DeepPeptide predicts cleaved peptides in proteins using conditional random fields.

MOTIVATION: Peptides are ubiquitous throughout life and involved in a wide range of biological processes, ranging from neural signaling in higher organisms to antimicrobial peptides in bacteria. Many peptides are generated post-translationally by cleavage of precursor proteins and can thus not be detected directly from genomics data, as the specificities of the responsible proteases are often not completely understood. RESULTS: We present DeepPeptide, a deep learning model that predicts cleaved peptides directly from the amino acid sequence. DeepPeptide shows both improved precision and recall for peptide detection compared to previous methodology. We show that the model is capable of identifying peptides in underannotated proteomes. AVAILABILITY AND IMPLEMENTATION: DeepPeptide is available online at ku.biolib.com/DeepPeptide.

Excess mortality in Denmark, Finland, Norway and Sweden during the COVID-19 pandemic 2020-2022.

BACKGROUND: The Nordic countries represent a unique case study for the COVID-19 pandemic due to socioeconomic and cultural similarities, high-quality comparable administrative register data and notable differences in mitigation policies during the pandemic. We aimed to compare weekly excess mortality in the Nordic countries across the three full pandemic years 2020-2022. METHODS: Using data on weekly all-cause mortality from official administrative registers in Denmark, Finland, Norway and Sweden, we employed time series regression models to assess mortality developments within each pandemic year, with the period 2010-2019 used as reference period. We then compared excess mortality across the countries in 2020-2022, taking differences in population size and age- and sex-distribution into account. Results were age- and sex-standardized to the Danish population of 2020. Robustness was examined with a variety of sensitivity analyses. RESULTS: While Sweden experienced excess mortality in 2020 [75 excess deaths per 100 000 population (95% prediction interval 29-122)], Denmark, Finland and Norway experienced excess mortality in 2022 [52 (14-90), 130 (83-177) and 88 (48-128), respectively]. Weekly death data reveal how mortality started to increase in mid-2021 in Denmark, Finland and Norway, and continued above the expected level through 2022. CONCLUSION: Although the Nordic countries experienced relatively low pandemic excess mortality, the impact and timing of excess mortality differed substantially. These estimates-arguably the most accurate available for any region in capturing pandemic-related excess deaths-may inform future research and policy regarding the complex mortality dynamics in times of a health crisis such as the COVID-19 pandemic.

Systematic inference of indirect transcriptional regulation by protein kinases and phosphatases.

Gene expression is controlled by pathways of regulatory factors often involving the activity of protein kinases on transcription factor proteins. Despite this well established mechanism, the number of well described pathways that include the regulatory role of protein kinases on transcription factors is surprisingly scarce in eukaryotes. To address this, PhosTF was developed to infer functional regulatory interactions and pathways in both simulated and real biological networks, based on linear cyclic causal models with latent variables. GeneNetWeaverPhos, an extension of GeneNetWeaver, was developed to allow the simulation of perturbations in known networks that included the activity of protein kinases and phosphatases on gene regulation. Over 2000 genome-wide gene expression profiles, where the loss or gain of regulatory genes could be observed to perturb gene regulation, were then used to infer the existence of regulatory interactions, and their mode of regulation in the budding yeast Saccharomyces cerevisiae. Despite the additional complexity, our inference performed comparably to the best methods that inferred transcription factor regulation assessed in the DREAM4 challenge on similar simulated networks. Inference on integrated genome-scale data sets for yeast identified ∼ 8800 protein kinase/phosphatase-transcription factor interactions and ∼ 6500 interactions among protein kinases and/or phosphatases. Both types of regulatory predictions captured statistically significant numbers of known interactions of their type. Surprisingly, kinases and phosphatases regulated transcription factors by a negative mode or regulation (deactivation) in over 70% of the predictions.

Endothelial Cell Insulin Signaling Regulates CXCR4 (C-X-C Motif Chemokine Receptor 4) and Limits Leukocyte Adhesion to Endothelium.

BACKGROUND: An activated, proinflammatory endothelium is a key feature in the development of complications of obesity and type 2 diabetes and can be caused by insulin resistance in endothelial cells. METHODS: We analyzed primary human endothelial cells by RNA sequencing to discover novel insulin-regulated genes and used endothelial cell culture and animal models to characterize signaling through CXCR4 (C-X-C motif chemokine receptor 4) in endothelial cells. RESULTS: CXCR4 was one of the genes most potently regulated by insulin, and this was mediated by PI3K (phosphatidylinositol 3-kinase), likely through FoxO1, which bound to the CXCR4 promoter. CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared with lean controls and 37% higher in db/db mice than db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. SDF-1 (stromal cell-derived factor-1)-the ligand for CXCR4-increased leukocyte adhesion to cultured endothelial cells. This effect was lost after deletion of CXCR4 by gene editing while 80% of the increase was prevented by treatment of endothelial cells with insulin. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling after intravenous injection of SDF-1, but most of this response was prevented in transgenic mice with endothelial overexpression of IRS-1 (insulin receptor substrate-1). CONCLUSIONS: Endothelial cell insulin signaling limits leukocyte/endothelial cell interaction induced by SDF-1 through downregulation of CXCR4. Improving insulin signaling in endothelial cells or inhibiting endothelial CXCR4 may reduce immune cell recruitment to the vascular wall or tissue parenchyma in insulin resistance and thereby help prevent several vascular complications.

Deorphanizing Peptides Using Structure Prediction.

Many endogenous peptides rely on signaling pathways to exert their function, but identifying their cognate receptors remains a challenging problem. We investigate the use of AlphaFold-Multimer complex structure prediction together with transmembrane topology prediction for peptide deorphanization. We find that AlphaFold's confidence metrics have strong performance for prioritizing true peptide-receptor interactions. In a library of 1112 human receptors, the method ranks true receptors in the top percentile on average for 11 benchmark peptide-receptor pairs.

Incidence rates of treated mental disorders before and during the COVID-19 pandemic-a nationwide study comparing trends in the period 2015 to 2021.

BACKGROUND: There is a concern that exposure to psychosocial stressors during the COVID-19 pandemic may have led to a higher incidence of mental disorders. Thus, this study aimed to compare trends in incidence rates of depressive disorder, anxiety disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and eating disorders in primary- and specialist health care before (2015-2019) and during the COVID-19 pandemic (2020-2021). METHODS: We used aggregated population registry data to calculate incidence rates of mental disorders from primary- (The Norwegian Control and Payment of Health Reimbursements Registry (KUHR)) and specialist (The Norwegian Patient Registry (NPR)) health care. The analyses included all Norwegian residents aged 18-65 during the study period. Incident cases were defined as having no previous registration with the same mental disorder in KUHR (from 2006) or NPR (from 2008). We used linear prediction models and mean models to compare incidence rates and test trends before and during the pandemic. RESULTS: During the pandemic, the incidence rates among women were higher or as predicted for OCD in specialist health care and for eating disorders in both primary- and specialist health care. These findings were strongest among women aged 18-24 years. Incidence rates for depression and phobia/OCD among both genders in primary health care and phobic anxiety disorders among both genders in specialist health care were lower or as predicted. CONCLUSION: The COVID-19 pandemic may have led to more women needing treatment for OCD and eating disorders in the Norwegian population. The decreased incidence rates for some disorders might indicate that some individuals either avoided seeking help or had improved mental health during the pandemic.

Contact with primary care physicians among adults with pre-existing common mental health problems during the COVID-19 pandemic: a registry-based study from Norway.

BACKGROUND: During the COVID-19 pandemic, individuals with pre-existing mental health problems may have experienced additional stress, which could worsen symptoms or trigger relapse. Thus, this study aimed to investigate if the number of consultations with general practitioners (GPs) among individuals with a pre-existing common mental health problem during the pandemic differed from pre-pandemic years. METHODS: Data on consultations with GPs among 18-65-year-olds registered with common mental health problems in 2017-2021 were retrieved from the Norwegian Control and Payment of Health Reimbursements Database. Based on data from the pre-pandemic years (2017-2019), we predicted the number of consultations per week for depression, anxiety disorder, phobia/obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and eating disorders during the pandemic (March 2020-December 2021) among individuals with pre-existing mental health problems. The forecasted and observed trends in GP consultations per week during the pandemic were stratified by diagnosis, gender, and age groups. RESULTS: The observed number of consultations for anxiety disorder, PTSD, and eating disorders were significantly higher than forecasted during extended periods of the two pandemic years. The differences were largest for PTSD (on average 37% higher in men and 47% higher in women during the pandemic), and for eating disorders among women (on average 87% higher during the pandemic). There were only minor differences between the predicted and observed number of consultations for depression and phobia/OCD. CONCLUSIONS: During the pandemic, individuals with a recent history of mental health problems were more likely to seek help for anxiety disorder, PTSD, and eating disorders, as compared to pre-pandemic years.

Forearm fractures - are we counting them all? An attempt to identify and include the missing fractures treated in primary care.

OBJECTIVE: Norway has a high incidence of forearm fractures, however, the incidence rates based on secondary care registers can be underestimated, as some fractures are treated exclusively in primary care. We estimated the proportion of forearm fracture diagnoses registered exclusively in primary care and assessed the agreement between diagnosis for forearm fractures in primary and secondary care. DESIGN: Quality assurance study combining nationwide data from 2008 to 2019 on forearm fractures registered in primary care (Norwegian Control and Payment of Health Reimbursement) and secondary care (the Norwegian Patient Registry). SETTING AND PATIENTS: Forearm fracture diagnoses in patients aged ≥20 treated in primary care (n = 83,357) were combined with injury diagnoses for in- and outpatients in secondary care (n = 3,294,336). MAIN OUTCOME MEASURES: Proportion of forearm fractures registered exclusively in primary care, and corresponding injury diagnoses for those registered in both primary and secondary care. RESULTS: Of 189,105 forearm fracture registrations in primary and secondary care, 13,948 (7.4%) were registered exclusively in primary care. The proportion ranged from 4.9% to 13.5% on average between counties, but was higher in some municipalities (>30%). Of 66,747 primary care forearm fractures registered with a diagnosis in secondary care, 62% were incident forearm fractures, 28% follow-up controls, and 10% other fractures or non-fracture injuries. CONCLUSION: An overall small proportion of forearm fractures were registered only in primary care, but it was larger in some areas of Norway. Failing to include fractures exclusively treated in primary care could underestimate the incidence rates in these areas.

Norwegian forearm fracture incidence based on secondary care may be underestimated by not including fractures treated exclusively in primary care.The mean proportion of forearm fractures exclusively handled in primary care is 7% and varies from 5% to 14% between counties.Fractures treated in primary care can be considered for more accurate national incidence rates. Correct fracture diagnosis needs further investigation.

Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

BACKGROUND: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. METHODS: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. RESULTS: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). CONCLUSIONS: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Novel Insights From Human Studies on the Role of High-Density Lipoprotein in Mortality and Noncardiovascular Disease.

The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.

The transcriptional coregulator CITED2 suppresses expression of IRS-2 and impairs insulin signaling in endothelial cells.

Endothelial cell insulin resistance contributes to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIFs) modulate insulin sensitivity, and we have previously shown that a negative regulator of HIF activity, CREB-binding protein/p300 (CBP/p300) interacting transactivator-2 (CITED2), is increased in the vasculature of people with type 2 diabetes. Therefore, we examined whether CITED2 regulates endothelial insulin sensitivity. In endothelial cells isolated from mice with a "floxed" mutation in the Cited2 gene, loss of CITED2 markedly enhanced insulin-stimulated Akt phosphorylation without altering extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation. Similarly, insulin-stimulated Akt phosphorylation was increased in aortas of mice with endothelial-specific deletion of CITED2. Consistent with these observations, loss of CITED2 in endothelial cells increased insulin-stimulated endothelial nitric oxide synthase phosphorylation, Vegfa expression, and cell proliferation. Endothelial cells lacking CITED2 exhibited an increase in insulin receptor substrate (IRS)-2 protein, a key mediator of the insulin signaling cascade, whereas IRS-1 was unchanged. Conversely, overexpression of CITED2 in endothelial cells decreased IRS-2 protein by 55% without altering IRS-1, resulting in impaired insulin-stimulated Akt phosphorylation and Vegfa expression. Overexpression of HIF-2α significantly increased activity of the Irs2 promoter, and coexpression of CITED2 abolished this increase. Moreover, chromatin immunoprecipitation (ChIP) showed that loss of CITED2 increased occupancy of p300, a key component of the HIF transcriptional complex, on the Irs2 promoter. Together, these results show that CITED2 selectively inhibits endothelial insulin signaling and action through the phosphoinositide 3-kinase (PI3K)/Akt pathway via repression of HIF-dependent IRS-2 expression. CITED2 is thus a promising target to improve endothelial insulin sensitivity and prevent the vascular complications of diabetes.NEW & NOTEWORTHY Endothelial cell insulin resistance is a major contributor to the development of diabetic complications. In this study, we have shown that CITED2, a transcriptional coregulator, inhibits endothelial insulin signaling through the PI3K/Akt pathway via repression of HIF-dependent IRS-2 expression, and that deletion of CITED2 enhances insulin signaling. Thus, CITED2 represents a novel and promising target to improve insulin sensitivity in endothelial cells and prevent vascular complications in diabetes.

Genetic Variants Associated With Increased Plasma Levels of Triglycerides, via Effects on the Lipoprotein Lipase Pathway, Increase Risk of Acute Pancreatitis.

BACKGROUND & AIMS: Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2-10 mmol/L or 177-886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population. METHODS: In a prospective cohort study, men and women randomly selected from the area of Copenhagen were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that are associated with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of the plasma level of triglycerides to determine the association between the plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles. RESULTS: The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08-2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores with an increased risk of acute pancreatitis (odds ratio [OR], 1.76; 95% CI, 1.16-2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01-1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01-2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05-1.14) after multivariable adjustment. CONCLUSIONS: Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated an increased plasma levels of triglycerides with an increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglycerides, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis.

Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention: A Population-Based Study.

OBJECTIVE: High Lp(a) (lipoprotein[a]) cause cardiovascular disease (CVD) in a primary prevention setting; however, it is debated whether high Lp(a) lead to recurrent CVD events. We tested the latter hypothesis and estimated the Lp(a)-lowering needed for 5 years to reduce CVD events in a secondary prevention setting. Approach and Results: From the CGPS (Copenhagen General Population Study; 2003-2015) of 58 527 individuals with measurements of Lp(a), 2527 aged 20 to 79 with a history of CVD were studied. The primary end point was major adverse cardiovascular event (MACE). We also studied 1115 individuals with CVD from the CCHS (Copenhagen City Heart Study; 1991-1994) and the CIHDS (Copenhagen Ischemic Heart Disease Study; 1991-1993). During a median follow-up of 5 years (range, 0-13), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1000 person-years were 29 (95% CI, 25-34) for individuals with Lp(a)<10 mg/dL, 35 (30-41) for 10 to 49 mg/dL, 42 (34-51) for 50 to 99 mg/dL, and 54 (42-70) for ≥100 mg/dL. Compared with individuals with Lp(a)<10 mg/dL (18 nmol/L), the multifactorially adjusted MACE incidence rate ratios were 1.28 (95% CI, 1.03-1.58) for 10 to 49 mg/dL (18-104 nmol/L), 1.44 (1.12-1.85) for 50 to 99 mg/dL (105-213 nmol/L), and 2.14 (1.57-2.92) for ≥100 mg/dL (214 nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS. To achieve 20% and 40% MACE risk reduction in secondary prevention, we estimated that plasma Lp(a) should be lowered by 50 mg/dL (95% CI, 27-138; 105 nmol/L [55-297]) and 99 mg/dL (95% CI, 54-273; 212 nmol/L [114-592]) for 5 years. CONCLUSIONS: High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population. This study suggests that Lp(a)-lowering by 50 mg/dL (105 nmol/L) short-term (ie, 5 years) may reduce CVD by 20% in a secondary prevention setting.

Vitamin D levels and the risk of prostate cancer and prostate cancer mortality.

BACKGROUND: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. METHODS: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25-50 (insufficient), 50-75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. RESULTS: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33-3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. CONCLUSION: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

Low and high pancreatic amylase is associated with pancreatic cancer and chronic pancreatitis.

Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20-100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004-2015 during a median 9 years of follow-up (range 0-15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48-67) and the median plasma pancreatic amylase 32 U/L (26-40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st-60th percentiles, those with extreme low (1st-2.5th percentiles) and extreme high (97.5th-100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6-3.6) and 2.2 (1.4-3.7) for pancreatic cancer, of 1.8 (1.1-3.3) and 3.2 (1.8-5.6) for chronic pancreatitis, and of 1.1 (0.6-1.8) and 1.5 (0.8-2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2-threefold higher risk of both pancreatic cancer and chronic pancreatitis.

Impact of the COVID-19 pandemic on the treatment of injuries during lockdown in Norway.

AIMS: In order to prevent a major outbreak of COVID-19 disease in Norway, a series of lockdown measures was announced on 12 March 2020. The aim of the present paper was to describe the impact of this lockdown on the treatment of injuries. METHODS: We collected hospital data on injury diagnoses from a national emergency preparedness register established during the pandemic. We identified the number of injured patients per day in the period 1 January-30 June 2020, and analysed the change in patient volumes over two three-week periods before and during the lockdown by sex, age, level of care, level of urgency, type of contact and type of injury. RESULTS: Compared to pre-lockdown levels, there was an overall reduction of 43% in injured patients during the first three weeks of lockdown. The decrease in patient contacts did not differ by sex, but was most pronounced among young people. Substantial reductions were observed for both acute and elective treatment and across all levels of care and types of contact, with the exception of indirect patient contacts. The change in patient contacts varied considerably by injury type, with the largest reduction observed for dislocations/sprains/strains. The decrease was much lower for burns/corrosions and poisoning. CONCLUSIONS: A substantial reduction in the treatment of injuries was observed during lockdown in Norway. Possible explanations for this finding include an overall decrease in injury risk, a redistribution of hospital resources and a higher threshold for seeking medical attention as a result of the pandemic.

The effect of nitrogen dioxide on low birth weight in women with inflammatory bowel disease: a Norwegian pregnancy cohort study (MoBa).

Background: Adverse birth outcomes are more frequent among mothers with inflammatory bowel diseases (IBDs) than non-IBD mothers. In recent studies, air pollution, such as high concentrations of nitrogen dioxide (NO2), is reckoned as a risk factor for preterm birth in the general population. In this study, we investigated whether IBD mothers are at higher risk of preterm birth when exposed to NO2 compared to non-IBD mothers.Methods: We used information from the Norwegian Mother, Father and Child Cohort Study (MoBa). The pregnancy cohort was linked to the Norwegian Medical Birth Registry and air-pollution exposure data available from a subset of the study cohort. The relevant outcome in this study was preterm birth. A total of 16,170 non-IBD and 92 IBD mothers were included in the study.Results: The mean exposure of NO2 during the pregnancy was similar for IBD and non-IBD mothers, 13.7 (6.9) µg/m3 and 13.6 (4.2) µg/m3, respectively.IBD mothers with higher exposure of NO2 in the second and third trimester were at significant risk of preterm birth compared to non-IBD mothers [OR = 1.28 (CI 95%: 1.04-1.59) and OR = 1.23 (95% CI: 1.06-1.43), respectively]. The mean NO2 exposure was significantly higher in IBD mothers with preterm birth than in IBD mothers who delivered at term, at 19.58 (1.57) µg/m3 and 12.89 (6.37) µg/m3, respectively.Conclusions: NO2 exposure influenced the risk of preterm birth in IBD mothers. Higher risk of preterm birth in IBD was associated with higher exposure of NO2, suggesting vulnerability of preterm birth in IBD when exposed to NO2.

Evaluation of incomplete maternal smoking data using machine learning algorithms: a study from the Medical Birth Registry of Norway.

BACKGROUND: The Medical Birth Registry of Norway (MBRN) provides national coverage of all births. While retrieval of most of the information in the birth records is mandatory, mothers may refrain to provide information on her smoking status. The proportion of women with unknown smoking status varied greatly over time, between hospitals, and by demographic groups. We investigated if incomplete data on smoking in the MBRN may have contributed to a biased smoking prevalence. METHODS: In a study population of all 904,982 viable and singleton births during 1999-2014, we investigated main predictor variables influencing the unknown smoking status of the mothers' using linear multivariable regression. Thereafter, we applied machine learning to predict annual smoking prevalence (95% CI) in the same group of unknown smoking status, assuming missing-not-at-random. RESULTS: Overall, the proportion of women with unknown smoking status was 14.4%. Compared to the Nordic country region of origin, women from Europe outside the Nordic region had 15% (95% CI 12-17%) increased adjusted risk to have unknown smoking status. Correspondingly, the increased risks for women from Asia was 17% (95% CI 15-19%) and Africa 26% (95% CI 23-29%). The most important machine learning prediction variables regarding maternal smoking were education, ethnic background, marital status and birth weight. We estimated a change from the annual observed smoking prevalence among the women with known smoking status in the range of - 5.5 to 1.1% when combining observed and predicted smoking prevalence. CONCLUSION: The predicted total smoking prevalence was only marginally modified compared to the observed prevalence in the group with known smoking status. This implies that MBRN-data may be trusted for health surveillance and research.

Incidence of injuries in Norway: linking primary and secondary care data.

Aims: Most studies of injury incidence underestimate the total burden of injury, as they do not include injuries treated in primary care. The aim of this study was to measure the total incidence of medically treated injuries in Norway. We further investigated the epidemiology of injuries treated in primary and secondary care. Methods: We collected individual-level data on injury diagnoses from the Norwegian Patient Registry and the national registry dataset for reimbursement of primary care providers for the period 2009-2014, and estimated the annual incidence of patients registered with an injury diagnosis in either or both of these registries. We also converted ICD-10 codes in secondary care into ICPC-2 codes to compare the types of injuries treated in primary and secondary care. Results: The annual incidence of medically treated injuries in Norway was 125 patients per 1000 inhabitants. Fifty-five per cent of injured patients received treatment exclusively in primary care. We observed stable time trends over the six-year period. Incidence rates were higher in primary care for the youngest children and in middle adulthood, but were higher in secondary care for older people. Overall, injury incidence was higher for men, but women became more injury prone with age. We only observed this gender reversal in secondary care. With the exception of fractures, all injury types were predominantly treated in primary care. Conclusions: A substantial proportion of injured patients in Norway are treated exclusively in primary care. The demographic profile of these patients differs from those treated in secondary care.

Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice.

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.