CRP, C-Peptide, and Risk of First-Time Cardiovascular Events and Mortality in Early Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS: During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07-1.96]) and with even greater risk of all-cause mortality (2.47 [1.88-3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10-2.34]) and all-cause mortality risk (2.36 [1.73-3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. CONCLUSIONS: The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Fever of Unknown Origin: A Validation Study of Danish ICD-10 Diagnosis Codes.

Background: Real-world data in form of routinely collected clinical data are a valuable resource for epidemiological research in infectious disease. We examined the validity of a discharge diagnosis of fever of unknown origin from hospital discharge registries. Methods: We identified patients with a first in- or outpatient diagnosis (primary or secondary) of fever of unknown origin (ICD-10 code R50.0; R50.8, R50.9) recorded in the Danish National Patient Registry (DNPR) between 2010 and 2017 in the North Denmark Region. We based the validation cohort on a mix of patients diagnosed at a highly specialized university department of infectious diseases (n=100), other internal medicine departments (n=50), and patients diagnosed at a regional non-university hospital (n=50). We estimate positive predictive value (PPV) of diagnosis for fever of unknown origin using medical records as reference. Results: The PPV of a diagnosis of fever of unknown origin for patients diagnosed at the infectious disease department was 61% (95% CI: 51-71%). For other internal medicine departments, it was 14% (95% CI: 6-27%), and for the non-university hospital it was 16% (95% CI: 7-29%). To achieve higher PPVs, we excluded immunocompromised patients, patients who were diagnosed with infection, cancer or rheumatic disease within 7 days after admission, and/or patients with a short hospital stay (maximum 3 days) and no subsequent hospital contact within 1 month. The PPV for diagnoses from the Department of Infectious Diseases improved to 82% (95% CI: 68-91%) for other internal medicine departments it improved to 31% (95% CI: 11-59%), and for the non-university hospital it improved to 36% (95% CI: 13-65%). Conclusion: We found that only diagnoses made in the Department of Infectious Diseases accurately identified fever of unknown origin, whereas diagnoses made in other units mainly covered infection-related fever, cancer-related fever, or short unspecific fever without further diagnostic work-up.

Mannose-binding lectin and risk of infections in type 2 diabetes: A Danish cohort study.

AIMS: In individuals at increased risk of infections, e.g., patients with type 2 diabetes, low MBL may have detrimental effects. We used the Mendelian randomization principle to examine whether genetically low MBL is a risk factor for developing infections in patients with type 2 diabetes. METHODS: Serum MBL (n = 7305) and MBL genotype (n = 3043) were determined in a nationwide cohort of patients with new type 2 diabetes and up to 8 years follow-up for hospital-treated infections and community-based antimicrobial prescriptions. The associations were examined in spline and Cox regression analyses. RESULTS: 1140 patients (16%) were hospitalized with an infection and 5077 patients (70%) redeemed an antimicrobial prescription. For low (≤100 µg/L) versus intermediate (101-1000 µg/L) serum MBL concentration, the adjusted hazard ratios (aHRs) were 1.13(95% confidence interval, 0.96-1.33) for any hospital-treated infections and 1.19(1.01-1.41) for bacterial infections. Low MBL expression genotype was not associated with risk of any hospital-treated infections except for diarrheal diseases (aHR 2.23[1.04-4.80]). Low MBL expression genotype, but not low serum MBL, was associated with increased risk for antimicrobial prescriptions (aHR 1.18[1.04-2.34] and antibacterial prescriptions 1.20[1.05-1.36]). CONCLUSIONS: Low MBL is a weak causal risk factor for developing infections in patients with type 2 diabetes.

Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and all-cause mortality. The association with outcomes was examined by spline and Cox regression analyses. RESULTS: Serum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34-2.46) for the low-MBL category and 1.48 (95% CI 1.14-1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87-2.25) for the low-expression genotype and 1.44 (95% CI 1.01-2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality. CONCLUSIONS: Both serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population.

Do probiotics prevent colonization with multi-resistant Enterobacteriaceae during travel? A randomized controlled trial.

BACKGROUND: Travelers to India are often colonized with extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) or Carbapenemase-producing Enterobacteriaceae (CPE). The aim of this study was to investigate if the probiotic species Lactobacillus Rhamnosus GG (LGG) could prevent the colonization of the gut with multi-drug resistant bacteria. METHODS: Adult Danish travelers traveling to India for 10-28 days were randomized to receive either LGG or no probiotics during travel. Rectal swabs and questionnaires were obtained before travel, immediately after and six months after return. Swaps were screened for the presence of ESBL-E and CPE. RESULTS: 31 travelers were randomized to the LGG group and 30 to the control group. Before traveling, 6/50 (12.0%) were colonized with ESBL-E. After return, 41/44 (93.2%) of those not colonized before travel were colonized and 11/36 (30.6%) were still colonized after six months. There was no statistically significant difference in the colonization rate between the group receiving LGG and the control group. No CPE was detected in any cases. CONCLUSIONS: The study confirms the very high incidence of colonization with ESBL-E associated with travel to India with >90% colonized upon return and one third were intestinal carriers for at least six months. Use of LGG did not have any effect on the risk of colonization with ESBL-E.

Prediction of mortality in patients with chronic obstructive pulmonary disease with the new Global Initiative for Chronic Obstructive Lung Disease 2017 classification: a cohort study.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classification separates the spirometric 1-4 staging from the ABCD groups defined by symptoms and exacerbations. Little is known about how this new classification predicts mortality in patients with chronic obstructive pulmonary disease (COPD). We aimed to establish the predictive ability of the GOLD 2017 classification, compared with earlier classifications, for all-cause and respiratory mortality, both when using its main ABCD groups and when further subdividing according to spirometric 1-4 staging. METHODS: In this nationwide cohort study, we enrolled patients with COPD with data available in the Danish registry for COPD. To be included in this registry, individuals must have been outpatients in hospital-based pulmonary clinics in Denmark. Eligible patients were aged 30 years or older; had received a primary diagnosis of COPD (International Classification of Diseases [ICD]-10 J44.X) or acute respiratory failure (ICD-10 J96.X) in combination with COPD (ICD-10 J44.X) as a secondary diagnosis; and had complete data on FEV1, body-mass index, modified Medical Research Council dyspnoea scale score, and smoking status. We categorised eligible patients with complete data according to the 2007, 2011, and 2017 GOLD classifications at the first contact with an outpatient clinic. For the GOLD 2017 classification, we further subdivided the patients by spirometry into 16 subgroups (1A to 4D). We calculated adjusted hazard ratios (HRs) for all-cause and respiratory mortality and compared the predictive ability of the three GOLD classifications (2007, 2011, and 2017) using receiver operating curves. FINDINGS: We enrolled 33 765 patients with COPD, who were outpatients in Danish hospitals between Jan 1, 2008, and Nov 30, 2013, in the main cohort assessed for all-cause mortality. 22 621 of these patients had data available on cause-specific mortality (respiratory) and were included in a subcohort followed from Jan 1, 2008, to Dec 31, 2011. For the GOLD 2017 classification, 3 year mortality increased with increasing exacerbations and dyspnoea from group A (all-cause mortality 10·0%, respiratory mortality 3·0%) to group D (all-cause mortality 36·9%, respiratory mortality 18·0%). However, 3 year mortality was higher for group B patients (all-cause mortality 23·8%, respiratory mortality 9·7%) than for group C patients (all-cause mortality 17·4%, respiratory mortality 6·4%). Compared with group A, adjusted HRs for all-cause mortality ranged from 2·05 (95% CI 1·87-2·26) for group B, to 1·47 (1·31-1·65) for group C, and to 3·01 (2·75-3·30) for group D. Area under the curve for all-cause mortality was 0·61 (95% CI 0·60-0·61) for GOLD 2007, 0·61 (0·60-0·62) for GOLD 2011, and 0·63 (0·53-0·73) for GOLD 2017. Area under the curve for respiratory mortality was 0·64 (0·62-0·65) for GOLD 2007, 0·63 (0·62-0·64) for GOLD 2011, and 0·65 (0·53-0·78) for GOLD 2017. The GOLD 2017 classification based on ABCD groups only did not predict mortality better than the earlier 2007 and 2011 GOLD classifications. However, when 16 subgroups (1A to 4D) were defined, the new classification predicted mortality more accurately than the previous systems (p<0·0001). INTERPRETATION: We showed that the new GOLD 2017 ABCD classification does not predict all-cause and respiratory mortality more accurately than the previous GOLD systems from 2007 and 2011. FUNDING: Danish Lung Association, Program for Clinical Research Infrastructure.

Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.

AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis. METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression. RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of ≥7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C-peptide≥800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00-1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti-hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy. CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications.

An OXA-48-producing Escherichia coli isolated from a Danish patient with no hospitalization abroad.

Carbapenemase-producing organisms are disseminating globally and are now emerging as a worrying threat in Scandinavia. Before August 2013, OXA-48-producing organisms had not been detected in Danish patients. Here we report the isolation of an ST746 OXA-48-producing Escherichia coli with the plasmid pOXA-48a carrying the blaOXA-48 gene isolated from a Danish patient without history of hospitalization abroad. The patient reported tourist travel to Egypt and Turkey. The potential acquisition of carbapenemase-producing organisms by ingestion of contaminated food is discussed.

IL-20, IL-21 and p40: potential biomarkers of treatment response for ustekinumab.

Although biological drugs in psoriasis treatment show clinical efficacy, there are still a proportion of patients in whom little treatment response is obtained. The aim of this study was to identify molecular biomarkers for treatment response and to investigate the molecular effects of ustekinumab treatment of psoriasis. The mRNA expression of various genes in skin biopsies was analysed by quantitative polymerase chain reaction (qPCR). At baseline, there was no significant clinical difference be-tween responders and non-responders. Ten patients were clinical responders, with a mean baseline Psoriasis Area and Severity Index (PASI) score of 15.4 and a mean percentage improvement of 89.6%. No significant reduction in PASI during treatment was seen among the 5 non-responders. In the responder group, ustekinumab therapy reduced the mRNA expression of the majority of the studied genes in lesional psoriatic skin. IL-20, IL-21 and p40 mRNA expression in lesional psoriatic skin at baseline were significantly upregulated by factors of 2.7, 2.4 and 2.3, respectively, among non-responders compared with responders. The mRNA levels of p40, IL-20 and IL-21 at baseline may serve as potential predictors of treatment response to ustekinumab treatment.

Tumor necrosis factor α-mediated induction of interleukin 17C in human keratinocytes is controlled by nuclear factor κB.

IL-17C is a member of the IL-17 family of cytokines. The expression of IL-17C has been demonstrated to be strongly induced by TNFα in human keratinocytes, and recently the level of IL-17C was found to be increased in the inflammatory skin disease psoriasis. However, little is known about the molecular mechanisms involved in the regulation of IL-17C. Here, we show that pretreatment of cultured human keratinocytes with the inhibitor of κB kinase 2 inhibitor, SC-514, resulted in a significant reduction in both IL-17C mRNA and protein expression, indicating the significance of this pathway in the regulation of IL-17C. NF-κB binding sites were identified upstream from the IL-17C gene, and by electrophoretic mobility shift assay NF-κB was shown to bind to all three identified binding sites. Moreover, NF-κB binding to these sites was inducible by TNFα. Supershift analysis revealed binding of the NF-κB subunits p65 and p50 to all three NF-κB binding sites. To determine the contribution of NF-κB in IL-17C expression, we conducted luciferase gene reporter experiments and demonstrated that a 3204-bp promoter fragment of IL-17C containing three putative NF-κB binding sites was strongly activated by TNFα. Interestingly, mutations of the three NF-κB binding sites revealed that one specific NF-κB binding site was crucial for the TNFα-mediated IL-17C induction because mutation of this specific site completely abolished TNFα-induced IL-17C promoter activation. We conclude that the activation of NF-κB (p65/p50) is crucial for the TNFα-induced stimulation of IL-17C expression in human keratinocytes.