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Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice., Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT., Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT., Exposures: Suspicion of HIT., Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests., Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively., Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

Objective: Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders., Methods: In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects., Results: Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49-1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53-1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14-1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18-1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91-1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88-1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07-1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88-1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03)., Conclusion: In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.

Aims/hypothesis: These secondary analyses aimed to investigate the effects of different volumes of exercise in adjunct to diet-induced weight loss and standard care on advanced glycation end-products (AGEs) and receptor for AGE (RAGE). We hypothesized that exercise in adjunct to a diet-induced weight loss would dose-dependently increase the soluble decoy receptor for AGE (sRAGE) more than diet-induced weight loss and standard care alone. Secondarily, we expected changes in sRAGE to be associated with improved glycaemic control and inversely associated with low-grade inflammation., Methods: The DOSE-EX study was a 16-week parallel-group, 4-arm, single-centre, assessor-blinded, randomised, controlled trial (NCT03769883). We included persons living with T2D, duration ≤7 years, BMI >27 kg/m 2 and <40 kg/m 2 , without severe diabetic complications. Participants were randomised (1:1:1:1) to either 1) standard care as control (CON), 2) standard care + diet (DCON), 3) standard care + diet + moderate exercise dose (MED) or 4) standard care + diet + high exercise dose (HED). Standard care included algorithm-guided pharmacological treatment. The diet intervention aimed at 25% reduced energy intake. The supervised exercise sessions included two aerobic sessions + one combined (aerobic and resistance training) session per week for the MED group, and four aerobic sessions + two combined sessions per week for the HED group. Primary outcome was the change in sRAGE from baseline to 16-week follow-up. Secondary outcomes encompassed changes in advanced glycation endproducts (AGE), glycaemic control and markers of low-grade inflammation., Results: A total of 80 participants (CON: n = 20, DCON: n = 19, MED: n = 20, HED: n = 21) were included in this secondary analysis. The mean age was 58.3 years (SD 9.9), 53% males, and median T2D duration was 4.1 years (IQR 2.0-5.5). No change in sRAGE was observed in any of the groups from baseline to follow-up (p > 0.05)., Conclusion/interpretation: A 16-week intervention with either three or six exercise sessions per week in adjunct to diet-induced weight loss did not change the levels of sRAGE in persons living with well-regulated, short standing T2D., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Synthetic corticosteroids are widely used due to their anti-inflammatory and immunosuppressant effects. Their use has been associated with venous thromboembolism, but it is unknown whether thromboembolism has a causal relationship with corticosteroid treatment. In a randomised, double-blind, placebo-controlled trial in normal to overweight healthy men, the effect of the corticosteroid prednisolone on haemostasis using either 50 mg prednisolone or matching placebo once daily for ten days was investigated. The primary outcome was a change from baseline in the viscoelastic measurement maximal amplitude of clot in kaolin-activated thromboelastography (TEG). Changes from baseline in other TEG measurements, D-dimer, von Willebrand factor (VWF) antigen, and ristocetin cofactor activity (RCo), antithrombin, protein C, prothrombin, fibrinogen, INR, APTT, and platelet count were secondary outcomes. Thirty-four men participated in this study. Compared to placebo, prednisolone treatment did not affect maximal amplitude of clot (difference -0.77 (95% confidence interval (CI) -2.48, 0.94) mm, p = 0.37, missing: n = 2), but it altered VWF antigen (28%, p = 0.0004), VWF:RCo (19%, p = 0.0006), prothrombin (5%, p = 0.05), protein C (31%, p < 0.0001), antithrombin (5%, p = 0.013), and fibrinogen (-15%, p = 0.004). Thus, prednisolone treatment did not alter TEG-assessed maximal amplitude of clot, despite that it affected prothrombotic markers (increased prothrombin, VWF antigen, VWF:RCo, prothrombin, and decreased fibrinogen) and increased antithrombotic markers (protein C and antithrombin).

Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes ( n  = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes ( n  = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: -4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: -4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by -0.17 nmol/mmol (95% CI: -0.29 to -0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: -0.02 to 0.22)) resulting in a significant between-group difference ( p  = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691.HighlightsPlasma ferritin correlated with DNA and RNA oxidation in individuals with T2D.Twelve weeks dapagliflozin treatment decreased DNA oxidation.Dapagliflozin and empagliflozin treatment did not change RNA oxidation.Lipid peroxidation was unaffected by two weeks empagliflozin treatment.

Objective: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine., Methods: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period., Results: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale., Conclusion: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache., (© 2022. The Author(s).)

Aims/hypothesis: This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress., Methods: The study was based on the single-centre, assessor-blinded, randomised, controlled U-turn trial (ClinicalTrial.gov NCT02417012). Persons with type 2 diabetes ˂ 10 years, ˂ 3 glucose lowering medications, no use of insulin, BMI 25-40 kg/m 2 and no severe diabetic complications were included. Participants were randomised (2:1) to either intensive exercise-based lifestyle intervention and standard (n = 64) or standard care alone (n = 34). Standard care included individual education in diabetes management, advice on a healthy lifestyle and regulation of medication by a blinded endocrinologist. The lifestyle intervention included five to six aerobic exercise sessions per week, combined with resistance training two to three times per week and an adjunct dietary intervention aiming at reduction of ∼500 kcal/day (month 0-4). The diet was isocaloric from months 5-12. The primary outcome of this secondary analysis was change in oxidative stress measured by 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and secondarily in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), as markers of RNA and DNA oxidation, respectively, from baseline to 12-months follow-up., Results: A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (-0.15 nmol/mmol creatinine [95% CI -0.27, -0.03]), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine [95% CI 0.00, 0.40]). The between group difference in 8-oxoGuo was -0.35 nmol/mmol creatinine [95% CI -0.58, -0.12,], p = 0.003. No between group difference was observed in 8-oxodG., Conclusion/interpretation: A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate the association of urinary oxidized guanine/guanosine (OxGuo) levels with incident type 2 diabetes (T2D) among older adults., Methods: A nested case-control design was applied with 440 cases of incident T2D and 440 controls, randomly sampled from all 65-75 year-old study participants of the ESTHER study, which is a population-based German cohort study with 14 years of follow-up. Analyses of 8-hydroxy-2'-deoxyguanosine (8-oxo-dGuo; DNA oxidation product) and 8-hydroxyguanosine (8-oxo-Guo; RNA oxidation product) were measured by ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS). The sum of the two OxGuo molecule concentrations was calculated and called OxGuo-UPLC-MS/MS. The corresponding OxGuo-ELISA levels were measured by Cayman's DNA/RNA oxidative damage ELISA, which detects a mix of 8-oxo-dGuo, 8-oxo-Guo and one other OxGuo molecule. Logistic regression was applied and models were adjusted for age, sex, BMI, HbA 1c , and C-reactive protein levels., Results: 8-oxo-dGuo and 8-oxo-Guo were highly correlated with each other (r = 0.642) and weakly correlated with OxGuo-ELISA (r = 0.22 and r = 0.14, respectively). OxGuo-ELISA levels were statistically significant associated with T2D incidence (odds ratio (OR) and 95% confidence interval [95%CI] for comparison of top and bottom quartile: 1.77 [1.14; 2.76]). In contrast, the ORs did not increase stepwise from quartile 2 to 4 for neither 8-oxo-Guo, 8-oxo-dGuo levels nor OxGuo-UPLC-MS/MS and comparisons of top and bottom quartile were not statistically significant. In a post-hoc analysis comparing bottom quartile 1 with a combined group of quartile 2-4, the association of OxGuo-UPLC-MS/MS with T2D incidence reached statistical significance (OR [95%CI]: 0.66 [0.46; 0.96]) and was very similar with the one obtained for OxGuo-ELISA (OR [95%CI]: 0.66 [0.45; 0.95])., Conclusions: Although only the measurements of the DNA/RNA oxidative damage ELISA kit of Cayman were statistically significantly associated with T2D incidence in the main analysis, confidence intervals overlapped and the post-hoc analysis showed that results for OxGuo-UPLC-MS/MS were quite comparable., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The importance of preconception health for lifelong physical and mental health in the next generation has gained increasing recognition in recent years. Preconception paternal and maternal risk factors such as obesity and inadequate diet affect the metabolic and cardiovascular health of their offspring later in life. This highlights the importance of diet and dietary behaviour in the years before parenthood. In our project, PREPARED, we will evaluate the effectiveness of a digital intervention targeting young adults. Our primary aim is to improve participants' preconception diet, and our secondary aim is to improve preconception quality of life and maternal and child perinatal outcomes., Methods and Analysis: We plan to recruit 7000 men and women individually, aged 20-35 years without children, to be randomised to an intervention or a control group. The intervention group will receive access to a digital resource for 6 months promoting a healthy diet for their health now, later in life and for the next generation. Follow-up is up to 20 years or until they have their first child. To evaluate intervention effects, we will collect dietary data (2×24-hour dietary recalls and a screener). For those participants for which birth ensues, we will link study data with data from the Medical Birth Registry of Norway on maternal and child perinatal outcomes., Ethics and Dissemination: The study is approved by the Regional Ethics Committee, the Norwegian Data Protection Service and our Faculty Ethical Committee (REC: 78104, NSD: 907212, FEC 20/10119). Participation is voluntary and all participants will provide informed consent. Participants can withdraw their consent without giving any reason. Findings will be communicated to the public through a project website and social media, and to professionals through conferences and peer-reviewed papers., Trial Registration Number: ISRCTN44294662., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Among markers for oxidative stress urinary excretion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 8-oxo-7,8-dihydro-guanosine (8-oxoGuo) have been widely used in controlled and epidemiological studies, and are considered to represent intracellular markers of oxidation of DNA and RNA in the entire organism, respectively. Although being non-invasive, urinary methods have shortcomings. There is no established method for analysis of 8-oxodGuo and 8-oxoGuo in plasma and the few plasma values presented in the literature vary greatly. We here present a liquid chromatography mass spectrometry method with full validation for analysis of 8-oxodGuo and 8-oxoGuo in plasma. Further, we investigated the basis for our previously physiological model and show that a single plasma sample can be used to estimate the 24-h production of 8-oxoGuo, whereas we challenge the use of urinary 8-oxodGuo/creatinine ratio or plasma 8-oxodGuo as measures of oxidative stress., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Whole-body oxidative stress can be estimated by the urine excretion of oxidized guanosine species, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), derived from RNA and DNA, respectively. These oxidative stress markers are not well explored in thyroid disorders., Objective: We aimed to determine whether treatment of hyperthyroid patients affects the levels of these oxidative stress markers., Methods: Urinary excretion of 8-oxoGuo and 8-oxodG was measured in 51 hyperthyroid patients (toxic nodular goiter [TNG], n = 30; Graves disease [GD], n = 21) before or shortly after initiation of therapy and when stable euthyroidism had been achieved for at least 12 months., Results: Adjusting for age, the baseline urinary excretion of oxidative stress markers correlated positively with plasma thyroxine (8-oxoGuo, P = 0.002; 8-oxodG, P = 0.021) and was significantly higher in GD than in TNG patients (P = 0.001 for both oxidative stress markers). Restoration of euthyroidism significantly affected the excretion of the oxidative stress markers. In TNG, 8-oxoGuo decreased from geometric mean 2.11 nmol/mmol creatinine (95% CI, 1.85-2.39) to 1.91 nmol/mmol (95% CI, 1.67-2.19; P = 0.001), while 8-oxodG decreased from 1.65 nmol/mmol (95% CI, 1.41-1.93) to 1.48 nmol/mmol (95% CI, 1.27-1.74; P = 0.026). In GD, 8-oxoGuo decreased from 2.25 nmol/mmol (95% CI, 1.95-2.59) to 1.79 nmol/mmol (95% CI, 1.63-1.97; P = 0.0003), while 8-oxodG decreased from 2.02 nmol/mmol (95% CI, 1.73-2.38) to 1.54 nmol/mmol (95% CI, 1.31-1.81; P = 0.001). In the euthyroid state, there were no differences between groups., Conclusion: Restoration of euthyroidism in patients with hyperthyroidism significantly decreased the systemic oxidative stress load by 10% to 25%. Our findings may help to explain the higher morbidity and mortality linked to hyperthyroid diseases, as shown in observational studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (- 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (- 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

Biotin (or Vitamin B7) is a vitamin where deficiency can be caused by inadequate intake. Biotin deficiency is rare, as most people get enough biotin from diet, since many foods contain biotin. In addition to biotin from food, intestinal bacteria can synthesize biotin, which can then be absorbed by the body. Supplementation with biotin has been advocated, mainly due to proposed beneficial effects on skin, nail and hair growth. There is no evidence that high biotin intakes are toxic, but a high intake may interfere with diagnostic assays that use biotin-streptavidin technology. These tests are commonly used to measure plasma concentrations of a wide range of hormones. Erroneous results may lead to misdiagnosis of various endocrine disorders. Supplementation with high-dose biotin has been used experimental for the treatment of diseases (e.g. multiple sclerosis) and high doses are used to obtain effect on nail and hair growth. On this background a demand for tests to determine if there is a risk of obtaining false test results when using biotin-streptavidin based tests have appeared. In this paper we present a method based on column switching liquid chromatography tandem mass spectrometry for the quantification of biotin in plasma and serum and explore the effects of biotin on an immunoassay based on biotin strept(avidin) chemistry.

We study where privately insured individuals receive planned MRI scans. Despite significant out-of-pocket costs for this undifferentiated service, privately insured patients often receive care in high-priced locations when lower priced options were available. The median patient in our data has 16 MRI providers within a 30-minute drive of her home. On average, patients bypass 6 lower-priced providers between their homes and their actual treatment locations. Referring physicians heavily influence where patients receive care. The share of the variance in the prices of patients' MRI scans that referrer fixed effects (52 percent) explain is dramatically greater than the share explained by patient cost-sharing (< 1 percent), patient characteristics (< 1 percent), or patients' home HRR fixed effects (2 percent). In order to access lower cost providers, patients must generally diverge from physicians' established referral patterns., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Carbohydrate-restricted diets are increasingly recognized as options for dietary management of type 2 diabetes mellitus (T2DM). We investigated the effects of a carbohydrate-reduced high-protein (CRHP) and a conventional diabetes (CD) diet on oxidative stress and inflammation in weight stable individuals with T2DM. We hypothesized that the CRHP diet would improve markers of oxidatively generated RNA and DNA modifications as well as inflammatory parameters. Thirty participants with T2DM were randomized to 6 weeks of CRHP or CD dietary treatment (30/50 energy percentage (E%) carbohydrate, 30/17E% protein, 40/33E% fat), followed by a cross-over to the opposite diet for a subsequent 6-week period. All meals were provided during the study and body weight was controlled. Diurnal urine samples were collected after 4 weeks on each diet and oxidatively generated RNA and DNA modifications were measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Fasting concentrations of soluble urokinase plasminogen activator receptor, high-sensitivity C-reactive protein, tumor necrosis factor alpha and interleukin-6 were measured before and after 6 weeks of interventions. Compared with the CD diet, the CRHP diet increased 24-hour urinary excretion of 8-oxoGuo by 9.3% (38.6 ± 12.6 vs. 35.3 ± 11.0 nmol/24 h, p =  .03), whereas 8-oxodG did not differ between diets (24.0 ± 9.5 vs. 24.8 ± 11.1 nmol/24 h, p  = .17). Changes in plasma inflammatory parameters did not differ between CRHP and CD diets, all p ≥  .2. The clinical implications of increased RNA oxidation following a CRHP diet as well as long-term effects of carbohydrate-restriction on markers of oxidatively generated nucleic acid modifications should be a field of future study.

Aims: To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes., Materials and Methods: In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m 2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported., Results: Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker)., Conclusions: Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk., (© 2020 John Wiley & Sons Ltd.)

Acute and adaptive changes in systemic markers of oxidatively generated nucleic acid modifications (i.e., 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo)) as well as inflammatory cytokines (i.e., C-reactive protein, interleukin-6, interleukin-10, and tumour necrosis factor alpha), a liver hormone (i.e., fibroblast growth factor 21 (FGF21)), and bone metabolism markers (sclerostin, osteocalcin, C-terminal telopeptide, and N-terminal propeptide of type 1 procollagen) were investigated following a marathon in 20 study participants. Immediate changes were observed in inflammatory cytokines, FGF21, and bone metabolism markers following the marathon. In contrast, no immediate changes in urinary excretion of 8-oxodG and 8-oxoGuo were evident. Four days after the marathon, decreased urinary excretion of 8-oxodG (-2.9 (95% CI -4.8;-1.1) nmol/24 h, P  < 0.01) and 8-oxoGuo (-5.8 (95% CI -10.3;-1.3) nmol/24 h, P  = 0.02) was observed. The excretion rate of 8-oxodG remained decreased 7 days after the marathon compared to baseline (-2.3 (95%CI -4.3;-0.4) nmol/24 h, P  = 0.02), whereas the excretion rate of 8-oxoGuo was normalized. In conclusion marathon participation immediately induced a considerable inflammatory response, but did not increase excretion rates of oxidatively generated nucleic acid modifications. In fact, a delayed decrease in oxidatively generated nucleic acid modifications was observed suggesting adaptive antioxidative effects following exercise., Abbreviations: 8-oxodG: 8-oxo-7,8-dihydro-2'-deoxyguanosine; 8-oxoGuo: 8-oxo-7,8-dihydroguanosine; CI: confidence interval; CTX: C-terminal telopeptide of type 1 collagen; DXA: dual-energy X-ray absorptiometry; ELISA: enzyme-linked immunosorbent assay; FGF21: Fibroblast growth factor 21; h: hour; hsCRP: high sensitivity C-reactive protein; IL: interleukin; IQR: interquartile range; MS: mass spectrometry: P1NP: N-terminal propeptide of type 1 procollagen; TNFα: tumour necrosis factor alpha; UPLC: ultra-performance liquid chromatography.

Background: Persons with dementia tend to be vulnerable to mobility challenges and hence face a greater risk of fall and subsequent fractures, morbidity, and mortality. Motion-based technologies (MBTs), also called sensor-based technologies or virtual reality, have the potential for assisting physical exercise and training as a part of a disease management and rehabilitation program, but little is known about its' use for people with dementia., Objective: The purpose of this pilot study was to investigate the feasibility and efficacy of MBT physical training at home for people with dementia., Methods: A 3-phase pilot study: (1) baseline start-up, (2) 15 weeks of group training at a local care center twice a week, and (3) 12 weeks of group training reduced to once a week, supplemented with individual MBT training twice a week at home. A total of 26 people with dementia from a municipality in Southern Denmark were eligible and agreed to participate in this study. Three withdrew from the study, leaving 23 participants for the final analysis. Feasibility was measured by the percentage of participants who trained with MBT at home, and their completion rate of total scheduled MBT sessions. Efficacy was evaluated by physical function, measured by Sit-to-Stand (STS), Timed-Up-and-Go (TUG), 6-minute Walk Test (6MW), and 10-meter Dual-task Walking Test (10MDW); cognitive function was measured by Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory-Questionnaire (NPI-Q); and European Quality of Life 5 dimensions questionnaire (EQOL5) was used for measuring quality of life. Descriptive statistics were applied accordingly. Wilcoxon signed-rank and rank-sum tests were applied to explore significant differences within and between the groups., Results: As much as 12 of 23 participants (52%) used the supplemental MBT training at home. Among them, 6 (50%) completed 75% or more scheduled sessions, 3 completed 25% or less, and 3 completed between 25% and 75% of scheduled sessions. For physical and cognitive function tests, supplementing with MBT training at home showed a tendency of overall stabilization of scores among the group of participants who actively trained with MBT; especially, the 10MDW test even showed a significant improvement from 9.2 to 7.1 seconds (P=.03). We found no positive effect on EQOL5 tests., Conclusions: More than half of the study population with dementia used MBT training at home, and among them, half had an overall high adherence to the home training activity. Physical function tended to remain stable or even improved among high-adherence MBT individuals. We conclude that MBT training at home may be feasible for some individuals with dementia. Further research is warranted., (©Jindong Ding Petersen, Eva Ladekjær Larsen, Karen la Cour, Cecilie von Bülow, Malene Skouboe, Jeanette Reffstrup Christensen, Frans Boch Waldorff. Originally published in JMIR Mental Health (http://mental.jmir.org), 26.08.2020.)

Background: Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury., Methods: A single-center, non-randomized, single-arm, open-label study of erenumab for adults aged 18-65 years with persistent PTH. Patients were assigned to receive 140-mg erenumab monthly by two subcutaneous 1-mL injections, given every 4 weeks for 12 weeks. The primary outcome measure was the mean change in number of monthly headache days of moderate to severe intensity from baseline (4-week pretreatment period) to week 9 through 12. Tolerability and safety endpoints were adverse events (i.e. number and type)., Results: Eighty-nine of 100 patients completed the open-label trial. At baseline, the mean monthly number of headache days of moderate to severe intensity was 15.7. By week 9 through 12, the number was reduced by 2.8 days. The most common adverse events were constipation (n = 30) and injection-site reactions (n = 15). Of 100 patients who received at least one dose of erenumab, two patients discontinued the treatment regimen due to adverse events., Conclusions: Among patients with persistent PTH, erenumab resulted in a lower frequency of moderate to severe headache days in this 12-week open-label trial. In addition, erenumab was well-tolerated as discontinuations due to adverse events were low. Placebo-controlled randomized clinical trials are needed to adequately evaluate the efficacy and safety of erenumab in patients with persistent PTH., Trial Registration: ClinicalTrials.Gov, NCT03974360. Registered on April 17, 2019 - Retrospectively registered.

Aims: Sevelamer has been reported to have anti-oxidative and anti-inflammatory effects as well as effects on glycaemic control and plasma lipids. The aim of this study was to determine the effects of one-week treatment with sevelamer on oxidative nucleic acid modifications and inflammation markers., Methods: Two double-blinded studies including 30 patients with type 2 diabetes (T2D) and 20 healthy individuals were conducted. Participants were randomised to one week of treatment with sevelamer (1600 mg three times daily) or placebo. RNA and DNA oxidation, measured by urinary excretion of 8-oxo-7,8-dihydroguanosine(8-oxoGuo) and (8-oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodG), and markers of inflammation were determined before and after the intervention., Results: In patients with T2D there was no significant placebo-corrected reduction in 8-oxoGuo or 8-oxodG. However, a reduction in 8-oxoGuo was observed within the group treated with sevelamer (∆8-oxoGuo/creatinine (median[IQR]): -0.04 [-0.24; 0.01] nmol/mmol, p = 0.02). A sevelamer-mediated reduction in interleukin-2 (p = 0.04) and a trend towards reduction in interleukin-6 (p = 0.053) were found in patients with T2D., Conclusions: This study reveals a potential effect of sevelamer treatment on inflammation and possible oxidative RNA modifications. The potential protective effects of sevelamer in terms of cardiovascular disease in patients with T2D need further investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

Background: The oxidized guanine nucleosides, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), derived from DNA and RNA, respectively, were used to investigate the importance of oxidative stress to nucleic acids in vivo. High urinary excretion of 8-oxodG is associated with cancer development, whereas high urinary excretion of 8-oxoGuo is associated with mortality in type 2 diabetes. Like creatinine, these small water-soluble molecules are not reabsorbed in the kidney. Therefore, 8-oxo nucleoside/creatinine reciprocal concentration ratios are identical in plasma and urine. The total amount of 8-oxo guanine nucleosides excreted by the kidneys is the product of plasma concentration and glomerular filtration rate., Methods: With relevant equations and an estimated glomerular filtration rate, the 24-h urinary excretion of 8-oxodG and 8-oxoGuo was calculated in 2679 subjects with type 2 diabetes, displaying good correlation with the measured urinary 8-oxo nucleoside/creatinine ratio: DNA oxidation r = 0.86 and RNA oxidation r = 0.84 (p < 0.05 for both)., Results: Survival analyses based on the quartiles of the 8-oxodG/creatinine ratio and the quartiles of calculated 24-h urinary excretion rate of the 2679 subjects gave similar hazard ratio estimates for death due to all causes. This finding was similar for the 8-oxoGuo hazard ratio estimates., Conclusions: This study shows that oxidatively generated modifications to DNA and RNA in vivo can be measured using 1) a spot urine sample, normalized to urinary creatinine, 2) 24-h urine, or 3) a single plasma sample based on concentrations of 8-oxo nucleoside and creatinine and glomerular filtration rate., (Copyright © 2019. Published by Elsevier Inc.)

Oxidative stress is associated with the development and progression of numerous diseases. However, targeting oxidative stress has not been established in the clinical management of any disease. Several methods and markers are available to measure oxidative stress, including direct measurement of free radicals, antioxidants, redox balance, and oxidative modifications of cellular macromolecules. Oxidatively generated nucleic acid modifications have attracted much interest due to the pre-mutagenic oxidative modification of DNA into 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), associated with cancer development. During the last decade, the perception of RNA has changed from that of a 'silent messenger' to an 'active contributor', and, parallelly oxidatively generated RNA modifications measured as 8-oxo-7,8-dihydro-guanosine (8-oxoGuo), has been demonstrated as a prognostic factor for all-caused and cardiovascular related mortality in patients with type 2 diabetes. Several attempts have been made to modify the amount of oxidative nucleic acid modifications. Thus, this review aims to introduce researchers to the measurement of oxidatively generated nucleic acid modifications as well as critically review previous attempts and provide future directions for targeting oxidatively generated nucleic acid modifications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Post-traumatic headache (PTH) is associated with considerable disability and reduced health-related quality of life. Despite the very high prevalence of PTH, there are no evidence-based guidelines for PTH treatment. Thus, we found it timely to provide a systematic review of the current literature on acute and preventive pharmacological treatment of PTH using PubMed and Embase databases., Findings: Included studies involved acute and preventive pharmacological treatment of headache attributed to traumatic injury to the head in adherence to the International Classification of Headache Disorders (ICHD) criteria. Of 1424 potentially relevant articles identified, 63 were retrieved for detailed evaluation and seven studies (one prospective and six retrospective) met the inclusion criteria. None of the seven included studies were randomized clinical trials (RCTs) or used a placebo-controlled study design., Conclusion: We found that there is a lack of high-quality evidence-based studies on the pharmacological treatment of PTH. Future studies are highly needed and must emphasize open-label studies with rigorous methodology or RCTs with a placebo-controlled design.

Background Patient acceptance is an important factor when implementing imaging methods in clinical practice in line with availability, diagnostic accuracy, and cost-effectiveness. Purpose To investigate patient experience and acceptance regarding18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT), 11 C-choline-PET/CT, whole-body magnetic resonance imaging (WB-MRI), and 99mTc-hydroxymethane diphosphonate (HDP) single photon emission/computed tomography (SPECT/CT). Material and Methods One hundred and forty-nine patients with prostate cancer filled in a questionnaire regarding their experience of the imaging procedures they had been undergoing as part of a diagnostic accuracy study. Each patient had been undergoing a NaF-PET/CT, a WB-MRI, and either a SPECT/CT (group A) or a choline-PET/CT (group B). Results All four imaging methods received overall experience ratings at the favorable end of a 5-point Likert scale with the two PET/CT scans receiving marginally better average ratings (2.0) compared to SPECT/CT (2.2) and WB-MRI (2.3). The arm positioning above the head was the most uncomfortable part of the three nuclear medicine scans, whereas the acoustic noise was the most unpleasant part of the WB-MRI. The experience of staff instruction was relatively strongly correlated to the overall scanning experience of all four imaging modalities. Overall, the patients were willing to repeat the four imaging methods and NaF-PET/CT was the method most preferred in both groups. Conclusion Four imaging procedures were evaluated from the perspective of a selected group of prostate cancer patients. NaF-PET/CT, choline-PET/CT, WB-MRI, and bone SPECT/CT are well accepted imaging methods, and most patients prefer NaF-PET/CT.

Elevated levels of oxidative nucleic acid modifications have been proposed to be associated with some of the clinical characteristics of Down syndrome. Oral intake of coenzyme Q10 improves oxidative status and shows a tendency toward protective effect on DNA oxidation in certain age groups of children with Down syndrome. Here, we demonstrate that long-term (i.e., 4 years) treatment with coenzyme Q10 (ubiquinone) at the dosage of 4 mg/kg/d does not affect whole body DNA and RNA oxidation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs., Methods: This study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively., Results: Clarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6-40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7-26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8-37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde., Conclusion: Clarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications., (© 2017 The British Pharmacological Society.)

Introduction: Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). Although glycaemic control reduces microvascular complications, the effect of intensive treatment strategies or individual drugs on macrovascular diseases is still debated. RNA oxidation is associated with increased mortality in patients with T2D. Inspired by animal studies showing effect of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (empagliflozin) on oxidative stress and a recent trial evaluating empagliflozin that demonstrated improved cardiovascular outcomes in patients with T2D at high risk of cardiovascular events, we hypothesise that empagliflozin lowers oxidative stress., Methods and Analysis: In this randomised, double-blinded and placebo-controlled study, 34 adult males with T2D will be randomised (1:1) to empagliflozin or placebo once daily for 14 days as add-on to ongoing therapy. The primary endpoints will be changes in 24-hour urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) determined before and after intervention (by ultra-performance liquid chromatography tandem mass-spectrometry). Additionally, fasting levels of malondialdehyde (MDA) will be determined in plasma before and after intervention (by high-performance liquid chromatography). Further, the plasma levels of iron, transferrin, transferrin-saturation, and ferritin are determined to correlate the iron metabolism to the markers of oxidative modifications., Ethics and Dissemination: The study protocol has been approved by the Regional Committee on Biomedical Research Ethics (approval number H-16017433), the Danish Medicines Agency, and the Danish Data Protection Agency, and will be carried out under the surveillance and guidance of the GCP unit at Bispebjerg Frederiksberg Hospital, University of Copenhagen in compliance with the ICH-GCP guidelines and in accordance with the Declaration of Helsinki. The results of this study will be presented at national and international conferences, and submitted to a peer-reviewed international journal with authorship in accordance with Internation Committee of Medical Journal Editors (ICMJE) Recommendations state., Trial Registration: Study name: EMPOX; Pre-results: clinicaltrials.gov (NCT02890745). Protocol version 5.1 - August, 2016., Competing Interests: Competing interests: JR has received lecture fees from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk and Sanofi, and is a member of the Advisory boards of Novo Nordisk, Merck Sharp & Dohme and Sanofi. TV has received lecture fees from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Novartis, Sanofi, and Zealand Pharma, and is a member of the Advisory Boards of Amgen, Novo Nordisk, Merck Sharp & Dohme and Bristol-Myers Squibb/AstraZeneca. FKK has received lecture fees from, is a member of the Advisory Boards of, has consulted for, and/or received research support from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Gilead Sciences, Merck Sharp & Dohme, Novo Nordisk, Ono Pharmaceuticals, Sanofi and Zealand Pharma. ELL has received a 12 months scholarship from Boehringer Ingelheim. All other authors declare no conflict of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: The purpose of the study is to identify domains of influence on co-workers' ability to be supportive of returning worker during the work reintegration (WR) process., Methods: An ethnographic study design was chosen involving fieldwork at four different workplaces, at an emergency care service, a waste disposal company and at two nursing homes. Qualitative methods for inquiry were used including participant observation, individual- and group interviews of 30 participants. Data were coded and analysed according to a grounded theory approach., Results: Four themes were identified related to domains of influence on co-workers' ability to be supportive of returning worker during the WR process: (1) organisation of work and level of interaction; (2) disruption of work routines, (3) relationship with returning worker and (4) attitudes towards sick leave., Conclusion: The WR process after long-term sick leave is not only influenced by the WR's arrangements made, but also by the co-workers' responses to the process. Work arrangements not only affect the returning worker's ability to return-to-work (RTW) successfully, but also the co-workers' ability to be supportive and their ability to take active part in the process. Implications for Rehabilitation The process of WR after long-term sick leave involves interaction with co-workers. Domains of influence is in the co-workers' perspective influencing their ability to be supportive during reintegration of a returning worker. Future WR management could benefit from integrating the conditions for co-worker support. We encourage co-workers to be involved in the RTW planning, monitoring and evaluation with particular focus on how the WR arrangements are influencing their work and their ability to be supportive.

Background: In the health and care sector, sickness absence and sickness presenteeism are frequent phenomena and constitute a field in need of exploration. Attitudes towards sickness absence involve also attitudes towards sickness presenteeism, i.e. going to work while sick, confirmed by previous studies. Sickness behavior, reflecting attitudes on work absence, could differ between countries and influence absence rates. But little is known about attitudes towards sickness absence and sickness presenteeism in the health and care sectors in Norway and Denmark. The aim of the present paper is therefore to explore attitudes towards sickness absence and sickness presenteeism among nursing home employees in both countries., Methods: Eight focus group discussions (FGDs) were conducted using a semi-structured interview guide, the main attention of which was attitudes towards sickness absence and sickness presenteeism. FGDs were conducted in two nursing homes in Norway and two in Denmark, with different geographic locations: one in a rural area and one in an urban area in each country. FGDs were recorded, transcribed and analyzed using framework analysis to identify major themes and explanatory patterns., Results: Four major significant themes were identified from the FGDs: a) sickness absence and sickness presenteeism, b) acceptable causes of sickness absence, c) job identity, and d) organization of work and physical aspects of the workplace. Our analyses showed that social commitment and loyalty to residents and colleagues was important for sickness absence and sickness presenteeism, as were perceived acceptable and non-acceptable reasons for sickness absence. Organization of work and physical aspects of the workplace were also found to have an influence on attitudes towards sickness absence., Conclusions: The general interpretation of the findings was that attitudes towards sickness absence and sickness presenteeism among nursing home employees were embedded in situational patterns of moral relationships and were connected to a specific job identity. These patterns were constituted by the perception of colleagues, the social commitment to residents, and they influence on what was deemed as acceptable and non-acceptable reasons for sickness absence. In other words, attitudes towards sickness absence and sickness presenteeism were socially and morally determined at personal levels by an overall concept of work, independent of country.

Purpose: Biopsychosocial interventions in low back pain (LBP) rehabilitation aim at preparing patients to accept and manage their pain conditions and to encourage them to maintain their everyday life routines. Although such approaches have demonstrated a positive effect, for example, in relation to return to work (RTW), few studies have explored how social contexts influence how pain is being managed. Using a theoretical approach that addresses pain as social performance, we illustrate how pain is expressed and managed in three different contexts: at the clinic, at home and at work., Methods: Qualitative in-depth interviews were conducted with eight patients who had followed a hospital-based RTW intervention., Results: Low back patients experience dilemmas of how to express their pain sensations and constantly evaluate whether the activities they participate in will ease or worsen their pain sensations. In this process, their behavior is guided by how they think their social role will be affected by their decision to abstain from or undertake the activities in question., Conclusions: Interventions in rehabilitation may benefit from knowledge of the social processes at play when LBP patients articulate, express and suppress their symptoms in their interaction with health professionals, workmates, families and friends., Implications for Rehabilitation: Low back pain • In order to manage pain, patients with low back pain are encouraged to exercise and to maintain their everyday activities. • Choosing to become physically active, although in pain, is related to those social roles one wishes to maintain or support. • Future interventions could offer support so that patients will be able both to maintain their social roles and to retire from social activities without their social roles being threatened.

Background: The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials., Procedures: Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome., Results: The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥ 100,000/microliter. Day 29 marrow MRD positive (≥ 0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors., Conclusions: Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients., (Copyright © 2011 Wiley-Liss, Inc.)

Communities in health literature are often treated as homogeneous entities, in which community members are believed to share needs, goals, resources and social and cultural values. This perception of community is too narrow to grasp the complexity and dynamics of community life and neglect the different ways community members use, perceive and interact in their community. In this study, we outline a theoretical approach that embraces community diversity, by focusing on how community life is being practiced by its members and how they interact with each other. Adopting this theoretical approach, ethnographic fieldwork was conducted in a multi-ethnic and socially deprived neighbourhood in Denmark, which had undergone a long process of community building. We found five major ways of community practices based on interactions (i) in specific community spaces, (ii) related to specific activities, (iii) in sharing experiences of community history, (iv) on loyalty within one's social networks and (v) on sharing ethnicity. Distinguishing between different modes of interacting in community, offers a holistic perspective that includes those 'invisible' community members who usually do not participate in community development programmes. We argue that working with a more thorough understanding of the contrasting realities of community life is particularly useful for health professionals who are engaged in community organizing and in encouraging members to participate in building healthy communities.

Orthotopic bladder cancer model in rats mimics human bladder cancer with respect to urothelial tumorigenesis and progression. Utilizing this model at pT1 (superficial stage), we analyze the tissue responses to hexyl 5-aminolevulinate-induced photodynamic therapy (HAL-PDT). In comparison to untreated rats, HAL-PDT causes little change in tumor-free rat bladder but induces inflammatory changes with increased lymphocytes and mononuclear cell infiltration in rat bladders with tumor. Immunohistochemistry reveals that HAL-PDT is without effect on proliferating cell nuclear antigen expression within the tumor and increases caspase-3 expression in both normal urothelium and the tumor. Transmission electron microscopy reveals severe mitochondrial damage, formations of apoptotic bodies, vacuoles, and lipofuscin bodies, but no microvillus-formed niches in HAL-PDT-treated bladder cancer rats. Bioinformatics analysis of the gene expression profile indicates an activation of T-cell receptor signaling pathway in bladder cancer rats without PDT. HAL-PDT increases the expression of CD3 and CD45RA in the tumor (determined by immunohistochemistry). We suggest that pathways of action of HAL-PDT may include, at least, activations of mitochondrial apoptosis and autophagy, breakdown of cancer stem cell niches, and importantly, enhancement of T-cell activation.

Vulnerable plaques constitute a risk for serious heart problems, and are difficult to identify using existing methods. Hyperspectral imaging combines spectral- and spatial information, providing new possibilities for precise optical characterization of atherosclerotic lesions. Hyperspectral data were collected from excised aorta samples (n = 11) using both white-light and ultraviolet illumination. Single lesions (n = 42) were chosen for further investigation, and classified according to histological findings. The corresponding hyperspectral images were characterized using statistical image analysis tools (minimum noise fraction, K-means clustering, principal component analysis) and evaluation of reflectance/fluorescence spectra. Image analysis combined with histology revealed the complexity and heterogeneity of aortic plaques. Plaque features such as lipids and calcifications could be identified from the hyperspectral images. Most of the advanced lesions had a central region surrounded by an outer rim or shoulder-region of the plaque, which is considered a weak spot in vulnerable lesions. These features could be identified in both the white-light and fluorescence data. Hyperspectral imaging was shown to be a promising tool for detection and characterization of advanced atherosclerotic plaques in vitro. Hyperspectral imaging provides more diagnostic information about the heterogeneity of the lesions than conventional single point spectroscopic measurements.

Hyperspectral imaging, image analysis and diffusion theory were used to visualize skin vasculature and to monitor the development of fresh skin bruises. Bruises were inflicted in a porcine model, and the development of the hemorrhage was monitored using white light hyperspectral imaging (400-1000 nm). Hyperspectral images from human volunteers were also included in the study. Statistical image analysis was used to classify bruised regions and to visualize the skin vasculature. Biopsies were collected from the animals to reveal the true depth of the bruising. A three-layer diffusion model and an analytic hemoglobin transport model were used to model the reflectance spectra from the images. The results show that hyperspectral images contain depth information, and that the approximate depth and extent of bruises can be retrieved using a combination of statistical image analysis and diffusion theory. This technique also shows potential to visualize vascular structures in human skin., (2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Health promotion at a community level has gained popularity in recent decades within and outside academic environments. The health promotion discourse is part of a wider political discourse, aimed at empowering individuals to take control of their own lives and enabling them to be engaged, responsible and active citizens in their own communities. Key values of the discourse, deriving from a democratic and individualistic culture, are evident in how local authorities develop and implement policies aimed at promoting population health and wellbeing. In this article, we draw on data from a relatively poor multicultural Danish community incorporated in the WHO Healthy Cities Programme. We explore how key terms of the health promoting discourse are constructed, operationalized and resisted by different subgroups. The contradictions that emerge challenge how we comprehend communities in relation to safety and harmony, and how people within defined communities are involved in common community life.

Monitoring of the tissue response to photodynamic therapy (PDT) can provide important information to help optimize treatment variables such as drug and light dose, and possibly predict treatment outcome. A urinary bladder cancer cell line (AY-27) was used to induce orthotopic transitional cell carcinomas (TCC) in female Fischer rats, and hexyl 5-aminolevulinate (HAL, 8 mM, 1 h)-induced PDT was performed on day 14 after instillation of the cancer cells (20 J/cm(2) fluence at 635 nm). In vivo optical reflectance and fluorescence spectra were recorded from bladders before and after laser treatment with a fiberoptic probe. Calculated fluorescence bleaching and oxygen saturation in the bladder wall were examined and correlated to histology results. Reflectance spectra were analyzed using a three-layer optical photon transport model. Animals with TCC treated with PDT showed a clear treatment response; decreased tissue oxygenation and protoporphyrin IX (PpIX) fluorescence photobleaching were observed. Histology demonstrated that 3 of 6 animals with treatment had no sign of the tumor 7 days after PDT treatment. The other 3 animals had significantly reduced the tumor size. The most treatment-responsive animals had the highest PpIX fluorescence prior to light irradiation. Thus, optical spectroscopy can provide useful information for PDT. The model has proved to be very suitable for bladder cancer studies.

Background and Objective: Bruises are currently evaluated by visual inspection, and little is known about the first phase after injury. The temporal development of fresh injuries must be accurately described to be able to age bruises in a reliable manner. Color changes in a bruise caused by hemoglobin breakdown products will depend on the severity of the trauma, and thus on the local immune response in the skin. It is therefore important to relate the nature of the impact to the temporal tissue responses., Materials and Methods: Controlled injuries were inflicted on anesthetized domestic pigs. Trauma was induced either by a pendulum device, or by paintballs released using pressurized air. The speed of the projectiles was recorded using a high speed camera. Biopsies and reflection spectra (400-850 nm) were collected from normal and bruised skin. The experiments were approved by the national animal research authority., Results: The temporal development of the injury was found to depend strongly on the weight and speed of the object. Low speed, blunt objects did not cause persistent skin changes. However, deep muscular bleeding could be found in most cases. High speed, light weight objects caused a rapidly developing bruise. These bruises were fully developed within 15-20 minutes. No deep muscular hemorrhages were observed in those cases. White blood cells (neutrophilic granulocytes) could be found in biopsies from high speed injuries. The amount of white blood cells depended on the time between injury and collection of the biopsies., Conclusion: Further investigations utilizing a larger range of object weight and velocities are required to be able to fully classify minor traumatic injuries. Preliminary results indicate that this can be achieved by controlled experiments using a porcine model. Reflectance spectroscopy was found to be a useful tool to study immediate skin reactions to the trauma., ((c) 2007 Wiley-Liss, Inc.)

Intravascular thermography has been proposed as a method for detecting vulnerable plaque. A marker of vulnerability in a plaque is inflammation, which is believed to reduce its mechanical stability. It has been hypothesized that this inflammation leads to a higher metabolic rate and therefore higher heat generation, causing increased temperature in the vicinity of the plaque. This temperature increase could be measured intravascularly using a temperature sensor, e.g., a thermistor or a thermocouple. The aim of this study is to present a thorough mathematical and physical analysis of the thermal distribution that can be expected in the plaque under various physiological conditions. To get reasonable predictions on the expected temperature distributions, idealized models with simple geometries are solved analytically. More realistic models, with more complex geometries, are solved numerically using the finite element method (FEM). Based on this analysis, the maximum temperature increase that can be expected in a plaque due to increased metabolism is less than 0.1 K.