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Michael D Kappelman,1 Aksel Lange,2 Rachel L Randell,3 Patricia V Basta,4 Robert S Sandler,5 Kristina Laugesen,2 Anna Byrjalsen,2 Tina Christensen,2 Trine Frøslev,2 Rune Erichsen2,6 1Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Department of Clinical Epidemiology,Aarhus University Hospital, Aarhus, Denmark; 3Department of Pediatrics, Duke University School of Medicine, Duke University, Durham, NC, USA; 4Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6Surgical Department, Horsens Regional Hospital, Horsens, Denmark Background: Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene–environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn’s disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls.Subjects and methods: Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs).Results: A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls.Conclusion: This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene–environment interactions in complex chronic conditions such as CD. Keywords: Crohn’s disease, children, genetic, DNA, SNP

Ane Birgitte Telén Andersen,1 Rune Erichsen,1 Michael David Kappelman,2 Trine Frøslev,1 Vera Ehrenstein1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Pediatrics, Division of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Objective: The incidences of celiac disease (CD) and asthma are increasing and the two conditions are associated in individuals. Risk of asthma may be passed on to the next generation through shared risk factors. We examined whether parental CD is associated with risk of asthma in offspring. Methods: We conducted a population-based Danish nationwide cohort study, using medical databases, covering the period 1 January 1979 to 31 December 2009. For each child with a parental history of CD, we randomly sampled 100 children without this history from the children born in the same calendar year. We used Cox proportional-hazards regression to estimate incidence rate ratios for asthma, adjusting for measured covariates. Results: We identified 1,107 children with a parental history of CD and 110,700 children without this parental history. During up to 32 years of follow-up, 6,125 children received a hospital diagnosis of asthma. The adjusted incidence rate ratio for asthma associated with a parental history of CD was 1.09 (95% confidence interval: 0.86–1.39) and was similar for maternal and paternal CD. Inclusion of asthma-medication in the definition of asthma did not substantially change the results. Conclusion: There was no convincing evidence of an increased risk of asthma among offspring of parents with CD. Keywords: asthma, celiac disease, children, cohort study, parents

Ane Birgitte Telén Andersen, Vera Ehrenstein, Rune Erichsen, Trine Frøslev, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Purpose: Inflammatory bowel disease (IBD) and autism spectrum disorders (ASD) may share genetic and environmental risk factors. We examined whether parental IBD is associated with an increased risk of ASD in offspring. Methods: We conducted a registry-based nationwide cohort study including children born alive in Denmark from January 1, 1994 to December 31, 2009, with follow-up throughout 2010. IBD in parents and ASD in offspring were identified using inpatient and outpatient hospital diagnoses. We computed risk of ASD and crude and adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CI) using Cox proportional-hazards regression. We evaluated the risk of ASD according to maternal and paternal IBD, and separately for maternal and paternal Crohn's disease (CD) and ulcerative colitis (UC). Children with parents free of IBD were the comparison cohort. Results: We identified 1,005,330 children during the study period. Among them, 11,888 (1.2%) had a parent with IBD and 8,087 (0.8%) had a diagnosis of ASD during up to 17 years of follow-up. The 10-year risks of ASD were 0.7% among children of parents with IBD and 0.9% among children of parents without IBD. The aIRR for ASD among children with parental IBD was 0.8 (95% CI: 0.6–1.0), and results were similar regardless of parent of IBD origin or whether a parent had CD or UC. The estimates were similar for different ASD subtypes. Conclusion: We found no evidence of an increased risk of ASD among children born to parents with IBD. Keywords: autistic disorder, children, cohort study, epidemiology, inflammatory bowel disease, parents

Jennifer L Lund,1 Trine Frøslev,1 Thomas Deleuran,1,2 Rune Erichsen,1 Tove Nilsson,1 Annette Nørkær Pedersen,3 Morten Høyer4 1Department of Clinical Epidemiology, 2Department of Medicine V (Hepatology and Gastroenterology), 3Hospital Pharmacy, 4Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Background: The Danish National Registry of Patients (DNRP) is a potentially valuable resource for monitoring national trends in the use of chemotherapy and evaluating the benefits and harms of alternative treatments among colorectal cancer (CRC) patients in Denmark. However, the validity of chemotherapy reporting in the DNRP is unknown. In this study, we evaluated the validity of the DNRP for identifying the receipt of chemotherapy and specific treatments, and the timing and number of treatments among CRC patients, using medical records and pharmacy data as the reference standard. Methods: We selected a random sample of CRC patients with lymph node involvement who were diagnosed at Aarhus University Hospital (n = 25) or Aalborg University Hospital (n = 25) from 2009 to 2010. Administration dates, specific treatments, and number of treatment courses were abstracted for the 180 days post diagnosis from the DNRP, medical records, and pharmacy production databases. The prevalence of chemotherapy, timing of first administration, and number of courses were described. DNRP data were compared with the reference standard for each hospital, and the kappa, sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated for the receipt of any chemotherapy and specific treatments. Results: The prevalence of chemotherapy was 72% and 68% among CRC patients treated in Aarhus and Aalborg, respectively, with >90% of patients without distant metastasis receiving treatment within 90 days from diagnosis. Patients received on average 4.6 and 4.7 treatment courses in Aarhus and Aalborg, respectively. Kappa, sensitivity, and specificity of chemotherapy reporting in the DNRP was high (≥0.88), but the sensitivity of individual chemotherapies varied by hospital. Conclusion: The validity of chemotherapy reporting in the DNRP was high, although some variation by hospital exists. The DNRP represents a population-based nationwide resource that can be used to provide timely and accurate evaluations of chemotherapy use among CRC patients in Denmark. Keywords: chemotherapy, colorectal cancer, administrative data

Inès Ben Ghezala, Johan Frederik Berg Arendt, Rune Erichsen, Jihen Zalfani, Henrik Gammelager, Trine Frøslev, Morten OlsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkPurpose: The aim of this validation study was to assess the positive predictive value (PPV) of the International Classification of Diseases, 10th revision (ICD-10) diagnosis of vitamin B12 (cobalamin [Cbl]) deficiency anemia in the Danish National Patient Register (DNPR).Patients and methods: We identified all patients above 18 years of age recorded in the DNPR with a diagnosis of Cbl deficiency anemia (ICD-10 code: D51) admitted to two Danish university hospitals and one Danish regional hospital from 2000 through 2009. We assessed the PPV using biochemical parameters on Cbl deficiency with or without anemia as reference standards. These data were obtained from the Laboratory Information Systems Database. Data on prescriptions with Cbl supplementation drugs were obtained from the Aarhus University Prescription Database.Results: We identified 1089 patients coded with a Cbl deficiency anemia diagnosis in the DNPR. The PPV was 31.5% (95% confidence interval [CI]: 28.8%–34.3%) and 36.8% (95% CI: 34.0%–39.7%) depending on definitions of Cbl deficiency with anemia. When using Cbl deficiency without anemia as a reference standard, the PPV was 51.3% (95% CI: 48.4%–54.3%). The PPV for Cbl supplemented patients was 22.2% (95% CI: 18.0%–26.9%) and for non-Cbl supplemented patients 63.9% (95% CI: 60.5%–67.3%).Conclusion: The PPVs of the ICD-10 diagnosis coding for Cbl deficiency anemia were generally low in the DNPR. Therefore, this register should be used with caution to study patients with Cbl deficiency anemia.Keywords: vitamin B12 deficiency anemia, Danish National Patient Register, Laboratory Information Systems Database, International Classification of Diseases, positive predictive value, validation study

Jihen Zalfani, Trine Frøslev, Morten Olsen, Inès Ben Ghezala, Henrik Gammelager, Johan FB Arendt, Rune ErichsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkObjective: Valid data on anemia caused by bleeding are needed for epidemiological research and monitoring health care. The Danish National Registry of Patients (DNRP) is a nationwide medical database with information on all Danish residents' hospital history. We aimed to assess the positive predictive value (PPV) of the diagnostic coding of anemia caused by bleeding in the DNRP.Methods: In the DNRP, we identified all patients with International Classification of Disease, 10th edition codes for anemia caused by bleeding (acute: D50.0; chronic: D62.6) at three Danish hospitals from 2000 through 2009. For these patients we computed the PPV using hemoglobin level data, from Aarhus University laboratory database, as reference standard. Anemia was defined by a hemoglobin level less than 7.0 mmol/L for women and less than 8.0 mmol/L for men.Results: We identified 3391 patients in the DNRP with a diagnosis of anemia caused by bleeding. The overall PPV was 95.4% (95% confidence interval [CI]: 94.6%–96.0%). The PPV was 97.6% (95% CI: 96.6%–98.3%) for men and 94.0% (95% CI: 92.9%–94.9%) for women, and the PPV increased with age at diagnosis. The PPV varied according to type of discharging departments, from 89.2% (95% CI: 83.4%–93.4%) in gynecology to 96.8% (95% CI: 94.9%–98.2%) in surgery, and was lower for outpatients compared with inpatients.Conclusion: We found a high PPV of the coding for anemia caused by bleeding in the DNRP. The registry is a valid source of data on anemia caused by bleeding for various purposes including research and monitoring health care.Keywords: anemia, Danish National Registry of Patients, International Classification of Diseases, predictive value, laboratory database, validation

Malene Schou Nielsson,1 Rune Erichsen,1 Trine Frøslev,1 Aliki Taylor,2 John Acquavella,2 Vera Ehrenstein11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research International, Amgen Ltd Thousand Oaks, CA, USA Background: The purpose of this study was to estimate the positive predictive value (PPV) of the coding for bisphosphonate treatment in selected cancer patients from the Danish National Patient Registry (DNPR).Methods: Through the DNPR, we identified all patients with recorded cancer of the breast, prostate, lung, kidney, and with multiple myeloma. We restricted the study sample to patients with bisphosphonate treatment recorded during an admission to Aalborg Hospital, Denmark, from 2005 through 2009. We retrieved and reviewed medical records of these patients from the initial cancer diagnosis onwards to confirm or rule out bisphosphonate therapy. We calculated the PPV of the treatment coding as the proportion of patients with confirmed bisphosphonate treatment.Results: We retrieved and reviewed the medical records of 60 cancer patients with treatment codes corresponding to bisphosphonate therapy. Recorded code corresponded to treatment administered intravenously for 59 of 60 patients, corresponding to a PPV of 98.3% (95% confidence interval 92.5–99.8). In the remaining patient, bisphosphonate treatment was also confirmed but was an orally administered bisphosphonate; thus, the treatment for any bisphosphonate regardless of administration was confirmed for all 60 patients (PPV of 100%, 95% confidence interval 95.9–100.0).Conclusion: The PPV of bisphosphonate treatment coding among cancer patients in the DNPR is very high and the recorded treatment nearly always corresponds to intravenous administration.Keywords: bisphosphonate, neoplasm metastases, predictive value of tests, validation studies

Anne Fia Grann, Rune Erichsen, Anders Gunnar Nielsen, Trine Frøslev, Reimar W ThomsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkAbstract: This paper provides an introduction to the clinical laboratory information system (LABKA) research database in Northern and Central Denmark. The database contains millions of stored laboratory test results for patients living in the two Danish regions, encompassing 1.8 million residents, or one-third of the country's population. More than 1700 different types of blood test analyses are available. Therefore, the LABKA research database represents an incredible source for studies involving blood test analyses. By record linkage of different Danish registries with the LABKA research database, it is possible to examine a large number of biomarkers as predictors of disease risk and prognosis and as markers of disease severity, and to evaluate medical treatments regarding effectiveness and possible side effects. Large epidemiological studies using routinely stored blood test results for individual patients can be performed because it is possible to link the laboratory data to high-quality individual clinical patient data in Denmark.Keywords: biochemistry, laboratory procedures, diagnosis, therapeutic drug monitoring, epidemiological methods, registries

Based on molecular and morphological data we investigated the taxonomy and phylogeny of the ectomycorrhizal genus Tricholoma in northern Europe. Our phylogenetic tree confirmed the presence of at least 72 well circumscribed species within the region. Of these, three species, viz. T. boreosulphurescens, T. bryogenum and T. ilkkae are described as new to science, based on morphological, distributional, ecological and molecular data. Several other terminal branches represent putative cryptic taxa nested within classical species or species groups. Molecular type studies and/or designation of sequenced neotypes are needed in these groups, before the taxonomy can be settled. In general our phylogenetic analysis supported previous suprageneric classification systems, but with some substantial changes. Most notably, T. virgatum and allies were found to belong to sect. Tricholoma rather than sect. Atrosquamosa, while T. focale was found to be clearly nested in sect. Genuina rather than in sect. Caligata. In total, ten sections are accepted, with five species remaining unassigned. The combination of morphological and molecular data showed pileus colour, pileipellis structure, presence of clamp connections and spore size to be rather conservative characters within accepted sections, while the presence of a distinct ring, and especially host selection were highly variable within these. [ABSTRACT FROM AUTHOR]

Background: We recently found an inverse association between low-dose aspirin use and risk of Hodgkin lymphoma (HL) in northern Denmark. To strengthen the evidence for this association, we expanded the study base to include all of Denmark.Methods: Between 1997 and 2009, 1659 incident HL cases were identified in nationwide databases and matched with ≤5 population controls on age, sex, and residence. Use of aspirin, selective cyclooxygenase-2 (sCOX-2) inhibitors, and other non-steroidal anti-inflammatory drugs (NSAIDs) from 1995 through 2008 (≥1 year before the index date) was ascertained via the Danish National Prescription Database. Odds ratios (ORs) for associations with HL risk were estimated using conditional logistic regression.Results: Ever use (>2 prescriptions) vs never/rare use (≤2 prescriptions) of low-dose aspirin was not associated with HL risk, but the association with long-term use for ≥7 years vs never/rare use was clearly inverse, although statistically nonsignificantly so (OR=0.65, 95% confidence interval (CI): 0.39-1.09). By contrast, ever use of sCOX-2 inhibitors or other NSAIDs (OR=1.27, 95% CI: 1.10-1.47), especially short-term and low- or medium-intensity use, was associated with elevated HL risk.Conclusion: Our results are consistent with the hypothesis that long-term use of low-dose aspirin, but not other NSAIDs, protects against HL development. [ABSTRACT FROM AUTHOR]

Research has documented that neighborhood disadvantage is associated with increased cardiovascular disease risk, but it is unclear which mechanistic pathways mediate this association across the life course. Leveraging a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998 and using 30 years of follow-up data from population and health registers, we assessed whether and how individual-level poverty, unstable employment, and poor mental health mediate the relation between neighborhood disadvantage and the risk of hypertension, hyperlipidemia, and type 2 diabetes among Danish refugees (N= 40,811). Linear probability models using the discrete time-survival framework showed that neighborhood disadvantage was associated with increased risk of hypertension (0.05 percentage points [pp] per year [95%CI -0.00, 0.10]); hyperlipidemia (0.03 pp per year [95%CI -0.01, 0.07]), and diabetes (0.01 pp per year (95%CI -0.02, 0.03)). The Baron-Kenny product-of-coefficients method for counterfactual mediation analysis indicated that cumulative income mediated 6%-28% of the disadvantage effect on these outcomes. We find limited evidence of mediation by unstable employment and poor mental health. This study informs our theoretical understanding of the pathways linking neighborhood disadvantage with cardiovascular disease risk and identifies income security as a promising point of intervention in future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although copper (Cu 2+ ) is a micronutrient, the metal may be toxic if present in high concentrations in soil ecosystems and subsequently affect various organisms, ranging from microorganisms to earthworms. We performed a microcosm study with an array of Cu 2+ concentrations, with a specific focus on Cercozoa, an important protozoan group in most soil food webs. Research on Cercozoa is still scarce in terms of both diversity and ecology; hence, to explore this group in more depth, we used high-throughput sequencing to detect Cu 2+ induced community changes. Increased levels of Cu 2+ caused a shift in the cercozoan community, and we observed decreased cercozoan relative abundance across the majority of orders, families and genera. Due to their key role in soil food webs, especially as bacterial predators and providers of nutrients to plants, the reduction of cercozoan abundance and diversity may seriously affect soil functionality. Our results indicate that the increase of Cu 2+ concentrations in the soil could potentially have this effect and the consequences need exploration., 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 GmbH.. All rights reserved.)

Neighborhood socioeconomic disadvantage is associated with cardiovascular health, although it is unclear which specific aspects of neighborhoods matter most. We leveraged a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998, creating variation in exposure to various aspects of neighborhood disadvantage. The cohort was followed through December 2018. Exposures included neighborhood-level family income, educational attainment, unemployment, and welfare transfers measured in the first neighborhood after arrival to Denmark. Outcomes included cardiovascular risk factors (hyperlipidemia, hypertension, diabetes and anxiety/depression) and cardiovascular disease (acute myocardial infarction and ischemic heart disease). Neighborhood-level income and education were most consistently associated with cardiovascular risk factors, whereas welfare transfers were most consistently associated with cardiovascular disease. Addressing these specific aspects of neighborhood disadvantage could therefore lower the risk of poor cardiovascular health among refugees. Future research is warranted to examine if results are generalizable to other immigrant groups, countries or time periods., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Refugees are vulnerable to psychiatric disorders because of risk factors linked to migration. Limited evidence exist on the impact of the neighbourhood in which refugee resettle. We examined whether resettling in a socioeconomically disadvantaged neighbourhood increased refugees' risk of psychiatric disorders., Methods: This register-based cohort study included 42,067 adults aged 18 years and older who came to Denmark as refugees during 1986-1998. Resettlement policies in those years assigned refugees in a quasi-random fashion to neighbourhoods across the country. A neighbourhood disadvantage index was constructed using neighbourhood-level data on income, education, unemployment, and welfare receipt. Main outcomes were psychiatric diagnoses and psychiatric medication usage ascertained from nationwide patient and prescription drug registers, with up to 30-year follow-up. Associations of neighbourhood disadvantage with post-migration risk of psychiatric disorders were examined using Cox proportional hazards and linear probability models adjusted for individual, family, and municipality characteristics., Results: The cumulative risk of psychiatric diagnoses and medication was 13.7% and 46.1%, respectively. Refugees' risk of psychiatric diagnoses and psychiatric medication usage was higher among individuals assigned to high-disadvantage compared with low-disadvantage neighbourhoods in analyses including fixed effects for assigned municipality (psychiatric diagnoses: hazard ratio (HR) = 1.14, 95% CI 1.04, 1.25; psychiatric medication: HR = 1.05, 95% CI 1.00, 1.11). Consistent results were found using linear probability models. Results for diagnostic categories and subclasses of medications suggested that the associations were driven by neurotic and stress-related disorders and use of anxiolytic medications., Conclusion: Resettlement in highly disadvantaged neighbourhoods was associated with an increase in refugees' risk of psychiatric disorders, suggesting that targeted placement of newly arrived refugees could benefit refugee mental health. The results contribute quasi-experimental evidence to support links between neighbourhood characteristics and health., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objectives: Neighborhood disadvantage may increase the risk of adverse health outcomes among older refugees. Yet few studies rigorously estimate the effects of place-based factors on later-life health, particularly dementia and mortality. Evidence about refugees is especially sparse., Methods: This study leveraged a natural experiment in the form of a Danish policy (1986-1998) that dispersed refugees quasi-randomly across neighborhoods upon arrival. We used longitudinal registers allowing 30 years of follow-up among refugees aged 40+ years upon arrival in Denmark (N = 9,854). Cox models assessed the association between neighborhood disadvantage and risk of dementia and mortality. We examined heterogeneous effects by sex, age, and family size. We also examined associations among non-refugee immigrants and native-born Danes., Results: Neighborhood disadvantage was not associated with dementia in any group. One unit increase in neighborhood disadvantage index (ranges -8 to 5.7) was associated with greater mortality risk among non-refugee immigrants (HR 1.06, 95%CI: 1.02, 1.10) and native-born Danes (HR 1.11, 95%CI: 1.06, 1.17). In contrast, neighborhood disadvantage was associated with lower mortality risk among refugees (HR 0.96, 95%CI: 0.93, 0.99). Neighborhood disadvantage remained negatively associated with mortality risk in subgroups: refugees who are female (on moderate-disadvantage compared to low-disadvantage), aged 60+, and who arrived with families., Discussion: While neighborhood disadvantage was associated with lower mortality risk among refugees, it was associated with greater mortality risk among non-refugee immigrants and native-born Danes, perhaps due to confounding in the latter groups or different place-based experiences by immigration status. Future research is warranted to explain the reasons for contrasting findings., (© 2022 The Authors.)

Agri-environmental schemes (AES) are used to enhance pollinator diversity on agricultural farms within the UK. Though the impacts of these schemes on archetypal pollinator species such as the bumblebee ( Bombus ) and honeybee ( Apis ) are well-studied, the effects on non-target bee species like solitary bees, in the same environment, are generally lacking. One goal of AES is to alter floral provision and taxonomic composition of plant communities to provide better forage for pollinators, however, this may potentially impact other ecological communities such as fungal diversity associated with plant-bee communities. Fungi are integral in these bee communities as they can impact bee species both beneficially and detrimentally. We test the hypothesis that alteration of the environment through provision of novel plant communities has non-target effects on the fungi associated with solitary bee communities. We analyse fungal diversity and ecological networks formed between fungi and solitary bees present on 15 agricultural farms in the UK using samples from brood cells. The farms were allocated to two categories, low and high management, which differ in the number of agri-environmental measures implemented. Using internal transcribed spacer metabarcoding, we identified 456 fungal taxa that interact with solitary bees. Of these, 202 (approximately 44%) could be assigned to functional groups, the majority being pathotrophic and saprotrophic species. A large proportion was Ascosphaeraceae, a family of bee-specialist fungi. We considered the connectance, nestedness, modularity, nestedness overlap and decreasing fill, linkage density and fungal generality of the farms' bee-fungi ecological networks. We found no difference in the structure of bee-fungi ecological networks between low and high management farms, suggesting floral provision by AES has no significant impact on interactions between these two taxonomic groups. However, bee emergence was lower on the low management farms compared to high management, suggesting some limited non-target effects of AES. This study characterizes the fungal community associated with solitary bees and provides evidence that floral provision through AES does not impact fungal interactions.

Corrigendum of Acta Orthop 2022; 93: 760-766. doi: https://doi.org/10.2340/17453674.2022.4580.

Importance: Refugee children and adolescents are at increased risk of mental health difficulties, but little is known about how the characteristics of the neighborhood in which they resettle may affect vulnerability and resilience., Objective: To test whether neighborhood socioeconomic disadvantage is associated with risk of psychiatric disorders among refugee children and adolescents and examine whether the association differs by sex, age at arrival, and family structure., Design, Setting, and Participants: This quasi-experimental register-based cohort study included refugees in Denmark aged 0 to 16 years at the time of resettlement from 1986 to 1998. A refugee dispersal policy implemented during those years assigned housing to refugee families in neighborhoods with varying degrees of socioeconomic disadvantage in a quasi-random (ie, arbitrary) manner conditional on refugee characteristics observed by placement officers. Cox proportional hazard models were used to examine the association between neighborhood disadvantage and risk of psychiatric disorders, adjusting for relevant baseline covariates., Exposures: A neighborhood disadvantage index combining information on levels of income, education, unemployment, and welfare assistance in the refugees' initial quasi-randomly assigned neighborhood., Main Outcomes and Measures: First-time inpatient or outpatient diagnosis of a psychiatric disorder before age 30 years., Results: Median (IQR) baseline age in the sample of 18 709 refugee children and adolescents was 7.9 (4.7-11.7) years; 8781 participants (46.9%) were female and 9928 (53.1%) were male. During a median (IQR) follow-up period of 16.1 (10.2-20.8) years, 1448 refugees (7.7%) were diagnosed with a psychiatric disorder (incidence rate, 51.2 per 10 000 person-years). An increase of 1 SD in neighborhood disadvantage was associated with an 11% increase in the hazard of a psychiatric disorders (hazard ratio [HR], 1.11; 95% CI, 1.03-1.21). This association did not differ between male and female individuals, refugees who arrived at different ages, or those from single- vs dual-parent households. In secondary analyses using prescribed psychiatric medication as the outcome, a similar association with neighborhood disadvantage was found (HR, 1.08; 95% CI, 1.03-1.14)., Conclusions and Relevance: In this cohort study, neighborhood disadvantage was associated with an increase in risk of psychiatric disorders. The results suggest that placement of refugee families in advantaged neighborhoods and efforts to enhance the neighborhood context in disadvantaged areas may improve mental health among refugee children and adolescents.

Background and Purpose: Surgical site infection (SSI) after hip fracture surgery is a feared condition. We examined the trend in incidence of reoperation due to SSI up to 1 year following hip fracture surgery from 2005 to 2016 and risk factors of SSI by age, sex, comorbidity, type of fracture, and surgery., Patients and Methods: We conducted a population-based, nationwide cohort study using data from the Danish Multidisciplinary Hip Fracture Register (DMHFR). We included 74,771 patients aged 65 and up who underwent surgery from 2005 to 2016 for all types of hip fracture. We calculated net risk of reoperation using Kaplan–Meier method, and, with Cox regression, adjusted hazard ratios (HRs) with a 95% confidence interval (CI) for reoperation due to SSI., Results: Overall, the 1-year net risk of reoperation due to SSI was 1.6%. The HR was higher for patients undergoing total/hemiarthroplasty surgery versus internal fixation (HR = 1.5; 95%CI 1.3–1.8) and lower for patients with per-/subtrochanteric fracture versus femoral neck fracture (HR = 0.6; CI 0.6–0.7). The risk of reoperation due to SSI decreased over time; HR was 0.7 (CI 0.5–0.8) for 2015–2016 compared with 2005–2006. Risk of reoperation decreased with increasing age; the HR was 0.8 (CI 0.7–1.0) in the more than 85-year-olds compared with 65–74-year-old patients. Charlson Comorbidity Index of ≥ 3 was associated with a higher risk of reoperation due to SSI, HR was 1.3 (CI 1.1–1.6)., Interpretation: The net risk of reoperations due to SSI in our study was lower than previously assumed. We identified several risk factors for increased risk of reoperation due to SSI, most noticeably treatment with arthroplasty vs. internal fixation, as well as younger age, high comorbidity burden, and femoral neck fracture diagnosis.

Background: Early-life antibiotic use can alter the intestinal flora and modify the risk of developing Crohn disease (CD), but rigorous epidemiological evidence is limited, with inconsistent results., Methods: We identified all children born in Denmark from 1995 to 2009 and followed them from birth until death, emigration, a diagnosis of CD, or January 1, 2013. Using Cox regression, we assessed the association between antibiotic exposure in the first year of life and subsequent risk for CD, adjusting for sex, degree of urbanization, birth order, birth year, route of delivery, gestational age, smoking during pregnancy, intake of nonsteroidal anti-inflammatory drugs in the first year of life, and family history of CD., Results: During a median 9.5 years (9.3 million total person-years), CD was diagnosed in 208 of 979,039 children. Antibiotic use in the first year of life was associated with a higher risk of CD (adjusted hazard ratio, 1.4; 95% confidence interval [CI], 1.1-1.8), with the highest risk with ≥6 courses of antibiotics (adjusted hazard ratio, 4.1; 95% CI, 2.0-8.5). A family history of CD did not modify these risk associations. The cumulative risk of CD at the 11th birthday for children exposed to antibiotics in their first year of life was 0.16‰ (95% CI, 0.11‰-0.22‰) compared to 0.11‰ (95% CI, 0.08‰-0.15‰) for children unexposed to antibiotics in their first year of life., Conclusions: Antibiotic use in the first year of life is associated with a modestly increased risk for CD, although the absolute risk is very low., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and purpose - Hemiarthroplasty has lower reoperation frequency and better mobilization compared with internal fixation (IF) in patients with undisplaced femoral neck fractures (FNF), which might translate into lower mortality. In this population-based cohort study we compare the risk of mortality and reoperation in undisplaced FNF treated with IF and displaced FNF treated with arthroplasty in patients older than 70 years old. We assume that, per se, there is no difference in mortality risk between patients with a displaced and an undisplaced FNF.Patients and methods - Hip fracture patients were identified in the Danish Multidisciplinary Hip Fracture Registry during 2005-2015. Data on medication, comorbidities, reoperation, and mortality were retrieved from other Danish medical databases. IF and arthroplasty patients were compared with regards to mortality and reoperation up to 5 years postoperatively. We calculated hazard ratios (HR) with 95% confidence intervals (CI) adjusting for relevant confounders.Results - We included 19,260 FNF treated with arthroplasty and 10,337 FNF with IF. There was an increased risk of mortality for arthroplasty within 30 days, HR 1.3 (95% CI 1.3-1.4), compared with IF but not after 1 and 5 years. Arthroplasty patients had adjusted HRs for reoperation of 0.8 (0.8-0.9) within 1 year, 0.8 (0.7-0.9) within 2 years, and 0.8 (0.8-0.9) within 5 years postoperatively compared with IF.Interpretation - Patients treated for a displaced FNF with arthroplasty had a higher risk of 30-day mortality compared with patients who had an undisplaced FNF treated with IF. It has to be considered that there were baseline differences in the groups but there was no difference in mortality risk up to 5 years post-surgery. Concerning reoperation, patients with a displaced FNF treated with arthroplasty had a lower risk of reoperation compared with IF for undisplaced FNF.

Background: Psychological stress is commonly cited as a risk factor for melanoma, but clinical evidence is limited., Objectives: This study aimed to evaluate the association between partner bereavement and (i) first-time melanoma diagnosis and (ii) mortality in patients with melanoma., Methods: We conducted two cohort studies using data from the U.K. Clinical Practice Research Datalink (1997-2017) and Danish nationwide registries (1997-2016). In study 1, we compared the risk of first melanoma diagnosis in bereaved vs. matched nonbereaved people using stratified Cox regression. In study 2 we estimated hazard ratios (HRs) for death from melanoma in bereaved compared with nonbereaved individuals with melanoma using Cox regression. We estimated HRs separately for the U.K. and for Denmark, and then pooled the data to perform a random-effects meta-analysis., Results: In study 1, the pooled adjusted HR for the association between partner bereavement and melanoma diagnosis was 0·88 [95% confidence interval (CI) 0·84-0·92] across the entire follow-up period. In study 2, we observed increased melanoma-specific mortality in people experiencing partner bereavement across the entire follow-up period (HR 1·17, 95% CI 1·06-1·30), with the peak occurring during the first year of follow-up (HR 1·31, 95% CI 1·07-1·60)., Conclusions: We found decreased risk of melanoma diagnosis, but increased mortality associated with partner bereavement. These findings may be partly explained by delayed detection resulting from the loss of a partner who could notice skin changes. Stress may play a role in melanoma progression. Our findings indicate the need for a low threshold for skin examination in individuals whose partners have died. What is already known about this topic? Psychological stress has been proposed as a risk factor for the development and progression of cancer, including melanoma, but evidence is conflicting. Clinical evidence is limited by small sample sizes, potential recall bias associated with self-report, and heterogeneous stress definitions. What does this study add? We found a decreased risk of melanoma diagnosis, but increased mortality associated with partner bereavement. While stress might play a role in the progression of melanoma, an alternative explanation is that bereaved people no longer have a close person to help notice skin changes, leading to delayed melanoma detection. Linked Comment: Talaganis et al. Br J Dermatol 2020; 183:607-608., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Lactate is a robust prognostic marker for the outcome of critically ill patients. Several small studies reported that metformin users have higher lactate levels at ICU admission without a concomitant increase in mortality. However, this has not been investigated in a larger cohort. We aimed to determine whether the association between lactate levels around ICU admission and mortality is different in metformin users compared to metformin nonusers., Methods: This cohort study included patients admitted to ICUs in northern Denmark between January 2010 and August 2017 with any circulating lactate measured around ICU admission, which was defined as 12 h before until 6 h after admission. The association between the mean of the lactate levels measured during this period and 30-day mortality was determined for metformin users and nonusers by modelling restricted cubic splines obtained from a Cox regression model., Results: Of 37,293 included patients, 3183 (9%) used metformin. The median (interquartile range) lactate level was 1.8 (1.2-3.2) in metformin users and 1.6 (1.0-2.7) mmol/L in metformin nonusers. Lactate levels were strongly associated with mortality for both metformin users and nonusers. However, the association of lactate with mortality was different for metformin users, with a lower mortality rate in metformin users than in nonusers when admitted with similar lactate levels. This was observed over the whole range of lactate levels, and consequently, the relation of lactate with mortality was shifted rightwards for metformin users., Conclusion: In this large observational cohort of critically ill patients, early lactate levels were strongly associated with mortality. Irrespective of the degree of hyperlactataemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with metformin nonusers. Therefore, lactate levels around ICU admission should be interpreted according to metformin use.

Purpose: To examine risks of adverse birth outcomes in women exposed to varenicline during pregnancy., Methods: Population-based cohort study including live-born and stillborn infants from 1 May 2007 to 31 December 2012. Data from health and administrative registries in Denmark and Sweden, two Nordic countries with universal health care and routine registration of major life and health events. Infants were allocated to three cohorts on the basis of their in utero exposure: the exposed cohort consisting of infants whose mothers were dispensed varenicline during pregnancy; the unexposed cohort comprised infants unexposed to varenicline, but exposed to maternal smoking in utero; and the reference cohort of infants unexposed to varenicline and maternal smoking in utero. The primary outcome was major congenital malformations diagnosed from birth to the first year of life. Secondary outcomes included stillbirth, fetal growth restriction (measured as small for gestational age), preterm delivery, preterm premature rupture of membranes, and sudden infant death syndrome. We estimated the prevalence of the primary outcome and secondary outcomes in the exposed, unexposed, and reference cohorts. Prevalence odds ratios with 95% confidence intervals (CIs) were computed using logistic regression with propensity score adjustment to control for potential confounders., Results: The combined cohort included 885 185 infants. Of these, 335 infants were exposed, 78 412 were unexposed, and the remaining 806 438 comprised the reference cohort. Major congenital malformations were detected among 3.6% of exposed infants, 4.3% of unexposed infants, and 4.2% of infants in the reference cohort. The propensity score-adjusted prevalence odds ratio for major congenital malformations was 0.80 (95% CI, 0.45-1.42) for exposed vs unexposed infants. All analyses of primary and secondary outcomes comparing exposed with unexposed infants yielded odds ratio estimates below or close to unity. Use of varenicline during pregnancy does not appear to increase the risk of major congenital malformations or other adverse birth outcomes., (© 2019 John Wiley & Sons, Ltd.)

Objective: To investigate the influence of acetylsalicylic acid (ASA) use on risk and outcome of community-acquired Staphylococcus aureus bacteremia (CA-SAB)., Method: We used population-based medical databases to identify all patients diagnosed in northern Denmark with first-time CA-SAB and matched population controls from 2000-2011. Categories for ASA users included current users (new or long-term users), former users, and nonusers. The analyses were adjusted for comorbidities, comedication use, and socioeconomic indicators., Results: We identified 2638 patients with first-time CA-SAB and 26 379 matched population controls. Compared with nonusers, the adjusted odds ratio (aOR) for CA-SAB was 1.00 (95% confidence interval [CI], 0.88-1.13) for current users, 1.00 (95% CI, 0.86-1.16) for former users, 2.04 (95% CI, 1.42-2.94) for new users, and 0.95 (95% CI, 0.84-1.09) for long-term users. Thirty-day cumulative mortality was 28.0% among current users compared with 21.6% among nonusers, yielding an adjusted hazard rate ratio (aHRR) of 1.02 (95% CI, 0.84-1.25). Compared with nonusers, the aHRR was 1.10 (95% CI, 0.87-1.40) for former users, 0.60 (95% CI, 0.29-1.21) for new users, and 1.06 (95% CI, 0.87-1.31) for long-term users. We observed no difference in the risk or outcome of CA-SAB with increasing ASA dose or by presence of diseases commonly treated with ASA., Conclusions: Use of ASA did not seem to influence the risk or outcome of CA-SAB. The apparent increased risk among new users may relate to residual confounding from the circumstances underlying ASA treatment initiation. Our finding of no association remained robust with increasing ASA dose and across multiple patient subsets., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To investigate the risk of incisional hernia repair (IHR) and paracolostomy hernia repair (PHR) following open and laparoscopic rectal cancer resection with curative intent., Background: Laparoscopic rectal cancer resection has been implemented to varying degrees around the world. IHR and PHR following open and laparoscopic rectal cancer resection have only been sparingly evaluated., Methods: Patients who underwent rectal cancer resection were identified in the Danish Colorectal Cancer Group's database. To identify IHR and PHR following rectal cancer resection, we linked data to the Danish Ventral Hernia Database. The absolute risk of IHR and PHR was estimated as cumulative incidence proportions, treating death as competing risk. We used Cox proportional hazard regression analysis with multivariable adjustment to compute hazard ratios (HRs) comparing open and laparoscopic approach., Results: The 5-year risk of IHR was 4.1% among patients undergoing open resection (n = 3090) and 3.2% among those undergoing laparoscopic resection (n = 3099), corresponding to a risk difference of 0.9% (95% CI 0.0-2.0, P = 0.057). Laparoscopic rectal resection was not associated with lower risk of IHR (adjusted HR 0.94, 95% CI 0.67-1.31, P = 0.709). A total of 2577 patients had a colostomy at rectal cancer resection and the 5-year risk of PHR was 2.1% after open surgery compared with 6.7% after laparoscopic surgery, corresponding to a risk difference of -4.6% (95% CI -6.4 to -2.7, P < 0.001). Laparoscopic surgery was associated with increased risk of PHR (adjusted HR 2.56, 95% CI 1.53-4.29, P < 0.001)., Conclusion: We observed no association between surgical approach of rectal cancer resection and subsequent IHR. Laparoscopic surgery was associated with increased risk of PHR.