervention in four different settings: general practice, out of hours services, nursing homes and community pharmacies in four high antibiotic prescribing countries (France, Poland, Greece, and Spain) and one low prescribing country (Lithuania). About 25 individuals from each professional group will be recruited in each country, who will register at least 25 patients with community-acquired infections during each audit period. Shortly before the second registration participants will undertake a multifaceted intervention and will receive the results from the first registration to allow the identification of possible quality problems. At these meetings participants will receive training courses on enhancement of communication skills, dissemination of clinical guidelines with recommendations for diagnosis and treatment, posters for the waiting rooms, and leaflets for patients. The results of the second registration will be compared with those obtained in the first audit. DISCUSSION: HAPPY PATIENT is an EU-funded project aimed at contributing to the battle against antibiotic resistance through improvement of the quality of management of common community-acquired infections based on interventions by different types of HCPs. It is hypothesized that the use of multifaceted strategies combining active intervention will be effective in reducing inappropriate prescribing and dispensing of antibiotics. STUDY REGISTRATION: EU Health programmes project database https://webgate.ec.europa.eu/chafea_pdb/health/projects/900024/summary ; date of registration: 1 January 2021.

Antibiotic prescribing among elderly living in long-term care facilities versus elderly living at home: a Danish registry-based study.

BACKGROUND: The objective of this study was to compare antibiotic prescription rates in Denmark among elderly living in long-term care facilities to elderly living at home, with regards to total antibiotic use and antibiotic use for urinary tract infection. METHODS: This is an observational registry-based study. The study population included all elderly Danish residents aged ≥75 years in 2016. Linear regression models were used to examine the difference in antibiotic prescription rates between elderly living in long-term care facilities and elderly living at home. Results were adjusted for age, sex and comorbidity, the latter assessed via the Charlson Comorbidity Index. RESULTS: The study population consisted of 416,627 elderly. Regression models showed that elderly living in long-term care facilities were prescribed 1.7 [CI 1.7-1.7] prescriptions/individual/year more than elderly living at home. For urinary tract infections the difference between elderly living in long-term care facilities and elderly living at home was 1.2 [CI 1.2-1.3] prescriptions/individual/year. CONCLUSIONS: Elderly living in long-term care facilities have a higher antibiotic prescribing rate than elderly living at home, despite controlling for age, sex and comorbidity. This indicates that long-term care facilities continuously should be a focus for antibiotic stewardship interventions.

Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB.

BACKGROUND: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. OBJECTIVE: We sought to identify genetic interaction associated with the development of childhood asthma. METHODS: We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. RESULTS: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. CONCLUSIONS: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

A Framework for Standardizing Emergency Nursing Education and Training Across a Regional Health Care System: Programming, Planning, and Development via International Collaboration.

INTRODUCTION: The challenges related to providing continuing education and competence management for emergency nurses are not unique to any one organization, health system, or geographic location. These shared challenges, along with a desire to ensure high-quality practice of emergency nursing, were the catalyst for an international collaboration between emergency nurse leaders in Region Zealand, Denmark, and nurse leaders and educators from a large academic medical center in Boston, Massachusetts. The goal of the collaboration was to design a competency-based education framework to support high-quality emergency nursing care in Region Zealand. The core objectives of the collaboration included the following: (1) elevation of nursing practice, (2) development of a sustainable continuing education framework, and (3) standardization of training and nursing practice across the 4 emergency departments in Region Zealand. METHODS: To accomplish the core objectives, a multi-phased strategic approach was implemented. The initial phase, the needs assessment, included semi-structured interviews, a self-evaluation of skills of all regional emergency nurses, and a survey regarding nursing competency completed by emergency nurse leadership. Two hundred ninety emergency nurses completed the self-evaluation. The survey results were utilized to inform the strategic planning and design of a regional competency-based education framework. RESULTS: In 18 months, and through an international collaboration, emergency nursing education, training, and evaluation tools were developed and integrated into the 4 regional emergency departments. Initial feedback indicates that the education has had a positive impact. The annual competency day program has continued through 2021 and is now fully institutionalized within the regional emergency nursing continuing education program. Furthermore, use of this innovative education framework has expanded beyond the emergency department to other regional nursing specialties. DISCUSSION AND CONCLUSION: Through this unique collaboration with regional and international participants, a sustainable, regional emergency nursing education program was developed that has elevated and standardized the practice of emergency nurses in Region Zealand, Denmark. This program development can serve as a model for region-wide or health care system-wide collaborations in other countries.

Antibiotic prescribing in Danish general practice in the elderly population from 2010 to 2017.

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 PointsHigh 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.

Trend in antibiotic prescription to children aged 0-6 years old in the capital region of Denmark between 2009 and 2018: Differences between municipalities and association with socioeconomic composition.

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.

Effectiveness of a tailored intervention to reduce antibiotics for urinary tract infections in nursing home residents: a cluster, randomised controlled trial.

BACKGROUND: When suspecting a urinary tract infection (UTI), the nursing home staff contacts a physician with clinical information on behalf of the resident; hence, poor understanding of UTI or a lack of clinical communicative skills can cause overtreatment with antibiotics. We investigated whether a tailored intervention that improves knowledge about UTI and communication skills in nursing home staff influences antibiotic prescriptions for UTI. METHODS: This open-label, parallel-group, cluster randomised controlled trial was done at 22 participating nursing homes in Denmark. Patients were eligible if they were nursing home residents aged 65 years or older, had the nursing home listed as their permanent address, and resided in a living space designated for those with dementia or somatic health-care needs. We included nursing homes that were not participating in other UTI projects and those in which staff were present at all hours. Using computer-generated random numbers and stratification by municipality, a statistician randomised the nursing homes (1:1) to receive either interactive educational sessions and use of a dialogue tool or to continue standard practice. The statistical analysis was blinded. Staff attended 75 min sessions over 8 weeks to learn how to distinguish between UTIs and asymptomatic bacteriuria, evaluate non-specific symptoms, and use the dialogue tool. The primary outcome was the number of antibiotic prescriptions for acute UTI per resident per days at risk, defined as the number of days the resident had been present at the nursing home during the trial period. The trial is registered at ClinicalTrials.gov, NCT03715062. FINDINGS: Between June 1, 2017, and June 1, 2018, 22 of 68 invited nursing homes were recruited. Of 22 randomised nursing homes (n=1625 residents), 11 received the intervention (770 [92·2%] of 835 allocated residents) and 11 were in the control group (705 [89·2%] of 790 allocated residents). The standardised number of nursing home staff was 572 in the intervention group and 535 in the control group. All nursing homes completed the trial. 65 residents were excluded from data collection in the intervention group and 85 were excluded in the control group. 1470 residents (intervention n=765; control n=705) were analysed for the primary endpoint. The number of antibiotic prescriptions for UTI per resident was 134 per 84 035 days at risk in the intervention group and 228 per 77817 days at risk in the control group. The rate ratio (RR) of receiving an antibiotic for UTI was 0·51 (95% CI 0·37-0·71) in the unadjusted model and 0·42 (0·31-0·57) in the adjusted model. Of 140 diary entries of suspected UTIs, no deaths were reported. 421 (28·5%) of 1475 residents were admitted to hospital. The risk of all-cause hospitalisation increased in the intervention group (adjusted model RR 1·28, 95% CI 0·95-1·74), whereas all-cause mortality was lower in the intervention group (0·91, 0·62-1·33). INTERPRETATION: The intervention effectively reduced antibiotic prescriptions and inappropriate treatments for UTI without substantially influencing all-cause hospitalisations and mortality. FUNDING: Danish Ministry of Health and the Velux Foundation.

Native and foreign healthcare workers' knowledge of appropriate use of antibiotics: a prospective pre-post study in Danish nursing homes.

AIM: The aim was to determine the association between healthcare workers' (HCWs) country of birth and their knowledge of appropriate use of antibiotics, and whether the association changed after an educational intervention. BACKGROUND: Older residents in nursing homes have been recognized to receive excessively antibiotic treatments. HCWs often represent an important link between the older resident and the general practitioner prescribing the antibiotics, thus their knowledge of appropriate use of antibiotics is important. METHODS: This study was conducted as a prospective pre-post study. Totally, 312 HCWs from 7 nursing homes in Denmark were included. For statistical analyses, χ2 test and a linear mixed regression model were applied. FINDINGS: Native HCWs were more likely to have a higher percentage of correct responses to single statements related to knowledge of appropriate use of antibiotics. Native HCWs had a significantly higher knowledge-of-antibiotic score compared to foreign HCWs (-7.53, P < 0.01). This association remained significant after adjusting for relevant covariates (-5.64, P < 0.01). Native HCWs' mean change in knowledge-of-antibiotic score after the intervention did not differ from the foreign HCWs' mean change in knowledge-of-antibiotic score. CONCLUSION: Our findings indicate that HCWs born outside Denmark reveal a lower knowledge-of-antibiotic score than HCWs born in Denmark despite comparable educational backgrounds. All participants increased their knowledge from baseline to follow-up. Our findings also indicate that an educational seminar cannot equalize the difference in knowledge between native and foreign HCWs. Studies with larger sample size and a more detailed measurement of cultural identity should investigate this association further.