Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Neutralizing IgG4 antibodies are a biomarker of sustained efficacy after peanut oral immunotherapy.

BACKGROUND: Clinical efficacy of oral immunotherapy (OIT) has been associated with the induction of blocking antibodies, particularly those capable of disrupting IgE-allergen interactions. Previously, we identified mAbs to Ara h 2 and structurally characterized their epitopes. OBJECTIVE: We investigated longitudinal changes during OIT in antibody binding to conformational epitopes and correlated the results with isotype and clinical efficacy. METHODS: We developed an indirect inhibitory ELISA using mAbs to block conformational epitopes on immobilized Ara h 2 from binding to serum immunoglobulins from peanut-allergic patients undergoing OIT. We tested the functional blocking ability of mAbs using passive cutaneous anaphylaxis in mice with humanized FcεRI receptors. RESULTS: Diverse serum IgE recognition of Ara h 2 conformational epitopes are similar before and after OIT. Optimal inhibition of serum IgE occurs with the combination of 2 neutralizing mAbs (nAbs) recognizing epitopes 1.2 and 3, compared to 2 nonneutralizing mAbs (non-nAbs). After OIT, IgG4 nAbs, but not IgG1 or IgG2 nAbs, increased in sustained compared to transient outcomes. Induction of IgG4 nAbs occurs after OIT only in those with sustained efficacy. Murine passive cutaneous anaphylaxis after sensitization with pooled human sera is significantly inhibited by nAbs compared to non-nAbs. CONCLUSIONS: Serum IgE conformational epitope diversity remains unchanged during OIT. However, IgG4 nAbs capable of uniquely disrupting IgE-allergen interactions to prevent effector cell activation are selectively induced in OIT-treated individuals with sustained clinical efficacy. Therefore, the induction of neutralizing IgG4 antibodies to Ara h 2 are clinically relevant biomarkers of durable efficacy in OIT.

Correction: Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Mediating pathways between neighborhood disadvantage and cardiovascular risk: Quasi-experimental evidence from a Danish refugee dispersal policy.

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

Defining the cross-reactivity between peanut allergens Ara h 2 and Ara h 6 using monoclonal antibodies.

In peanut allergy, Arachis hypogaea 2 (Ara h 2) and Arachis hypogaea 6 (Ara h 6) are two clinically relevant peanut allergens with known structural and sequence homology and demonstrated cross-reactivity. We have previously utilized X-ray crystallography and epitope binning to define the epitopes on Ara h 2. We aimed to quantitatively characterize the cross-reactivity between Ara h 2 and Ara h 6 on a molecular level using human monoclonal antibodies (mAbs) and structural characterization of allergenic epitopes. We utilized mAbs cloned from Ara h 2 positive single B cells isolated from peanut-allergic, oral immunotherapy-treated patients to quantitatively analyze cross-reactivity between recombinant Ara h 2 (rAra h 2) and Ara h 6 (rAra h 6) proteins using biolayer interferometry and indirect inhibitory ELISA. Molecular dynamics simulations assessed time-dependent motions and interactions in the antibody-antigen complexes. Three epitopes-conformational epitopes 1.1 and 3, and the sequential epitope KRELRNL/KRELMNL-are conserved between Ara h 2 and Ara h 6, while two more conformational and three sequential epitopes are not. Overall, mAb affinity was significantly lower to rAra h 6 than it was to rAra h 2. This difference in affinity was primarily due to increased dissociation of the antibodies from rAra h 6, a phenomenon explained by the higher conformational flexibility of the Ara h 6-antibody complexes in comparison to Ara h 2-antibody complexes. Our results further elucidate the cross-reactivity of peanut 2S albumins on a molecular level and support the clinical immunodominance of Ara h 2.

Design of an Ara h 2 hypoallergen from conformational epitopes.

INTRODUCTION: Adverse reactions are relatively common during peanut oral immunotherapy. To reduce the risk to the patient, some researchers have proposed modifying the allergen to reduce IgE reactivity, creating a putative hypoallergen. Analysis of recently cloned human IgG from patients treated with peanut immunotherapy suggested that there are three common conformational epitopes for the major peanut allergen Ara h 2. We sought to test if structural information on these epitopes could indicate mutagenesis targets for designing a hypoallergen and evaluated the reduction in IgE binding via immunochemistry and a mouse model of passive cutaneous anaphylaxis (PCA). METHODS: X-ray crystallography characterized the conformational epitopes in detail, followed by mutational analysis of key residues to modify monoclonal antibody (mAb) and serum IgE binding, assessed by ELISA and biolayer interferometry. A designed Ara h 2 hypoallergen was tested for reduced vascularization in mouse PCA experiments using pooled peanut allergic patient serum. RESULTS: A ternary crystal structure of Ara h 2 in complex with patient antibodies 13T1 and 13T5 was determined. Site-specific mutants were designed that reduced 13T1, 13T5, and 22S1 mAbs binding by orders of magnitude. By combining designed mutations from the three major conformational bins, a hexamutant (Ara h 2 E46R, E89R, E97R, E114R, Q146A, R147E) was created that reduced IgE binding in serum from allergic patients. Further, in the PCA model where mice were primed with peanut allergic patient serum, reactivity upon allergen challenge was significantly decreased using the hexamutant. CONCLUSION: These studies demonstrate that prior knowledge of common conformational epitopes can be used to engineer reduced IgE reactivity, an important first step in hypoallergen design.

Outcome of pregnancy oral glucose tolerance test and preterm birth.

BACKGROUND: Gestational diabetes is associated with adverse outcomes such as preterm birth (<37 weeks). However, there is no international consensus on screening criteria or diagnostic levels for gestational diabetes, and it is unknown whether body mass index (BMI) or obesity modifies the relation between glucose level and preterm birth. METHODS: We studied a pregnancy cohort restricted to two Danish regions from the linked Danish Medical Birth Register to study associations between glucose measurements from the 2-hour post-load 75-gram oral glucose tolerance test (one-step approach) and preterm birth from 2004-2018. In Denmark, gestational diabetes screening is a targeted strategy for mothers with identified risk factors. We used Poisson regression to estimate rate ratios (RR) of preterm birth with z-standardized glucose measurements. We assessed effect measure modification by stratifying analyses and testing for heterogeneity. RESULTS: Among 11,337 pregnancies (6.2% delivered preterm), we observed an adjusted preterm birth RR of 1.2 (95% CI: 1.1-1.3) for a 1 standard deviation glucose increase of 1.4 mmol/L from the mean 6.7 mmol/L. There was evidence for effect measure modification by obesity, e.g., adjusted RR for non-obese (BMI <30): 1.2 (95%CI: 1.1-1.3) vs. obese (BMI ≥30): 1.3 (95%CI: 1.2-1.5), P=0.05 for heterogeneity. CONCLUSIONS: Among mothers screened for gestational diabetes, increased glucose levels, even those below the diagnostic level for gestational diabetes in Denmark, were associated with increased preterm birth risk. Obesity (BMI ≥30) may be an effect measure modifier, not just a confounder, of the relation between blood glucose and preterm birth risk.

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality: a systematic review and meta-analysis.

CNS relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis with most clinical guidelines recommending CNS prophylaxis to patients deemed at high risk for CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. OBJECTIVES: To evaluate: 1) whether addition of prophylactic intravenous HD-MTX reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar and 2) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. METHODS: A systematic search of MEDLINE/PubMed and EMBASE on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar receiving HD-MTX as intervention and a comparator arm receiving no prophylaxis and/or IT prophylaxis. Risk of Bias was estimated using the ROBINS-I tool and the quality of the evidence by the GRADE approach. Finally, a meta-analysis based on the systematic review was conducted. RESULTS: A total of 1812 studies were screened. No RCT's were identified. Seven observational studies comprising 1661 patients met inclusion criteria. We found a statistically non-significant relative risk of 0.54 [0.27-1.07, 95% CI] of CNS relapse for patients receiving HD-MTX vs. controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 [0.44-1.11, 95% CI] for HD-MTX treated vs. controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as low. CONCLUSION: Our data indicate that HD-MTX does not prevent, or at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

Diagnostic accuracy of anti-3-[18F]-FACBC PET/MRI in gliomas.

PURPOSE: The primary aim was to evaluate whether anti-3-[18F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI alone in glioma diagnostics. The ability of anti-3-[18F]FACBC to differentiate between molecular and histopathological entities in gliomas was also evaluated. METHODS: In this prospective study, patients with suspected primary or recurrent gliomas were recruited from two sites in Norway and examined with PET/MRI prior to surgery. Anti-3-[18F]FACBC uptake (TBRpeak) was compared to histomolecular features in 36 patients. PET results were then added to clinical MRI readings (performed by two neuroradiologists, blinded for histomolecular results and PET data) to assess the predicted tumor characteristics with and without PET. RESULTS: Histomolecular analyses revealed two CNS WHO grade 1, nine grade 2, eight grade 3, and 17 grade 4 gliomas. All tumors were visible on MRI FLAIR. The sensitivity of contrast-enhanced MRI and anti-3-[18F]FACBC PET was 61% (95%CI [45, 77]) and 72% (95%CI [58, 87]), respectively, in the detection of gliomas. Median TBRpeak was 7.1 (range: 1.4-19.2) for PET positive tumors. All CNS WHO grade 1 pilocytic astrocytomas/gangliogliomas, grade 3 oligodendrogliomas, and grade 4 glioblastomas/astrocytomas were PET positive, while 25% of grade 2-3 astrocytomas and 56% of grade 2-3 oligodendrogliomas were PET positive. Generally, TBRpeak increased with malignancy grade for diffuse gliomas. A significant difference in PET uptake between CNS WHO grade 2 and 4 gliomas (p < 0.001) and between grade 3 and 4 gliomas (p = 0.002) was observed. Diffuse IDH wildtype gliomas had significantly higher TBRpeak compared to IDH1/2 mutated gliomas (p < 0.001). Adding anti-3-[18F]FACBC PET to MRI improved the accuracy of predicted glioma grades, types, and IDH status, and yielded 13.9 and 16.7 percentage point improvement in the overall diagnoses for both readers, respectively. CONCLUSION: Anti-3-[18F]FACBC PET demonstrated high uptake in the majority of gliomas, especially in IDH wildtype gliomas, and improved the accuracy of preoperatively predicted glioma diagnoses. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04111588, URL: https://clinicaltrials.gov/study/NCT04111588.

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.

Men treated with BEACOPP for Hodgkin lymphoma may be at increased risk of testosterone deficiency.

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors.

Use of medication in pregnancy on the rise: Study on 1.4 million Danish pregnancies from 1998 to 2018.

INTRODUCTION: Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy (concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics. MATERIAL AND METHODS: A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy. RESULTS: Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short-time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period. CONCLUSIONS: Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age-based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks.

Informal care after hip fracture: prospective cohort.

BACKGROUND: Hip fracture is very common and it has life-shattering consequences for older persons. After discharge the older persons need help with even basic everyday activities from formal and informal caregivers. In Scandinavia formal care are well-developed however the presence of informal caregivers likely reflect on the amount of formal care and wears on the informal caregivers. This study explore how often and how much informal care (IC) older persons receive after hip fracture. METHOD: We contacted 244 community-dwelling older persons every two weeks the first twelve weeks after discharge after hip fracture and asked them if they received care from family and/or friends and how much. We used non-parametric statistics and level of significance was 95%. RESULTS: The proportion of older persons receiving IC was 90% and the median amount of IC was 32 hours (IQR 14-66). The number of older persons who received IC was highest the first four weeks after discharge and so was the amount of hours of IC. The older persons that were high-dependence on IC received a median of 66 (IQR 46-107) hours compared to the low-dependent of 11 hours (IQR 2-20). CONCLUSION: IC is very frequent, especially the first two to four weeks after discharge. The median IC was 32 hours from discharge to the 12-week follow-up. However, this figure tended to rise for persons with, among other, reduced functionality and those residing with a partner. IMPLICATIONS: With respect to local differences, the findings in this study are likely applicable to other Scandinavian countries. We strongly suggest that the variation in older person need for informal caregiver be given consideration in the prioritisation of resources. TRIAL REGISTRATION: This prospective cohort study of informal care, was part of a cluster-randomised stepped-wedge clinical controlled trial. Written consent was obtained required by regional ethics committee S-20200070. Data was collected in accordance with the Danish Data Protection Agency (20-21854).

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism.

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

Long-term risk of atrial fibrillation or flutter after transcatheter patent foramen ovale closure: a nationwide Danish study.

AIMS: Transcatheter closure of patent foramen ovale (PFO) is the recommended stroke prevention treatment in patients ≤60 years with cryptogenic ischemic stroke and PFO. Atrial fibrillation or flutter (AF) is a known potential procedure-related complication, but long-term risk of developing AF remains unknown. This paper studied the long-term risk of developing AF following PFO closure. METHODS AND RESULTS: A Danish nationwide cohort study was conducted. During 2008-2020, this study identified a PFO closure cohort, a PFO diagnosis cohort without PFO closure, and a general population comparison cohort matched 10:1 to the PFO closure cohort on age and sex. The outcome was first-time AF diagnosis. Risk of AF and multivariable-adjusted hazard ratio (HR) of the association between PFO closure or PFO diagnosis and AF were calculated. A total of 817 patients with PFO closure, 1224 with PFO diagnosis, and 8170 matched individuals were identified. The 5 year risk of AF was 7.8% [95% confidence interval (CI): 5.5-10] in the PFO closure cohort, 3.1% (95% CI: 2.0-4.2) in the PFO diagnosis cohort, and 1.2% (95% CI: 0.8-1.6) in the matched cohort. The HR of AF comparing PFO closure with PFO diagnosis was 2.3 (95% CI: 1.3-4.0) within the first 3 months and 0.7 (95% CI: 0.3-1.7) thereafter. The HR of AF comparing PFO closure with the matched cohort was 51 (95% CI: 21-125) within the first 3 months and 2.5 (95% CI: 1.2-5.0) thereafter. CONCLUSION: Patent foramen ovale closure was not associated with any substantial increased long-term risk of developing AF beyond the well-known procedure-related short-term risk.

Encounters with public and professional understandings of Down syndrome: A qualitative study of parents' experiences.

BACKGROUND: The meanings of neurodevelopmental conditions are socially and culturally defined. We explored how parents of a child with Down syndrome experienced public and professional understandings of Down syndrome. METHOD: Qualitative interviews with 25 parents of a child with Down syndrome living in Denmark. From a reflexive thematic analysis, we developed themes describing understandings (i.e., attitudes or perceptions) of Down syndrome. RESULTS: The parents experienced that the Down syndrome diagnosis acted as a 'label'; this had perceived positive and negative consequences for the child. The parents felt others understood Down syndrome as severe and undesirable. This attitude was tied to the existence of prenatal screening. Finally, to the parents, professional support for their child expressed an understanding of children with Down syndrome as valued individuals. CONCLUSIONS: Parents encountered ambiguous understandings of Down syndrome. This should be recognised by professionals who may shape such understandings.

Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

BACKGROUND: Migraine carries risk of myocardial infarction (MI) and stroke. The risk of premature MI (i.e., among young adults) and stroke differs between men and women; previous studies indicate that migraine is mainly associated with an increased risk of stroke among young women. The aim of this study was to examine impact of migraine on the risk of premature (age ≤60 years) MI and ischemic/hemorrhagic stroke among men and women. METHODS AND FINDINGS: Using Danish medical registries, we conducted a nationwide population-based cohort study (1996 to 2018). Redeemed prescriptions for migraine-specific medication were used to identify women with migraine (n = 179,680) and men with migraine (n = 40,757). These individuals were matched on sex, index year, and birth year 1:5 with a random sample of the general population who did not use migraine-specific medication. All individuals were required to be between 18 and 60 years old. Median age was 41.5 years for women and 40.3 years for men. The main outcome measures to assess impact of migraine were absolute risk differences (RDs) and hazard ratios (HRs) with 95% confidence intervals (CIs) of premature MI, ischemic, and hemorrhagic stroke, comparing individuals with migraine to migraine-free individuals of the same sex. HRs were adjusted for age, index year, and comorbidities. The RD of premature MI for those with migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.3% (95% CI [-0.1%, 0.6%]; p = 0.061) for men. The adjusted HR was 1.22 (95% CI [1.14, 1.31]; p < 0.001) for women and 1.07 (95% CI [0.97, 1.17]; p = 0.164) for men. The RD of premature ischemic stroke for migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.5% (95% CI [0.1%, 0.8%]; p < 0.001) for men. The adjusted HR was 1.21 (95% CI [1.13, 1.30]; p < 0.001) for women and 1.23 (95% CI [1.10, 1.38]; p < 0.001) for men. The RD of premature hemorrhagic stroke for migraine versus no migraine was 0.1% (95% CI [0.0%, 0.2%]; p = 0.011) for women and -0.1% (95% CI [-0.3%, 0.0%]; p = 0.176) for men. The adjusted HR was 1.13 (95% CI [1.02, 1.24]; p = 0.014) for women and 0.85 (95% CI [0.69, 1.05]; p = 0.131) for men. The main limitation of this study was the risk of misclassification of migraine, which could lead to underestimation of the impact of migraine on each outcome. CONCLUSIONS: In this study, we observed that migraine was associated with similarly increased risk of premature ischemic stroke among men and women. For premature MI and hemorrhagic stroke, there may be an increased risk associated with migraine only among women.

Effect of a FIT-Based Colorectal Cancer Screening Program on Mortality Estimated by the Regression Discontinuity Design.

The fecal immunochemical test (FIT) has been implemented in colorectal cancer (CRC) screening programs, but effect evaluations are lacking. We evaluated the effect of a positive FIT on all-cause and CRC mortality using the regression discontinuity design. The Danish CRC screening program invites all residents 50-74 years old, using a 20-µg hemoglobin/g feces cutoff for colonoscopy referral. In this cohort study, we followed all first-time screening participants from 2014-2019 until 2020. We estimated the local effect of screening results, of just above the cutoff vs. just below, as hazard ratios (HRs) between models fitted at each side of the cutoff. We conducted the analysis within a narrow hemoglobin range (≥17 and <23, n = 16,428) and a wider range (≥14 and <26, n = 35,353). Those screened just above the cutoff had lower all-cause mortality compared with below (HR = 0.87, 95% confidence interval: 0.69; 1.10), estimated from the narrow range. The CRC mortality analysis had few outcomes. In the wider range, those with a FIT just above the cutoff had a lower hazard of CRC mortality compared with just below the cutoff (HR = 0.49, 95% confidence interval: 0.17; 1.41). A FIT result just above the cutoff, leading to referral to colonoscopy, pointed towards reduced all-cause and CRC mortality compared with just below the cutoff.

Obesity in pregnancy-Long-term effects on offspring hypothalamic-pituitary-adrenal axis and associations with placental cortisol metabolism: A systematic review.

Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low-grade inflammation may have a long-term impact on the offspring's HPA axis through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long-term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11ß2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood (n = 2) or adulthood (n = 1). Maternal BMI was not associated with placental HSD11ß1 or HSD11ß2 mRNA expression, or placental HSD11ß2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11ß2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.

Root-cause Analysis of 762 Danish Post-colonoscopy Colorectal Cancer Patients.

BACKGROUND & AIMS: The term post-colonoscopy colorectal cancer (PCCRC) refers to colorectal cancer (CRC) diagnosed after a negative colonoscopy. Using the root-cause algorithm proposed by the World Endoscopy Organization, we aimed to investigate plausible explanations for PCCRCs and potential changes in plausible explanations for PCCRCs over time in a Danish Region. METHODS: During 1995 to 2021, we used national health registries and electronic medical records in the Central Denmark Region to identify PCCRC cases, defined as CRCs recorded within 6 to 48 months after a colonoscopy. We then applied the World Endoscopy Organization algorithm to categorize explanations for PCCRC as follows: (A) possible missed lesion, prior examination adequate; (B) possible missed lesion, prior examination inadequate; (C) detected lesion, not resected; or (D) likely incomplete resection of previously identified lesion. PCCRCs were identified before (1995-2013) and after (2014-2021) implementation of nationwide fecal immunochemical test-based CRC screening and quality indicators for colonoscopy. RESULTS: We identified 762 PCCRCs, 53.5% among males and 57% among individuals ≥70 years. Forty-five percent were located in the proximal colon. We identified 616 (80.8%; 95% confidence interval [CI], 74.6%-87.5%) category A PCCRCs; 36 (4.7%; 95% CI, 3.3%-6.5%) category B PCCRCs; 26 (3.4%; 95% CI, 2.2%-4.9%) category C PCCRCs; and 84 (11%; 95% CI, 8.8%-13.6%) category D PCCRCs. Similar patterns were observed during the early (1995-2013) and late (2014-2021) study periods. CONCLUSIONS: Most PCCRCs originate from possible missed lesions and incompletely resected lesions during the complete study period. These findings indicate the importance of quality assurance of colonoscopy procedures and polypectomy techniques.