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Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications. Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio-and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Objectives To evaluate the ability of an artificial intelligence (AI) model to predict the risk of cancer in patients referred from primary care based on routine blood tests. Results obtained with the AI model are compared to results based on logistic regression (LR). Methods An analytical profile consisting of 25 predefined routine laboratory blood tests was introduced to general practitioners (GPs) to be used for patients with non-specific symptoms, as an additional tool to identify individuals at increased risk of cancer. Consecutive analytical profiles ordered by GPs from November 29th 2011 until March 1st 2020 were included. AI and LR analysis were performed on data from 6,592 analytical profiles for their ability to detect cancer. Cohort I for model development included 5,224 analytical profiles ordered by GP’s from November 29th 2011 until the December 31st 2018, while 1,368 analytical profiles included from January 1st 2019 until March 1st 2020 constituted the “out of time” validation test Cohort II. The main outcome measure was a cancer diagnosis within 90 days. Results The AI model based on routine laboratory blood tests can provide an easy-to use risk score to predict cancer within 90 days. Results obtained with the AI model were comparable to results from the LR model. In the internal validation Cohort IB, the AI model provided slightly better results than the LR analysis both in terms of the area under the receiver operating characteristics curve (AUC) and PPV, sensitivity/specificity while in the “out of time” validation test Cohort II, the obtained results were comparable. Conclusions The AI risk score may be a valuable tool in the clinical decision-making. The score should be further validated to determine its applicability in other populations.

OBJECTIVE We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS During follow-up (median 4.8 years), high (>3 mg/L) versus low ( CONCLUSIONS The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Objective: We investigated the relationship between high-sensitivity C-reactive protein (hsCRP), a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). Research Design and Methods: We measured serum hsCRP (n=7301) and C-peptide (n=5765) in patients with recent-onset T2D in the prospective Danish DD2 cohort study. Patients with no prior CVE (n=6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n=7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for interaction between hsCRP and C-peptide. Results: During follow-up (median=4.8 years), high (>3 mg/L) versus low ( Conclusions: The finding of high hsCRP as a stronger prognostic biomarker of all-cause mortality than of CVE may facilitate improved early detection and prevention of deadly diseases besides CVE. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Modifications of nucleic acids (DNA and RNA) from oxidative stress is a potential driver of aging per se and of mortality in age-associated medical disorders such as type 2 diabetes (T2D). In a human cohort, we found a strong prediction of all-cause mortality by a marker of systemic oxidation of RNA in patients with T2D (n = 2672) and in nondiabetic control subjects (n = 4079). The finding persisted after the adjustment of established modifiers of oxidative stress (including BMI, smoking, and glycated hemoglobin). In contrast, systemic levels of DNA damage from oxidation, which traditionally has been causally linked to both T2D and aging, failed to predict mortality. Strikingly, these findings were subsequently replicated in an independent general population study (n = 3649). The data demonstrate a specific importance of RNA damage from oxidation in T2D and general aging. Modifications of nucleic acids (DNA and RNA) from oxidative stress is a potential driver of aging per se and of mortality in age-associated medical disorders such as type 2 diabetes (T2D). In a human cohort, we found a strong prediction of all-cause mortality by a marker of systemic oxidation of RNA in patients with T2D (n = 2672) and in nondiabetic control subjects (n = 4079). The finding persisted after the adjustment of established modifiers of oxidative stress (including BMI, smoking, and glycated hemoglobin). In contrast, systemic levels of DNA damage from oxidation, which traditionally has been causally linked to both T2D and aging, failed to predict mortality. Strikingly, these findings were subsequently replicated in an independent general population study (n = 3649). The data demonstrate a specific importance of RNA damage from oxidation in T2D and general aging.

AimsRare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants.MethodsThis is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years.ResultsTwenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up.ConclusionsApproximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients. Aims: Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants. Methods: This is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years. Results: Twenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up. Conclusions: Approximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients.

Background: This study aimed to develop a highly sensitive SARS-CoV-2 nucleocapsid antigen assay using the single molecule array (Simoa) technology and compare it with real time RT-PCR as used in routine clinical practice with the ambition to achieve a comparative technical and clinical sensitivity. Methods: Samples were available from 148 SARS-CoV-2 real time RT-PCR positive and 73 SARS-CoV-2 real time RT-PCR negative oropharyngeal swabs. For determination of technical sensitivity SARS-CoV-2 virus culture material was used. The samples were treated with lysis buffer and analyzed using both an in-house and a pre-commercial SARS-CoV-2 nucleocapsid antigen assay on Simoa. Results: Both nucleocapsid antigen assays have a technical sensitivity corresponding to around 100 SARS-CoV-2 RNA molecules/mL. Using a cut-off at 0.1 pg/mL the pre-commercial SARS-CoV-2 nucleocapsid antigen assay had a sensitivity of 96% (95% CI, 91.4-98.5%) and specificity of 100% (95% CI, 95.1-100%). In comparison the in-house nucleocapsid antigen assay had sensitivity of 95% (95% CI, 89.3-98.1%) and a specificity of 100% (95% CI, 95.1-100%) using a cut-off at 0.01 pg/mL. The two SARS-CoV-2 nucleocapsid antigen assays correlated with r=0.91 (p

Background Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome hallmarked by adult-onset degeneration of upper and lower motor neurons and their associated tracts. ALS may be difficult to differentiate from some other neurological disorders termed ALS mimics and to estimate prognosis. Methods We retrospectively measured the concentrations of neurofilaments (NFs) and cytokines in cerebrospinal fluid (CSF) and plasma in ALS patients (n = 234) and ALS mimics (n = 44), to assess their association to diagnosis and prognosis in ALS. Two in-house developed enzyme-linked immunosorbent assays were used to measure NF light chain (NFL) and phosphorylated NF heavy chain (pNFH) in CSF. Single-molecule array was used to measure NFL in plasma and cytokines in CSF and plasma. Results Significantly higher concentrations of CSF tumor necrosis factor (TNF)-α and lower concentrations of plasma interleukin (IL)-1β were found in bulbar-onset ALS compared with ALS mimics. Plasma IL-6, plasma IL-17A and plasma TNF-α concentrations in ALS patients were significantly negatively correlated with the ALS functional rating scale revised and significantly positively correlated with King’s ALS clinical staging. Furthermore, plasma IL-6 and plasma TNF-α concentrations were significantly negatively correlated with the disease duration and significantly positively correlated with the disease progression rate in ALS patients. In both CSF and plasma in ALS patients, TNF-α was significantly positively correlated with NFL. ALS patients having plasma NFL or plasma IL-6 concentrations equal to or higher than the upper quartile (≥ Q3) showed a shorter disease duration compared with ALS patients having plasma NFL or plasma IL-6 equal to or lower than the median (≤ Q2). Conclusions Combined analysis of inflammatory and neurodegenerative biomarkers may be useful in differentiation between ALS and ALS-mimics. Such analysis may also provide useful prognostic information and facilitate stratification of less heterogeneous groups in clinical drug trials.

The aim of this study was to evaluate the logistics and diagnostic performances of dipstick analyses compared to their counterpart central laboratory analyses for detection of bacteriuria, proteinuria, hyperglycemia, ketosis and hematuria.Urine dipstick results, urine culture results, flow cytometric cell counts, U-albumin-to-creatinine ratio, P-glucose and P-beta-hydroxybutyrate were retrospectively reviewed in a cohort of consecutive patients admitted to the medical emergency departments of two Danish hospitals. Sensitivity, specificity and predictive values of traditional dipstick analysis were estimated and dipstick was compared to flow cytometry for detection of significant bacteriuria using logistic regression. Turn-around-time for central laboratory analyses were assessed.For each comparison, 1,997 patients or more were included. Traditional dipstick analyses for proteinuria, bacteriuria and ketosis reached sensitivities of up to 90%, while sensitivity for hyperglycemia was 59%. Flow cytometry outperformed traditional dipstick analysis for detection of bacteriuria with a difference in the area under the ROC-curve of 0.07. Turn-around-times for 95% delivery of central laboratory analysis results ranged from approximately 1½ to 2 h.For the detection of bacteriuria and albuminuria, central laboratory analyses reach better performance than dipstick analysis while achieving acceptable turn-around-times and are thus viable alternatives to dipstick analysis. For detection of ketosis and hyperglycemia, dipstick analysis does not perform adequately, but as very short turn-around-time is often required, these conditions may be best diagnosed by point-of-care blood test rather than dipstick or central laboratory analyses. Dipstick hemoglobin analysis, flow cytometry and microscopic evaluation may serve each their distinct purposes, and thus are relevant in the emergency department.

Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1´10-16) and a stronger effect in men than in women (interaction P=7´10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides, and colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

The activation of intracellular signaling pathways plays a critical role in cancer pathogenesis. The current study aims to quantify intracellular signaling proteins in localized colon cancer tissue to investigate the prognostic value of these biomarkers and elucidate their possible relations to mutation status. Colon cancer tissue and autologous reference tissue were collected from 176 patients who underwent colon cancer surgery. Assays were developed to quantify ERK, AKT and cyclin d using single-molecule array technology. KRAS/BRAF/PIK3CA mutation status was determined using droplet digital PCR. Patients with BRAF mutations had decreased concentrations of ERK (p = 0.0003), AKT (p = 0.0001) and cyclin d (p = 0.003), while no significant differences were found between patients with KRAS mutations and wild-type patients. None of the investigated proteins were associated with disease-free survival or overall survival when all patients were included. However, when patients were stratified according to mutation status, significant correlations with overall survival were seen for patients with BRAF mutations and AKT (p = 0.002) or ERK (p = 0.03) and for KRAS mutations and cyclin d (p = 0.01). Conclusions: A strong correlation exists between intracellular signaling protein concentrations and mutational BRAF status. Overall survival in colon cancer patients depends on both gene mutation status and signaling protein concentrations.

Introduction During pregnancy, maternal cortisol levels are increased 3-fold by the third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates the balance between cortisol and cortisone levels. Perfluoroalkyl substances (PFAS) have been reported to inhibit 11β-HSD1 and more potently 11β-HSD2, which could lead to reduced levels of cortisol and more extensively cortisone. Aim The aim of this work is to investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in diurnal urine (dU) and blood samples. Methods This study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1628 pregnant women had serum (S) concentrations of 5 PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], and perfluorodecanoic acid (PFDA)) measured in the first trimester (median gestational week, GW 11). dU cortisol and cortisone (n = 344) and S-cortisol (n = 1048) were measured in the third trimester (median GW 27). Results In multiple regression analyses, a 2-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β = –9.1%, P Conclusion Early pregnancy maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2.

The epidermal growth factor receptor (EGFR) and its ligands are involved in cancer pathogenesis and they might serve as circulating biomarkers. The current study aims to investigate if abnormal pre-treatment serum levels of EGFR and EGFR ligands are present in women with early-stage breast cancer and if up- or downregulation of EGFR and EGFR ligands occur in defined patient subgroups. Pre-treatment serum samples were obtained from 311 women with newly diagnosed early-stage breast cancer and from 419 healthy women and analysed for EGFR and the ligands: Epidermal growth factor (EGF), heparin-binding epidermal growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), and transforming growth factor α (TGF-α). Previously, age-dependent 95% reference intervals for EGFR and the EGFR ligands have been established based on the healthy women population. S-EGFR, S-EGF, S-HBEGF, S-AREG, and S-TGFα were all significantly different in women with breast cancer compared to healthy women (p 120 ng/mL).

Objective: To investigate the associations between complement C3d and inflammatory and structural changes by magnetic resonance imaging (MRI) at the sacroiliac joints (SIJ) suggestive of axial spondyloarthritis, according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, in patients with low back pain.Method: This was a cross-sectional study of patients referred to the Spine Centre of Southern Denmark owing to unspecified low back pain (Spines of Southern Denmark cohort). The patients were divided into three groups: group 1: patients fulfilling the ASAS criteria for axial spondyloarthritis (axSpA, n = 96); group 2: patients with either a positive MRI of the SIJ and no spondyloarthritis features, or a negative MRI of the SIJ but positive human leucocyte antigen-B27 and one spondyloarthritis feature (non-axSpA, n = 38); group 3: patients with unspecified low back pain for > 3 months (control group, n = 82). Complement C3d was measured with double-decker rocket immunoelectrophoresis and evaluated in relation to the group division and baseline findings by SIJ MRI.Results: In total, 184 C3d analyses were performed. The mean ± sd level of C3d was 33.8 ± 8.1 AU/mL. There were no differences in C3d levels between the three patient groups, mean values being: axSpA = 34.3 ± 7.9 AU/mL, non-axSpA = 33.5 ± 6.9 AU/mL, and controls = 33.4 ± 9.2 AU/mL. The level of C3d was not related to MRI findings.Conclusions: In these patients, complement C3d was not associated with active or structural SIJ changes on MRI suggestive of axial spondyloarthritis.

BACKGROUND: Postpancreatitis diabetes mellitus (PPDM) is a common metabolic sequalae of acute and chronic pancreatitis. We conducted a cross-sectional study to examine the proportion of PPDM among patients clinically diagnosed with type 2 diabetes (T2D) in Denmark and their clinical and biochemical characteristics.METHODS: We identified all past diagnoses of pancreatitis among patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort through linkage with national health registries. Using International Classification of Diseases, Tenth Revision codes we categorized patients as PPDM and further divided them into acute/chronic subtypes (PPDM-A and PPDM-C). We assessed PPDM prevalence and examined associations with clinical and biochemical parameters using log binomial or Poisson regression to calculate age-/sex-adjusted prevalence ratios (aPRs).RESULTS: Among 5564 patients with a clinical diagnosis of T2D, 78 (1.4%) had PPDM. Compared to T2D, PPDM patients were more often underweight or normal weight (body mass index ≤25.0 kg/m2 : aPR 2.3; 95% confidence interval [CI]: 1.6-3.2) and had lower waist-to-hip ratio (≤0.95/≤0.80 in men/women: aPRs 1.8; 95% CI: 1.2-2.7). PPDM patients had lower plasma amylase levels (63: aPR 2.0; 95% CI: 1.2-3.2) and tended to have worse glycaemic control (HbA1c ≥8.0%: aPRs 1.4; 95% CI: 0.8-2.4). PPDM-A was largely indistinguishable from T2D, whereas PPDM-C had impaired insulin secretion, higher insulin sensitivity, and worse glycemic control.CONCLUSIONS: The proportion of PPDM among patients with clinically diagnosed T2D is ~1.5% in an everyday clinical care setting. Glucose metabolism of PPDM-A is largely indistinguishable from T2D, whereas PPDM-C differs in relation to insulin secretion and sensitivity.

Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5–20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.

ObjectiveMost genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered.Research Design and MethodsWe conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We then used two additional cohorts, FinnGen and a Danish cohort, for replication. For the most significant recessive signal, we conducted a phenome-wide association study across hundreds of traits to make inferences about the pathophysiology underlying the increased risk seen in homozygous carriers.ResultsWe identified 51 loci associated with type 2 diabetes, including five variants with recessive effects undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk. We replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1×10−16) and a stronger effect in men than in women (interaction P=7×10−7). Colocalization analysis linked this signal to reduced expression of the nearby PELO gene, and the signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides.ConclusionsOur results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

Objectives We hypothesized that the amount of antigen produced in the body during a COVID-19 infection might differ between patients, and that maximum concentrations would predict the degree of both inflammation and outcome for patients. Methods Eighty-four hospitalized and SARS-CoV-2 PCR swab-positive patients, were followed with blood sampling every day until discharge or death. A total of 444 serial EDTA plasma samples were analyzed for a range of biomarkers: SARS-CoV-2 nuclear antigen and RNA concentration, complement activation as well as several inflammatory markers, and KL-6 as a lung marker. The patients were divided into outcome groups depending on need of respiratory support and death/survival. Results Circulating SARS-CoV-2 nuclear antigen levels were above the detection limit in blood in 65 out of 84 COVID-19 PCR swab-positive patients on day one of hospitalization, as was viral RNA in plasma in 30 out of 84. In all patients, complete antigen clearance was observed within 24 days. There were definite statistically significant differences between the groups depending on their biomarkers, showing that the concentrations of virus RNA and antigen were correlated to the inflammatory biomarker levels, respiratory treatment and death. Conclusions Viral antigen is cleared in parallel with the virus RNA levels. The levels of antigens and SARS-CoV-2 RNA in the blood correlates with the level of IL-6, inflammation, respiratory failure and death. We propose that the antigens levels together with RNA in blood can be used to predict the severity of disease, outcome, and the clearance of the virus from the body.

STUDY QUESTIONAre higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)?SUMMARY ANSWERAGD was similar in 3-month-old children born of mothers with PCOS compared to controls.WHAT IS KNOWN ALREADYAGD is considered a marker of prenatal androgenization.STUDY DESIGN, SIZE, DURATIONMaternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (MAIN RESULTS AND THE ROLE OF CHANCEAGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P LIMITATIONS, REASONS FOR CAUTIONThe diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities.WIDER IMPLICATIONS OF THE FINDINGSOur finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain.STUDY FUNDING/COMPETING INTEREST(S)Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published

BACKGROUND: Lower thyroid function outside pregnancy is associated with an increased risk of type 2 diabetes mellitus. The relationship between thyroid function in early pregnancy and glucose status in 3rd trimester has not been investigated.AIMS: To study the association between 1st trimester thyroid function and 3rd trimester glucose status.DESIGN: In the prospective study Odense Child Cohort (OCC), 1,041 women had 1st trimester blood samples analysed for thyroid-stimulating hormone (TSH), free T4 (FT4), thyroid peroxidase antibody and HbA1c. Third trimester (week 28) fasting blood samples included plasma glucose, insulin and HbA1c. Oral glucose tolerance test (OGTT, 75 g glucose) was performed in 509 women. First trimester FT4 was dichotomized >vs. ≤ the 25th percentile (25p = 12.9 pmol/L). Homeostatic model assessment-insulin resistance (HOMA)-IR and HOMA-β were calculated.RESULTS: Women with FT4 ≤25p had significantly higher HbA1c in 1st and 3rd trimesters and higher 3rd trimester fasting glucose, insulin, HOMA-IR and HOMA-β compared to women with FT4 >25p. In multiple regression analyses, FT4 was an independent negative predictor of 3rd trimester HbA1c. FT4 levels in 3rd and 4th quartiles (high-normal FT4 levels) showed closest inverse associations with HbA1c (p-trend CONCLUSION: Women with lower levels of FT4 in early pregnancy had higher HbA1c in 3rd trimester and FT4 was an independent negative predictor of 3rd trimester HbA1c.