Iron, haemochromatosis genotypes, and risk of infections: a cohort study of 142,188 general population individuals.

It is unclear whether risk of infection is increased in individuals with hereditary haemochromatosis and in individuals with low or high plasma iron, transferrin saturation, or ferritin. Therefore, we tested whether high and low iron, transferrin saturation, and ferritin are associated with risk of infections observationally and genetically through HFE genotypes. We studied 142,188 Danish general population individuals. Iron, transferrin saturation, and ferritin were measured in 136,656, 136,599, and 38,020 individuals, respectively. HFE was genotyped for C282Y and H63D in 132,542 individuals. Median follow-up after study enrolment was 8 years(range:0-38years) for hospital and emergency room admissions with infections(n=20,394 individuals) using the National Patient Register, covering all Danish hospitals. Hazard ratios for any infection were 1.20(95%CI:1.12-1.28) and 1.14(1.07-1.22) in individuals with plasma iron≤5th or ≥95th percentile compared to individuals with iron from 26th-74th percentiles. Findings for transferrin saturation were similar, while infection risk was not increased in individuals with ferritin≤5th or ≥95th percentile. Hazard ratios in C282Y homozygotes versus non-carriers were 1.40(1.16-1.68) for any infection, 1.69(1.05-2.73) for sepsis, and 2.34(1.41-3.90) for death from infectious disease. Risk of infection was increased in C282Y homozygotes with normal plasma iron, transferrin saturation, or ferritin, and in C282Y homozygotes without liver disease, diabetes, and/or heart failure. In summary, low and high plasma iron and transferrin saturation were independently associated with increased infection risk. C282Y homozygotes had increased risk of any infection, sepsis, and death from infections. Even C282Y homozygotes with normal iron, transferrin saturation, or ferritin, not currently recommended for genotyping, had increased infection risk.

Electrocardiographic markers in patients with type 2 diabetes and the role of diabetes duration.

BACKGROUND: The association between type 2 diabetes and electrocardiographic (ECG) markers are incompletely explored and the dependence on diabetes duration is largely unknown. We aimed to investigate the electrocardiographic (ECG) changes associated with type 2 diabetes over time. METHODS: In this cross-sectional study, we matched people with type 2 diabetes 1:1 on sex, age, and body mass index with people without diabetes from the general population. We regressed ECG markers with the presence of diabetes and the duration of clinical diabetes, respectively, adjusted for sex, age, body mass index, smoking, heart rate, diabetes medication, renal function, hypertension, and myocardial infarction. RESULTS: We matched 988 people with type 2 diabetes (332, 34% females) with as many controls. Heart rate was 8 bpm higher (p < 0.001) in people with vs. without type 2 diabetes, but the difference declined with increasing diabetes duration. For most depolarization markers, the difference between people with and without type 2 diabetes increased progressively with diabetes duration. On average, R-wave amplitude was 6 mm lower in lead V5 (p < 0.001), P-wave duration was 5 ms shorter (p < 0.001) and QRS duration was 3 ms (p = 0.03). Among repolarization markers, T-wave amplitude (measured in V5) was lower in patients with type 2 diabetes (1 mm lower, p < 0.001) and the QRS-T angle was 10 degrees wider (p = 0.002). We observed no association between diabetes duration and repolarization markers. CONCLUSIONS: Type 2 diabetes was independently associated with electrocardiographic depolarization and repolarization changes. Differences in depolarization markers, but not repolarization markers, increased with increasing diabetes duration.

Systemic glucocorticoid exposure and postoperative infection risk in 143,782 appendectomy patients-a Danish longitudinal nationwide study.

BACKGROUND: Glucocorticoids are conventionally associated with increased postoperative infection risk. It is necessary to clarify if preoperative glucocorticoid exposure is associated with postoperative infection in appendectomy patients and if the association is different for open and laparoscopic appendectomies. METHODS: A Danish nationwide study of appendectomy patients between 1996 and 2018. Exposures were defined as high (≥ 5 mg) versus no/low (< 5 mg) glucocorticoid exposure in milligram prednisone-equivalents/day preoperatively. The main outcome was any postoperative infection. Then, 90-day cumulative incidences (absolute risk) and adjusted hazard ratios (relative risk) of the outcome were calculated for high versus no/low glucocorticoid exposure within all appendectomies and within open and laparoscopic subgroups. Propensity-score matching was used for sensitivity analysis. RESULTS: Of 143,782 patients, median age was 29 years, 74,543 were female, and 7654 experienced at least one infection during the 90-day follow-up. The 90-day cumulative incidence for postoperative infection was 5.3% within the no/low glucocorticoid exposure group and 10.0% within the high glucocorticoid exposure group. Compared to no/low glucocorticoid exposure, adjusted hazard ratios for 90-day postoperative infection with high glucocorticoid exposure were 1.25 [95% CI 1.02-1.52; p = 0.03] for all appendectomies, 1.59 [1.16-2.18; p = 0.004] for laparoscopic appendectomies, and 1.09 [0.85-1.40; p = 0.52] for open appendectomies (pinteraction < 0.001). The results were robust to sensitivity analyses. CONCLUSION: Preoperative high (≥ 5 mg/day) glucocorticoid exposure was associated with increased absolute risk of postoperative infections in open and laparoscopic appendectomies. The relative risk increase was significant for laparoscopic but not open appendectomies, possibly due to lower absolute risk with no/low glucocorticoid exposure in the laparoscopic subgroup.

Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

JAK2V617F drives gut microbiota differences in patients with myeloproliferative neoplasms.

BACKGROUND: Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are myeloproliferative neoplasms (MPN). Inflammation is involved in the initiation, progression, and symptomology of the diseases. The gut microbiota impacts the immune system, infection control, and steady-state hematopoiesis. METHODS: We analyzed the gut microbiota of 227 MPN patients and healthy controls (HCs) using next-generation sequencing. We expanded our previous results in PV and ET patients with additional PV, pre-MF, and MF patients which allowed us to compare MPN patients collectively, MPN sub-diagnoses, and MPN mutations (separately and combined) vs. HCs (N = 42) and compare within MPN sub-diagnoses and MPN mutation. RESULTS: MPN patients had a higher observed richness (median, 245 [range, 49-659]) compared with HCs (191.5 [range, 111-300; p = .003]) and a lower relative abundance of taxa within the Firmicutes phylum; for example, Faecalibacterium (6% vs. 14%, p < .001). The microbiota of CALR-positive patients (N = 30) resembled that of HCs more than that of patients with JAK2V617F (N = 177). In JAK2V617F-positive patients, only minor differences in the gut microbiota were observed between MPN sub-diagnoses, illustrating the importance of this mutation. CONCLUSION: The gut microbiota in MPN patients differs from HCs and is driven by JAK2V617F, whereas the gut microbiota in CALR patients resembles HCs more.

Pronounced gut microbiota signatures in patients with JAK2V617F-positive essential thrombocythemia.

Essential thrombocythemia (ET) is part of the Philadelphia chromosome-negative myeloproliferative neoplasms. It is characterized by an increased risk of thromboembolic events and also to a certain degree hypermetabolic symptoms. The gut microbiota is an important initiator of hematopoiesis and regulation of the immune system, but in patients with ET, where inflammation is a hallmark of the disease, it is vastly unexplored. In this study, we compared the gut microbiota via amplicon-based 16S rRNA gene sequencing of the V3-V4 region in 54 patients with ET according to mutation status Janus-kinase 2 (JAK2V617F)-positive vs JAK2V617F-negative patients with ET, and in 42 healthy controls (HCs). Gut microbiota richness was higher in patients with ET (median-observed richness, 283.5; range, 75-535) compared with HCs (median-observed richness, 191.5; range, 111-300; P < 0.001). Patients with ET had a different overall bacterial composition (beta diversity) than HCs (analysis of similarities [ANOSIM]; R = 0.063, P = 0.004). Patients with ET had a significantly lower relative abundance of taxa within the Firmicutes phylum compared with HCs (51% vs 59%, P = 0.03), and within that phylum, patients with ET also had a lower relative abundance of the genus Faecalibacterium (8% vs 15%, P < 0.001), an important immunoregulative bacterium. The microbiota signatures were more pronounced in patients harboring the JAK2V617F mutation, and highly similar to patients with polycythemia vera as previously described. These findings suggest that patients with ET may have an altered immune regulation; however, whether this dysregulation is induced in part by, or is itself inducing, an altered gut microbiota remains to be investigated. IMPORTANCE Essential thrombocythemia (ET) is a cancer characterized by thrombocyte overproduction. Inflammation has been shown to be vital in both the initiation and progression of other myeloproliferative neoplasms, and it is well known that the gut microbiota is important in the regulation of our immune system. However, the gut microbiota of patients with ET remains uninvestigated. In this study, we characterized the gut microbiota of patients with ET compared with healthy controls and thereby provide new insights into the field. We show that the gut microbiota of patients with ET differs significantly from that of healthy controls and the patients with ET have a lower relative abundance of important immunoregulative bacteria. Furthermore, we demonstrate that patients with JAK2V617F-positive ET have pronounced gut microbiota signatures compared with JAK2V617F-negative patients. Thereby confirming the importance of the underlying mutation, the immune response as well as the composition of the microbiota.

Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms.

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

JAK2V617F mutation is highly prevalent in patients with ischemic stroke: a case-control study.

Ischemic stroke has a high recurrence rate despite treatment. This underlines the significance of investigating new possible cerebrovascular risk factors, such as the acquired gene mutation JAK2V617F found in 3.1% of the general population. We aimed to investigate the prevalence of the JAK2V617F mutation in a population with ischemic stroke compared with that in matched controls. We enrolled 538 consecutive Danish patients with ischemic stroke (mean age, 69.5 ± 10.9 years; 39.2% female) within 7 days of symptom onset. Using multiple-adjusted conditional logistic regression analysis, we compared the prevalence of JAK2V617F with that in age- and sex-matched controls free of ischemic cerebrovascular disease (ICVD) from the Danish General Suburban Population Study. DNA was analyzed for JAK2V617F mutation using sensitive droplet digital polymerase chain reaction in patients and controls. Of the 538 patients with ischemic stroke, 61 (11.3%) had JAK2V617F mutation. There were no differences in patient demographics or cerebrovascular comorbidities between the patients with and without mutations. Patients with ischemic stroke were more likely to have the JAK2V617F mutation than matched controls, in whom the JAK2V617F prevalence was 4.4% (odds ratio, 2.37; 95% confidence interval, 1.57-3.58; P < .001). A subanalysis stratified by smoking history revealed that the association was strongest in current smokers (odds ratio, 4.78; 95% confidence interval, 2.22-10.28; P < .001). Patients with ischemic stroke were 2.4 times more likely to have the JAK2V617F mutation than matched controls without ICVD when adjusting for other cerebrovascular risk factors. This finding supports JAK2V617F mutation as a novel cerebrovascular risk factor.

High JAK2V617F variant allele frequency is associated with coronary artery but not aortic valve calcifications in patients with Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND: Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have a higher burden of cardiac calcifications compared to the general population. It is not known whether the JAK2V617F mutation is associated with increased cardiac calcification. AIM: To investigate if a higher JAK2V617F variant allele frequency (VAF) is associated with severe coronary atherosclerosis and the presence of aortic valve calcification (AVC). METHODS: Patients with MPNs were examined by cardiac computer tomography to establish coronary artery calcium score (CACS) and AVC score. The first VAF after diagnosis was registered. Severe coronary atherosclerosis was defined as a CACS >400 and AVC was defined as an AVC score >0. RESULTS: Among 161 patients, 137 were JAK2V617F mutation-positive, with a median VAF of 26% (interquartile range 12%-52%). A VAF in the upper quartile range was associated with a CACS >400 [odds ratio (OR) 15.96, 95% confidence interval [CI] 2.13-119.53, p = .0070], after adjustment for cardiovascular risk factors and MPN subtype. An association was not found for the presence of AVC (OR 2.30, 95% CI 0.47-11.33, p = 0.31). CONCLUSION: In patients with MPNs, there is a significant association between having a VAF in the upper quartile (>52%), and severe coronary atherosclerosis, defined as a CACS >400. The presence of AVC is not associated with VAF.

Specific prediction of mortality by oxidative stress-induced damage to RNA vs. DNA in humans.

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.

Case Report: First longitudinal study of a patient with CALR positive clonal hematopoiesis of indeterminate potential developing into pre-fibrotic myelofibrosis.

Initial diagnosis of overt myeloproliferative neoplasms (MPNs) represents the juncture during clonal evolution when symptoms or complications prompt an afflicted individual to seek medical attention. In 30-40% of the MPN subgroups essential thrombocythemia (ET) and myelofibrosis (MF), somatic mutations in the calreticulin gene (CALR) are drivers of the disease resulting in constitutive activation of the thrombopoietin receptor (MPL). In the current study, we describe a healthy CALR mutated individual during a 12 year follow-up from initial identification of CALR clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF. The pre-diagnostic exponential development dynamics of the malignant clone demonstrated close correlation with the platelet counts, neutrophil-to-lymphocyte (NLR) ratio, and inversely correlated to hemoglobin and erythrocyte counts. Backward extrapolation of the growth rate indicated the potential for discovery of the malignant clone many years prior to presentation of overt disease, opening a window of opportunity for early treatment intervention. We did not find any additional mutations associated with MPNs and the current case report provides novel information regarding the development of a driver mutation and the association with blood cell counts prior to clinical manifestation of symptoms suggesting that pre-diagnostic dynamics may supplement future diagnostic criteria for early diagnosis and intervention in MPN patients.

Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload: Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study.

OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes.

Risk of asthma in offspring of asthmatic fathers versus mothers: A population-based study of 21,000 individuals in Denmark.

Parental asthma or allergy have been linked to higher risk of asthma in a child; this occurs to a variable extent in different study populations. Moreover, it is debated whether maternal more so than paternal asthma history is a stronger predisposing factor: while in some countries/populations the maternal effect was clearly seen over paternal, in others the parental effects were equivalent, and in a few studies paternal effect dominated. Here we aimed to determine parental asthma and allergy effect in the Danish GEneral SUburban population Study (GESUS). This cross-sectional study has involved 21,362 adults aged 20+ years in the suburbs of Copenhagen. We used a combination of questionnaire approach, history of prescribed asthma medications and pulmonary function testing to determine odds ratios for maternal and paternal (and combined) asthma and allergy linked to asthma in the test subjects. We found that the input of maternal vs. paternal asthma effect was approximately equal (age and sex-adjusted OR 2.46, 95% CI: 2.15-2.81 for asthmatic mothers vs. 2.97, 2.58-3.42 for asthmatic fathers), except for the "ever asthma" age and sex-adjusted odds ratios where paternal allergy seems to have conferred a marginally greater effect (age and sex-adj. OR 1.96 for maternal allergy vs. 2.44 for paternal allergy, p = 0.03). Stratifying for gestational tobacco smoking did not affect the maternal results. We conclude that in the GESUS study parental asthma or allergy were strongly linked to higher asthma risk in offspring, without a prominent maternal or paternal effect.

The gut microbiota in patients with polycythemia vera is distinct from that of healthy controls and varies by treatment.

Chronic inflammation is believed to play an important role in the development and disease progression of polycythemia vera (PV). Because an association between gut microbiota, hematopoiesis, and inflammation is well established, we hypothesized that patients with PV have a gut microbiota distinct from healthy control participants (HCs). Recombinant interferon alfa 2 (IFN-α2)-treatment of patients with PV is reportedly disease modifying in terms of normalization of elevated blood cell counts in concert with a reduction in the JAK2V617F allelic burden. Therefore, we hypothesized that patients treated with IFN-α2 might have a composition of the gut microbiota toward normalization. Herein, via amplicon-based next-generation sequencing of the V3 to V4 regions of the 16S ribosomal RNA gene, we report on an abnormal gut microbiota in 102 patients with PV compared with 42 HCs. Patients with PV had a lower alpha diversity and a lower relative abundance of several taxa belonging to Firmicutes (45%) compared with HCs (59%, P <.001). Furthermore, we report the composition of the gut microbiota to differ between the treatment groups (IFN-α2, hydroxyurea, no treatment, and combination therapy with IFN-α2 and ruxolitinib) and the HCs. These observations are highly interesting considering the potential pathogenetic importance of an altered gut microbiota for development of other diseases, including chronic inflammatory diseases. Our observations call for further gut microbiota studies to decipher potential causal associations between treatment and the gut microbiota in PV and related neoplasms.

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon-alpha2.

BACKGROUND: Conventional cytoreductive therapy for patients with chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon-alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy. Such rapid oscillations may be harmful and potentially elicit thrombosis. Treatment with IFN gradually lowers elevated cell counts within weeks and when the dosage is reduced, the cell counts do not rapidly increase but are sustained within the normal range in the large majority of patients. Conventional hematological response criteria are among others based upon single absolute cell count values and do not take into account the relative decreases toward normal for each cell count. MATERIALS, METHODS & RESULTS: Using serial data from the Danish DALIAH trial, we herein describe a novel integrated biomarker index for the assessment of hematological and molecular (JAK2V617F) responses in patients with MPNs during treatment with IFN or HU. DISCUSSION: This novel tool convincingly displays the superiority of IFN versus HU in normalizing elevated cell counts. Our results need to be validated in larger studies but already now call for studies of the safety and efficacy of combination therapy during the initial treatment of patients with MPNs.

Association of Levothyroxine Treatment and Thyroid Peroxidase Antibodies with Antidepressant Use: A Danish Population-Based Longitudinal Study.

Background: Subjects receiving levothyroxine (LT4) treatment have increased prevalence of depression, anxiety, and antidepressant use, but whether the underlying mechanism relates to thyroid autoimmunity is still unclarified. Methods: This is a population-based longitudinal study. Baseline biochemical and questionnaire data from the Danish General Suburban Population Study (GESUS) in 2010-2013 were linked with individual-level longitudinal data in national health registries. The aim was to investigate the associations between thyroid peroxidase antibodies (TPOAbs) and LT4 treatment, separately and through interaction, and at least one redeemed prescription for antidepressants. Logistic and Cox regression were used to evaluate initiation of antidepressant use before and after the baseline examination in GESUS, respectively. All exposures and covariates were fixed at the date of baseline examination. Thyroid autoimmunity was defined as serum TPOAbs >60 U/mL. Adjustments included sex, age, education, income, Charlson comorbidity index, smoking, and alcohol. Sensitivity analyses were performed for missing variables, exclusion of lithium use, exclusion of thyroid surgery, and conservative definitions for LT4 treatment and antidepressant use requiring at least two prescriptions. Results: We included 12,894 individuals, of whom 2353 (18%) had "past or current" antidepressant use at baseline, leaving 10,541 individuals at risk for incident antidepressant use after baseline. The median follow-up was 7.8 years during which 783 individuals (7.4% of 10,541 individuals) had incident antidepressant use. TPOAb positivity was not associated with "past or current" (odds ratio [OR] 0.90 [confidence interval, CI 0.78-1.03], p = 0.13) nor incident antidepressant use (hazard ratio [HR] 1.02 [CI 0.83-1.25], p = 0.88). LT4 treatment was associated with increased "past or current" antidepressant use (OR 1.33 [CI 1.10-1.62], p = 0.004) and increased incident antidepressant use (HR 1.38 [CI 1.03-1.85], p = 0.03). There were no interactions between the effects of TPOAb positivity and LT4 treatment on the use of antidepressants in logistic (p = 0.87) or Cox regression models (p = 0.82). Sensitivity analyses were robust, except that incident use of at least two redeemed antidepressant prescriptions was not statistically significant. Conclusions: LT4 treatment, but not TPOAb positivity, was associated with increased prevalent or incident antidepressant use with at least one prescription. Our findings do not support that thyroid autoimmunity is an important factor for antidepressant use in patients receiving LT4 treatment.

Decreased Arterial Vascular Tone in Small Arteries in Severe Hidradenitis Suppurativa - A Study Using Finger Photopulseplethysmography.

A previous study has found an association between chronic inflammatory disorders e.g. psoriasis, rheumatoid arthritis, and inflammatory bowel disease and increased vascular stiffness(1). Psoriasis and hidradenitis suppurativa (HS) are believed to have shared comorbidities and pathophysiology despite their morphologically different manifestations in the skin. In order to evaluate a putative association between the chronic inflammatory skin disease HS and arterial stiffness, an observational cross-sectional retrospective study was carried out as part of the Danish General Suburban Population Study (GESUS) (1), in which 430 patients with HS from the general population (representing mild HS; Table 1), 32 patients with HS from a hospital-based out-patient clinic (representing severe HS, Table 1), and 20,780 controls underwent measurements of arterial vascular tone and stiffness using photoplethysmography (Pulse Trace PCA2®; Micro Medical Ltd, Kent, UK). The method of Pulse Trace has been validated by correlation with intra-arterial sensing techniques, and is a simple cost-effective screening method[2]. All analyses were performed using SAS 9.3. This study was accepted by the ethics committee of Region Zealand (project number SJ-191, SJ-113, SJ-114) in Denmark (2,3). RESULTS Reflection index (RI) is an expression of arterial vascular tone and stiffness of small arteries. The raw data showed a significantly lower RI for both HS groups groups, compared to controls. The results remained significant when adjusting for confounders (age, sex, smoking and metabolic syndrome) in the out-patient clinic HS group (-11.26 (-17.75- -4.76), P=0.0002*), but not in the population HS group (Table 2). Stiffness index (SI) expresses arterial stiffness in large arteries. Both HS groups showed no significant difference in either SI or vascular age in multivariate analysis, when compared with controls (Table 2). DISCUSSION This study suggests that decreased vascular tone and stiffness of small arteries may be associated with severe HS, and at the same time found no difference in arterial stiffness in large arteries. The significance for the out-patient clinic HS group, but not the population HS group may reflect a dose-response relationship. Vascular tone in vascular smooth muscle cells of small arteries depends on competing vasodilators and vasoconstrictors. We speculate that the inflammation of HS may induce a dysfunctional balance e.g. through increased TNF-alpha with subsequent increase of the vasodilator nitric oxide resulting in the lower arterial vascular tone observed. Additionally, mast cells are increased in HS [4], possibly increasing levels of the vasodilator histamine. HS patients often suffer from stress which could increase sympathetic activity, thereby adrenalin/cortisol and subsequent vasodilation in e.g. muscles. The more peripheral an artery is, the more collagen it contains and the stiffer it is. The finding of lower vascular tone may also be suggestive of a different elastin:collagen ratio in small arteries in HS. The healing process of HS lesions is known to involve scarring formation of sinus tracts [5], which may suggest a hypothesis of altered connective tissue. This study found no difference in SI expressing arterial stiffness of large arteries between HS and controls. Our previous study found an association between HS and myocardial infarction, but no association with stroke, nor peripheral arterial stiffness of lower extremities in medium/large arteries [6], suggesting regional differences in vascular beds in HS. The major limitation of the study is the missing values of pulse trace measurement (Table 1) creating possible selection bias. Although unable to draw any clinical conclusions, we believe these results may contribute to the future research of the complexity of HS and cardiovascular risk profiling. This study suggests that decreased vascular tone and stiffness of small arteries may be associated with severe HS, and at the same time found no difference in arterial stiffness in large arteries. The significance for the out-patient clinic HS group, but not the population HS group may reflect a dose-response relationship. Vascular tone in vascular smooth muscle cells of small arteries depends on competing vasodilators and vasoconstrictors. We speculate that the inflammation of HS may induce a dysfunctional balance e.g. through increased TNF-alpha with subsequent increase of the vasodilator nitric oxide resulting in the lower arterial vascular tone observed. Additionally, mast cells are increased in HS [4], possibly increasing levels of the vasodilator histamine. HS patients often suffer from stress which could increase sympathetic activity, thereby adrenalin/cortisol and subsequent vasodilation in e.g. muscles. The more peripheral an artery is, the more collagen it contains and the stiffer it is. The finding of lower vascular tone may also be suggestive of a different elastin:collagen ratio in small arteries in HS. The healing process of HS lesions is known to involve scarring formation of sinus tracts [5], which may suggest a hypothesis of altered connective tissue. This study found no difference in SI expressing arterial stiffness of large arteries between HS and controls. Our previous study found an association between HS and myocardial infarction, but no association with stroke, nor peripheral arterial stiffness of lower extremities in medium/large arteries [6], suggesting regional differences in vascular beds in HS. The major limitation of the study is the missing values of pulse trace measurement (Table 1) creating possible selection bias. Although unable to draw any clinical conclusions, we believe these results may contribute to the future research of the complexity of HS and cardiovascular risk profiling.

Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.

The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up.