Danish National Research Foundation Research Articles

Association between early life exposure to agriculture, biodiversity, and green space and risk of inflammatory bowel disease: a population-based cohort study

Specific pollutants and environmental exposures are implicated in modulating inflammatory bowel disease (IBD) risk. However, the role of environmental exposures, particularly during the early life period, towards IBD risk, has not been systematically evaluated. We conducted a nationwide population-based cohort study during the study period extending from January 1, 1995, to September 1, 2020, using cross-linked Danish registers, maps, and inventories to ascertain the impact of agricultural land use, biodiversity, green space, urban space, blue space, and normalized difference vegetation index during pregnancy and the first two years of life on IBD, Crohn's disease (CD), and ulcerative colitis (UC) risk, using adjusted Cox proportional hazards regression analyses. We adjusted for covariates sex, maternal age at delivery, calendar year of birth, municipal-level socioeconomic status, and first-degree relative with IBD. Of 1,438,487 individuals included in the study who were followed from age 2 years until a median (IQR) age of 14 (8-20) years, 3768 individuals were diagnosed with IBD. Exposure to the second, third and highest quartiles of agriculture land use during early life, relative to the lowest quartile, were associated with increased CD risk (aHR 1.12, 95% CI 1.01, 1.26, 1.19, 95% CI 1.05, 1.34 and, 1.24 95% CI 1.06, 1.46, respectively). There was no association of agriculture land use with UC risk. Conversely, exposure to the third quartile of biodiversity in early life, compared to the lowest quartile, were associated with a lower CD risk (aHR 0.86, 95% CI 0.75, 0.98). A protective effect of greenspace was noted in the highest quartile for CD (aHR 0.87, 95% CI 0.78, 0.98). In a nationwide cohort with long-term follow up data, early life environmental exposures were associated with modulation of CD risk, with a harmful effect of agriculture land use and protective effect of biodiversity and green space. Danish National Research Foundation, the International Organization for the Study of Inflammatory Bowel Disease, the National Institute of Diabetes and Digestive and Kidney Diseases.

Surface Curvature Effect on Dual-Atom Site Electrocatalysis

Oxygen, nitrogen, and carbon electrocatalysis are central in power-to-x innovations. Overpotentials of underlying processes are defined by the scaling relations between the adsorption energies of intermediates and, in turn, determine their efficiency. Our research explores the possibility of switching and tuning the scaling relations by applying metal-nitrogen-carbon (M-N-C) catalysts.In this presentation, we introduce dual-atom site models and demonstrate the effect of surface curvature on oxygen and nitrogen electrocatalysis. Our Density Functional Theory (DFT) calculations show how curving the surface switches the scaling and significantly lowers overpotentials. For instance, we predict a bifunctional overpotential as low as 0.45 V, markedly lower than the theoretical limit of 0.74 V given by the OOH–OH scaling. [1]Our study is among the first to investigate the surface curvature effect beyond the common scaling limitations. It will inspire the community to explore further this effect on oxygen electrocatalysis at M-N-C catalysts, as well as other challenging reactions and similarly curved materials. Funding V.I. and J.R. acknowledge the Danish National Research Foundation Centers of Excellence, The Center for High Entropy Alloys Catalysis (Project DNRF149), and the Independent Research Fund Denmark, grant no. 0217-00014B. V.I. receives funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska–Curie grant agreement no. 101031656. This research was also supported by the Estonian Research Council grant PSG250 and the EU through the European Regional Development Fund (TK141).

Non-Bayesian Statistical Discrimination

Models of statistical discrimination typically assume that employers make rational inference from (education) signals. However, there is a large amount of evidence showing that most people do not update their beliefs rationally. We use a model and two experiments to show that employers who are conservative, in the sense of signal neglect, discriminate more against disadvantaged groups than Bayesian employers. We find that such non-Bayesian statistical discrimination deters high-ability workers from disadvantaged groups from pursuing education, further exacerbating initial group inequalities. Excess discrimination caused by employer conservatism is especially important when signals are very informative. Out of the overall hiring gap in our data, around 40% can be attributed to Bayesian statistical discrimination, a further 40% is due to non-Bayesian statistical discrimination, and the remaining 20% is unexplained or potentially taste-based. This paper was accepted by Marie Claire Villeval, behavioral economics and decision analysis. Funding: F. Mengel thanks the European Research Council for financial support [Starting Grant 805017]. P. Campos-Mercade acknowledges funding from the Danish National Research Foundation [Grant DNRF134 (CEBI)]. Supplemental Material: The online appendix and data are available at https://doi.org/10.1287/mnsc.2023.4824 .

Longitudinal trajectories of anxiety, depression, and bipolar disorder in inflammatory bowel disease: a population-based cohort study.

Inflammatory bowel disease (IBD) is associated with psychiatric diseases, but it is unclear to what degree patients with IBD are affected over their lifetime. We aimed to longitudinally investigate the risk of anxiety, depression, and bipolar disorder before and after IBD diagnosis to understand the full burden of these diseases in patients with IBD. In this population based cohort study, we identified 22,103 patients diagnosed with IBD between January 1, 2003 and December 31, 2013 in the Danish National registers and 110,515 matched reference individuals from the general population. We calculated yearly prevalence of hospital contacts for anxiety, depression, and bipolar disorder and dispensed prescriptions for antidepressants from five years before to ten years after IBD diagnosis. We used logistic regression to calculate prevalence odds ratios (OR) for each outcome prior to IBD diagnosis, and Cox regression to calculate hazard ratios (HR) of new outcomes after IBD diagnosis. During >150,000 person years follow-up, patients with IBD had higher risk of anxiety (OR 1.4; 95% confidence interval (CI) 1.2-1.7) and depression (OR 1.4; 95% CI 1.3-1.6) starting at least five years before and continuing until at least ten years after IBD diagnosis (HR 1.3; 95% CI 1.1-1.5 for anxiety and HR 1.5; 95% CI 1.4-1.7 for depression). The risk was particularly high around IBD diagnosis and in patients diagnosed with IBD after the age of 40 years. We found no association between IBD and bipolar disorder. This population-based study suggests that anxiety and depression are clinically significant comorbidities of IBD both before and after IBD diagnosis, which warrant thorough evaluation and management, particularly around the time of IBD diagnosis. The Danish National Research Foundation [DNRF148], the Lundbeck Foundation [R313-2019-857], and Aage og Johanne Louis-Hansens Fond [9688-3374 TJS].

Methodology considerations for 'Safety and effectiveness of cannabinoids to Danish patients with treatment-refractory chronic pain' by Horsted et al.

The recently published exploratory, non-controlled, study by Horsted et al. (2023) reports on the potential safety and pain-relieving effects of cannabinoids (THC, CBD), or mixed in a non-randomized order. The authors conclude that ‘oral cannabinoid therapy in general appears to be safe and effective for relief of chronic pain in some patients, including a subset of patients with cancer-related pain (9%), not responding adequately to conventional treatment regimens or experiencing intolerable adverse events’. The author's conclusion is in direct contrast to the conclusion and recommendations from the International Associations for the Study of Pain (IASP) Cannabis Task Force. Based on a thorough evaluation of current evidence, Rice et al. (2021) concluded ‘That the available clinical evidence neither supports nor refutes claims of analgesic efficacy or safety for cannabinoids, cannabis, or cannabis-based medicines’ and suggested future studies and recommendations should follow rigid rules of conclusive randomized, placebo-controlled randomized controlled trials (RCTs) to provide evidence (Haroutounian et al., 2021). The study by Horsted et al. is a retrospective study and hence is not monitored by the Danish medical agency and executed as a good clinical practice (GCP) study although investigating the effect of a new treatment modality. Furthermore, the study was not registered at ClinicalTrials.gov as this is not normally mandatory for retrospective studies submitted to the European Journal of Pain. Many RCTs have been published demonstrating no effect of cannabinoids on clinical pain or potential underlying pain mechanisms when compared to placebo (e.g. Zubcevic et al., 2022). None of such studies and only one of the 14 IASP statement's current state-of-the-art papers are referenced in the manuscript by Horsted et al. and hence not discussed in the light of the current best evidence. The study found an average decrease in clinical pain intensity of 1.8 (baseline pain approx. 7 on a 0–10 numerical rating scale), which corresponds to an effect of approx. 25%. This is in the low end of placebo effects reported in previous high-quality pain studies and what is reported in other well-controlled placebo-controlled pain studies (McQuay et al., 1996). The expectancy and placebo effects are largely (and often exclusively) found responsible for the therapeutic effects of non-pharmacological treatments such as, e.g. cannabis. The Horsted et al. study was conducted in Denmark and here cannabis has attracted much attention in the media. The positive media promotion of cannabis products will increase the placebo effects and as the study was conducted without any control or placebo groups the effect size and the placebo responses can obviously not be separated. Most recent meta-analysis likewise concluded that ‘placebo responses contribute significantly to pain reduction in cannabinoid clinical trials’ and ‘the unusually high media attention surrounding cannabinoid trials, with positive reports irrespective of scientific results, may uphold high expectations and shape placebo responses in future’. The authors state that ‘with the relatively long follow-up it is likely that the placebo effect is of less importance’. This is not empirically validated as studies have shown long-lasting (up to 5 years) placebo effects in trials. The Horsted et al. study enrolled 826 patients, yet only 214 patients were follow-up for the last visit, 243 patients were registered as ‘lost to follow-up’ and an additional 122 patients were discontinued. In addition, among the included patients, data of interest were missing (e.g. 39 (18%) of the 214 included patients with the last visit recorded had missing values regarding pain intensity measured as numeric rating scale). Only 25.9% (214/826) of the included eligible patients were included in the analysis. All these excluded patients are likely to not benefit from the study drug (no effect or severe side effects), which is not addressed in details. Thus, the excluded patients (constituting +40% of the original sample) are a likely source of a major selection bias, compromising the study's validity and conclusions. The authors do refer to the supplementary material for a description of the excluded patients, but this material is not presented in a way that allows for further analyses. The exploratory nature of this non-placebo controlled cannabis study does not provide new evidence for the use of cannabinoids for the treatment of pain. The pain alleviation reported is at its best similar to placebo responses reported in multiple randomized pain cannabis trials. The concerningly high number of patients excluded from the analysis further compromises the integrity and validity of the study. Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121). The Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA) is funded by the Novo Nordisk Foundation (NNF21OC0065373). The authors declare no conflict of interest.

Between Concealment and Disclosure: Approaches to the History of Privacy in Knowledge-Making

Between Concealment and Disclosure: Approaches to the History of Privacy in Knowledge-Making

The association between mental disorders and subsequent years of working life: a Danish population-based cohort study

Mental disorders can affect workforce participation via a range of mechanisms. In this study, we aimed to estimate the association between different types of mental disorders and working years lost, defined as the number of years not actively working or enrolled in an educational programme. In this population-based cohort study, we included all people aged 18-65 years (mean 38·0 [SD 13·9]) in the Danish Civil Registration System from Jan 1, 1995 to Dec 31, 2016. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and information on labour market characteristics was obtained from administrative registers. Follow-up started at age 18 years, immigration to Denmark, or on Jan 1, 1995, whichever came later; and it ended at age 65 years, death, emigration from Denmark, disability pension, voluntary early retirement, or Dec 31, 2016 (whichever came earlier). As the main outcome, we estimated working years lost for those diagnosed with any mental disorder and 24 types of mental disorders, as well as for the general population of same age and sex. We decomposed total working years lost into periods of unemployment or sick leave, disability pension, voluntary early retirement, or death. Data on ethnicity were not available through administrative registers. A total of 5 163 321 individuals, 2 642 383 men and 2 520 938 women, were followed up for 65·4 million person-years. Overall, 488 775 (9·47%) individuals were diagnosed with a mental disorder. On average, individuals with mental disorders lost an additional 10·52 (95% CI 10·48-10·57) years of working life compared with the general Danish population. Receiving a disability pension (7·54 [7·49-7·59] years) and longer periods of unemployment (2·24 [2·21-2·27] years) accounted for most of this difference. Our findings foreground the substantial impact of mental disorders on workforce participation. There is a need to invest in programmes that reduce the burden of working years lost and assist people with mental disorders in returning to the workforce. Lundbeck Foundation and Danish National Research Foundation.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

SummaryBackgroundEarly 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%.MethodsSingle-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355.FindingsBetween August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92–2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45–1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29–2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44–15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20–68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028].InterpretationThe main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further.Funding10.13039/501100000781ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

Study Calculates Disability Caused by Schizophrenia

Back to table of contents Previous article Next article Clinical & ResearchFull AccessStudy Calculates Disability Caused by SchizophreniaNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:23 Aug 2021https://doi.org/10.1176/appi.pn.2021.9.31AbstractAn analysis using Danish registry data finds that though major depression was the most prevalent mental disorder in Denmark, schizophrenia was the leading cause of disability due to mental illness for both men and women, accounting for 273 years living with disability per 100,000 person-years.Making use of the abundant medical data available in Danish national health registries, researchers have developed new estimates on the amount of disability associated with different mental health and substance use disorders.When factoring in both the duration of illness and severity of disability, John McGrath, M.D., Ph.D., the Niels Bohr Professor at the National Centre for Register-based Research at Aarhus University in Denmark, and colleagues found schizophrenia to be the most burdensome mental illness at both an individual and population level. Personality disorders were second most disabling in both sexes, followed by anxiety disorder in women and alcohol use disorder in men. These findings were published in The Lancet Psychiatry.While previous studies have examined how mental and substance use disorders contribute to years lived with disability (YLD), these studies have largely relied on average incidence, remission, and prevalence rates in the population. McGrath’s team, together with researchers from Queensland Centre for Mental Health Research in Brisbane, Australia, instead relied on individual data from medical registries to calculate YLD. Such data included when people were diagnosed, how severe their symptoms were, and if/when they achieved remission.Using data from the Danish Psychiatric Central Research Register, McGrath and colleagues calculated the YLD for 18 mental health and substance use disorders. The YLD is calculated by multiplying the duration of an illness with a predefined disability index ranging from 0 to 1. (For example, the disability index of major depression is 0.15 for mild symptoms, 0.40 for moderate symptoms, and 0.66 for severe symptoms.)Though major depression was the most prevalent disorder in Denmark, schizophrenia was the leading cause of disability due to mental illness for both men and women, accounting for 273 YLDs per 100,000 person-years. Personality disorders were the secondmost disabling, followed by anxiety disorders.In contrast, most substance use disorders (with the exception of alcohol) contributed relatively little YLDs in the population. McGrath said these data should not imply that substance use is a minor societal concern in Denmark. “Our study focused on disability; if we had also looked at mortality, then substance use disorders would be near the top,” McGrath said. “Whether it’s overdoses, traffic accidents, or liver disease, alcohol and drugs are huge when it comes to years of life lost.”To gain more insight into disability at an individual level, McGrath and colleagues devised a metric called the Health Loss Proportion (HeLP) to quantify the disability associated with all mental comorbidities experienced by a person. On the individual level, schizophrenia was still the most disabling, as the researchers calculated the average person with schizophrenia loses 73% of his or her healthy life per year. Opioid use disorder (OUD) was second, resulting in a 67% loss of healthy life each year. (OUD is rare in Denmark, which is why it was not one of the top disorders for YLD at the population level.)For patients with schizophrenia and a comorbid disorder, the schizophrenia itself was the primary contributor of the disability, as was the case for patients with comorbid conduct disorder and autism spectrum disorder. But among other disorders, notably various substance use disorders, disability was heavily influenced by comorbid conditions the patients had.“These HeLP data reveal the subtle nuances in how different mental health disorders affect a person’s quality of life,” McGrath told Psychiatric News. “These HeLP metrics provide compelling evidence that we need mental health services that are better equipped as one-stop shots for a range of problems.”This study was supported by the Danish National Research Foundation. ■“Register-based Metrics of Years Lived With Disability Associated With Mental and Substance Use Disorders: A Register-Based Cohort Study in Denmark” is posted here. ISSUES NewArchived

(Invited) Resonator and SERS Sensing in the Field of Drug Delivery

Introduction Our research center of excellence IDUN combines research in nanosensors/centrifugal microfluidics and microfabricated devices for oral drug delivery. This allows us to explore the synergy between sensor development and search for new pharmaceutical delivery tools and materials. Our developed nanosensors get access to unique polymers and biomolecules and are able to characterize, among others, small volumes of materials and molecules, which are today not possible to analyze by any standard technologies. We will show examples of recent findings and results within drug/polymer characterization (1) and process monitoring (2) using nanomechanical sensors. Also, new applications within therapeutic drug monitoring using Surface Enhanced Raman Scattering (SERS) will be presented as well as sensor integration with centrifugal microfluidics platforms. Resonators By monitoring the resonance frequency shift of micrometer sized strings or cantilevers coated with thin layers of polymers, it is possible to monitor phase transitions using only ng of material. We have been able to observe beta relaxation of polymers (3) and drugs (2), see figure 1. These systems also allowed us to monitor degradation of biomaterials used in the fabrication of the microcontainers (4). Also, strings are inherently sensitive to temperature changes (5). The resonant frequency detunes as a function of temperature and temperature changes down to 10-5 °C can be detected. The effect has been used to perform photothermal IR spectra on samples deposited on resonating strings and resonating filters. This has been used to for example study the amorphous and crystalline forms of indomethacin (1). As an alternative to cleanroom fabricated resonators we have used single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom processing. This method additionally makes it possible to study the behavior of single crystals, which would otherwise be extremely difficult/impossible. This method has, among others, allowed us to study new phenomena in the hydration/dehydration of drugs (6). Centrifugal microfluidics The optics and mechanics from a DVD player can be used to realize compact and sensitive sensor systems. By rotating a polymer disc with integrated microfluidic channels it is possible to manipulate liquid samples such as blood – performing crucial operations like separation, valving and mixing. We integrate sensor elements such as cantilevers, nanoparticles, resonating strings and SERS substrates with centrifugal microfluidics (7). The sensors are read out by a DVD pick-up head, which can perform transmission/absorption measurements and can detect nm deflections. Also, electrodes and spectrometers are integrated on a disc platform, facilitating electrochemical/Raman measurements. Our nanopillar SERS substrate can be used for sample filtration and separation. Here the nanopillars function similarly to a filter paper in chromatography and can be used to distinguish e.g. different components in a urine sample as well as drug residuals. A SERS chip is placed in a centrifugal microfluidics platform, whereby the sample can be initially centrifuged. Subsequently half the SERS chip is exposed to the centrifuged liquid. Hereby, liquid can travel up the chip by the so-called wicking effect, and depending on affinity of molecules to the surface, different molecules will travel different lengths. Hereby, a separation is secured and the different molecules are read-out as bands on the SERS chip. Acknowledgements This research has received funding from the ERC grant agreement n° 320535 and from the Center of Excellence ’IDUN’ granted by Danish National Research Foundation, DNRF122/the Velux Foundations.

C * -simplicity of HNN extensions and groups acting on trees

The first author is supported by a PhD stipend from the Danish National Research Foundation (DNRF) through the Centre for Symmetry and Deformation at University of Copenhagen.

Measles Vaccination in the Presence of Maternal Measles Antibody Reduces All-Cause Child Mortality - A Planned Cohort Study Nested in a Randomised Trial

Background: Several smaller studies suggested that measles vaccination (MV) in the presence of maternal measles antibody (MatAb) reduces all-cause mortality. We tested the hypothesis that children receiving early MV at 4 months in the presence of MatAb would have 35% lower mortality than children receiving MV at 4 months with no detectable MatAb. We further hypothesised that among children, who did not receive early MV, there would be no difference in mortality between those with and without MatAb. Methods: The study was an observational study nested within a randomised controlled trial (RCT) of early MV, carried out in Guinea-Bissau from 2011-2019. The RCT compared the mortality between 4 and 60 months of age for children randomised 2:1 to two doses of MV at 4 and 9 months of age or to only one dose of MV at 9 months of age. At enrolment in the RCT, a blood sample was collected from all children. A multiplex immunoassay was used to determine the measles MatAb level; as control exposures, levels of varicella, mumps and rubella antibody were assessed. We assessed overall mortality as a function of randomisation group and presence of MatAb in Cox proportional hazards models. Results: 6,598 children were enrolled in the RCT, 6,239 (95%) had a valid enrolment blood sample. In children receiving early MV at enrolment, mortality was 50% (95% CI: 20-68%) lower for those vaccinated in the presence of MatAb (n=3132; 51 died) compared with those vaccinated in the presence of no MatAb (n=1028, 31 died). There was no beneficial effect of having MatAb in children who did not receive early MV (test of interaction, p=0.045). The result was specific for measles antibody; no effect was found for varicella, mumps or rubella antibodies. In a meta-analysis of five available studies, MV in the presence of MatAb was consistently associated with lower mortality compared with MV in the absence of MatAb, the combined meta-estimate indicating 55% (35-68%) lower mortality. Interpretation: The results support the previous findings that MV in the presence of maternal antibody enhances the beneficial effects of MV on child survival. Earlier measles vaccination should be considered. Further research is needed to examine whether it is beneficial to vaccinate women of fertile age to transfer higher level of maternal antibodies to their children. Trial Registration (for the RCT): NCT01486355 Funding: The RCT was funded by an ERC Starting Grant to Christine S Benn (ERC-2009-StG-243149) and by a “Center of Excellence” grant from the Danish National Research Foundation (DNRF108). The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). The funding agencies had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. Declaration of Interests: Authors declare no competing interests. Ethics Approval Statement: The protocol was approved by the National Ethical Committee in Guinea-Bissau and given consultative approval by the Danish Central Ethical Committee

Register-based metrics of years lived with disability associated with mental and substance use disorders: a register-based cohort study in Denmark

Mental disorders account for a substantial proportion of the years lived with disability (YLDs) globally. These estimates have generally been calculated top down based on summary statistics. The aim for this study was to calculate YLDs and a novel related measure, Health Loss Proportion (HeLP), for 18 mental and substance use disorders, based on person-level register data (bottom up). A cohort of 6 989 627 Danish residents (5·9% had a diagnosis of a mental or substance use disorder registered in the Danish Psychiatric Central Research Register) was investigated. YLDs (the duration of disease multiplied by a disability weight) were calculated for the disorder of interest and for comorbid mental and substance use disorders. HeLPs were estimated as YLDs associated with an index disorder and comorbid mental and substance use disorders divided by person-years at risk in persons with the index disorder. All analyses were adjusted for mental and substance use comorbidity using a multiplicative model of disability weights. Major depressive disorder was the most prevalent disorder, although schizophrenia was the leading cause of YLDs in both sexes combined (YLDs 273·3 [95 % CI 232·3-313·6] per 100 000 person-years). People diagnosed with schizophrenia lost the equivalent of 73% (63-83%) of healthy life per year due to mental and substance use disorders, the largest HeLP of all mental and substance use disorders. Comorbidity of mental and substance use disorders accounted for 69-83% of HeLPs in people with either cannabis use disorders, other drug use disorder and ADHD. By contrast, comorbidity explained 11-23% of the HeLPs in people with autism spectrum disorders, conduct disorder, and schizophrenia. Substantial variation in disability was observed across age, sex, and disorders. The new HeLP metric provides novel details of the contribution of comorbidity to the disability associated with mental and substance use disorders. The Danish National Research Foundation, Queensland Government Department of Health, European Union's Horizon 2020, Lundbeck Foundation, Stanley Medical Research Institute. For the Danish translation of the abstract see Supplementary Materials section.

Stopping Oral Polio Vaccine (OPV) after Defeating Poliomyelitis: A Pyrrhic Victory? Systematic Review of the Non-Specific Effects of OPV

Background: Previous studies revealed that the two live vaccines, BCG and measles vaccine (MV), have beneficial non-specific effects (NSEs) reducing morbidity and mortality more than could be explained by prevention of tuberculosis and measles infection. Since live oral polio vaccine (OPV) is stopped and replaced with inactivated polio vaccine (IPV) in high-income countries and will be stopped globally after polio eradication, we undertook a review of potential NSEs of OPV on mortality. Methods: We searched PubMed for all studies of OPV and death/mortality. In low-income settings, OPV has been provided in three different settings: First, as co-administration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine in three doses from 6 weeks of age. Second, as an early dose at birth (OPV0), often administered together with BCG. Third, in OPV campaigns to eradicate polio infection. We calculated relative risk (RR) of mortality for different combinations of vaccinations and RR of the mortality rate before and after OPV campaigns. Results: The majority of studies was from Guinea-Bissau. First, in three natural experiments, where DTP was missing, OPV-only compared with DTP+OPV co-administered was associated with 3-fold lower mortality rate in two community studies (RR=0.33 (0.14-0.77)) and in a hospital case fatality study (RR=0.29 (0.11-0.77)). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than co-administration of DTP+OPV (RR=3.23 (1.27-8.21)). Second, in two randomised controlled trials (RCTs), OPV0 vs. no OPV0 was associated with 32% lower infant mortality. The beneficial effects of OPV0 were stronger the earlier the vaccine had been given. Third, in six population-based studies from urban and rural Guinea-Bissau, Burkina Faso and Bangladesh, the mortality rate was lower with a RR=0.75 (0.69-0.82) after OPV campaigns than before OPV campaigns. Furthermore, OPV campaigns changed the mortality effect of health interventions in nine RCTs. The intervention had the strongest beneficial effect before OPV campaigns in all RCTs; hence, OPV campaigns reduced the mortality rate and the difference between randomisation groups disappeared. Interpretation: There have been no polio cases in Guinea-Bissau in this century and no confounding factors or bias would be able to explain these patterns. The only interpretation consistent with all data is that OPV has beneficial NSEs, reducing child mortality. Child mortality may increase again once OPV is removed or replaced with IPV. If no counter-measures are taken, eradicating polio and stopping OPV may become a Pyrrhic victory. Funding: The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3- 2011-261375). CSB held a starting grant from the ERC (ERC-2009-StG-243149). CVIVA was supported by a grant from the Danish National Research Foundation (DNRF108). PA held a research professorship grant from the Novo Nordisk Foundation. Declaration of Interest: Nothing to declare.

The Risk of Rheumatoid Arthritis, Psoriasis, and Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease Exposed to Anti-TNF: A Nationwide Danish Cohort Study

Background: Anti-TNF medications are effective therapies for rheumatoid arthritis (RA), psoriasis, hidradenitis suppurativa, and inflammatory bowel diseases, however, case reports have identified the occurrence of these diseases following initiation of anti-TNF therapy. We assessed the risk of RA, psoriasis, and hidradenitis suppurativa associated with anti-TNF therapies in patients with inflammatory bowel disease. Methods: A performed a nationwide Danish population-based cohort study, 2005-2018, to assess the effect of anti-TNF therapy on first occurrence of RA, psoriasis, or hidradenitis suppurativa (as a combined outcome and separately). Propensity scores were estimated based on covariates including comorbidities and co-medications, and anti-TNF exposed and unexposed patients were matched on propensity scores. We also compared the risk of RA, psoriasis, and hidradenitis suppurativa associated with anti-TNF monotherapy vs. azathioprine monotherapy. Findings: Our cohort included 9,036 anti-TNF exposed patients and 9,036 unexposed patients. The median age of anti-TNF exposed patients was 36 years (Q1-Q3: 26-48), 53% were female, and 50% had Crohn’s disease, while for unexposed patients the corresponding figures were 38 years (Q1-Q3: 28-51), 53%, and 48%. Anti-TNF therapy was associated with a significantly increased risk of the combined outcome (HR 1∙37, 95% CI 1∙12-1∙68), and with numerically increased HRs for RA (HR, 1∙60; 95% CI 0∙78-3∙31), psoriasis (HR, 1∙32; 95% CI 1∙05-1∙66), and hidradenitis suppurativa (HR, 1∙64; 95% CI 0∙86-3∙12). When compared to azathioprine monotherapy, anti-TNF monotherapy was also associated with a significantly increased risk of the combined outcome (HR 2∙42, 95% CI 1∙27-4∙62), with a 5-fold increased risk of RA (HR 5∙10, 95% CI 1∙03-25∙28). Interpretation: In this nationwide population-based cohort, anti-TNF therapy was, paradoxically, associated with an increased risk of RA, psoriasis, and hidradenitis suppurativa. These data are unexpected and warrant further investigation. Funding Information: This study was financially supported by the Danish National Research Foundation, grant no. DNRF148. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Ethics approval is not required for register based epidemiological research in Denmark.

Measles in the European Past: Outbreak of Severe Measles in an Isolated German Village, 1861

Background: In 1861, Hagelloch, an isolated village in Germany, experienced a measles epidemic, which affected nearly all children under 14 years of age. We examined determinants of severe measles. Methods: A contemporary medical thesis by Albert Pfeilsticker had sufficient information on timing of measles cases within all households in the village to make it possible to determine who were index cases, infected outside the household, and who were secondary cases, infected after exposure in the household. Results: The measles case fatality ratio (CFR) was 6.4% (12/187); 10.0% (7/70) for children under five years of age. The youngest class in the local school was the epicentre of the epidemic; all children aged 7-9 years contracted measles at school and became index cases in their own families. The frequency of secondary cases was higher among younger and older children. Overall 44% (82/187) of the children were secondary cases. Secondary cases tended to have higher CFR than index cases (RR=3.03 (95% confidence interval: 0.91-10.07)), whereas there was less difference in the risk of complications (RR=1.34 (0.78-2.28)). The CFR was higher for boys than girls (4.46 (1.03-19.22)), and boys were more likely to suffer severe complications than girls (RR=1.73 (0.97-3.08)). Boys who were infected by a girl had higher CFR than boys infected by other boys (RR=6.30 (1.18-85.64)). Children under five years of age, who survived measles infection, did not have higher mortality in 1862; the 11 children who had not had measles in 1861 had a RR of dying in 1862 of 4.17 (1.22-14.28) compared with those who had measles in 1861. Conclusion: When measles was severe in Europe, the determinants of fatal infection were similar to those observed more recently in low-income countries. Changes in intensity of exposure within the home, due to smaller family size, better housing, and more public childcare, may have been major causes of the mortality decline in the industrialized countries during the 19th and the early 20th centuries. Funding: PA has received support from the Danish Council for Development Research, the Danish Medical Research Council, the Danish National Research Foundation and the Novo Nordisk Foundation. Declaration of Interest: None to declare.

BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.

BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation.

Circadian rhythm influences induction of trained immunity by BCG vaccination

BACKGROUNDThe antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.METHODSEighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG.RESULTSCompared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes.CONCLUSIONSBCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.FUNDINGThe Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation.

A distinctive epigenetic ageing profile in human granulosa cells.

Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7years) compared to chronological age (average: 33.9years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4years) and leukocytes (average: 38.8years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P= 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P= 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n= 335) and in leukocytes (n= 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P= 3.96 × 10-08) and gene expression (152 genes, P= 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. N/A. No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.

The contagious nature of a vaccine scare: How the introduction of HPV vaccination lifted and eroded MMR vaccination in Denmark

BackgroundHuman papillomavirus (HPV) vaccine coverage was high in Denmark until it plunged following negative media coverage. We examined whether the decline in HPV vaccination undermined uptake of another adolescent vaccine, measles, mumps and rubella (MMR). MethodsThe Danish national health register provided data on uptake of MMR vaccine dose 2 (at age 13) for children born from 1991 to 2003 (n = 827,716). The primary exposure variable comprised three time periods: before HPV vaccine introduction, during high HPV vaccine coverage, and after the drop in HPV vaccine coverage. To examine the effect of HPV vaccination on MMR2 uptake, we estimated MMR2 uptake by age 13 using logistic regression, controlling for gender, birth month, birth year, and maternal education. FindingsMMR2 vaccination coverage was high for both girls and boys (86% and 85%) in 2009. Following the introduction of HPV vaccine for girls in 2009, MMR2 coverage increased for girls even as it decreased for boys (gender gap 4·6 percentage points, 95% CI 4·3 to 4·8). Coverage with MMR2 for girls continued to be high over the following four years, and almost all girls (91%) who received MMR2 vaccination also received HPV1 vaccination within the same week. When negative media coverage led to a decline in HPV vaccination, MMR2 uptake for girls also declined. By 2015, MMR2 coverage for girls and boys had become similar again (80% and 79%). Families with the highest level of maternal education showed the strongest decline in MMR2 coverage for girls. InterpretationConcomitant vaccine provision can increase overall vaccine uptake. However, reduced demand for one vaccine may reduce concomitant vaccination and undermine resiliency of a country’s vaccination program. FundingDrs. Gørtz and Ejrnæs appreciate generous funding from the Novo Nordisk Foundation (grant no. NNF17OC0026542) and from the Danish National Research Foundation through its grant (DNRF-134) to the Center for Economic Behavior and Inequality (CEBI) at the University of Copenhagen.