Complete clearance and psoriasis area and severity index response for brodalumab and ustekinumab in AMAGINE-2 and -3.

BACKGROUND: Modern biologics achieve complete skin clearance [100% improvement in psoriasis area and severity index (PASI 100)] in 30-45% of psoriasis patients. Cumulative benefit considering rapidity, frequency and sustainability of response has not been thoroughly investigated. OBJECTIVES: Compare the frequency, rapidity and sustainability of PASI 90 and 100 response in patients with moderate-to-severe psoriasis treated with brodalumab or ustekinumab. METHODS: Integrated analyses of the brodalumab Phase III AMAGINE-2 (NCT01708603) and -3 (NCT01708629) trials were performed to determine proportion of patients achieving PASI response per visit; corresponding odds ratios (OR) were calculated. Cumulative clinical benefit of treatment was determined with area-under-the-curve (AUC) analysis. Cumulative incidence of response was analysed using a competing risk model of PASI response or rescue. Sustained response was evaluated by time to inadequate response using Kaplan-Meier methods. Proportion of time spent in different response states was descriptively analysed. Association between PASI response and health-related quality of life [Dermatology Life Quality Index (DLQI)] was assessed using data from all treatment groups from AMAGINE-1, -2 and -3. RESULTS: A significantly higher proportion of patients treated with brodalumab achieved PASI 100 vs. ustekinumab (Week 52: 51% vs. 28%; OR [95% CI] 2.8 [2.1, 3.7]; P < 0.0001), with significant differences observed from Week 4. Cumulative benefit through 52 weeks was 69% higher with brodalumab (AUC ratio: 1.69; P < 0.001). Brodalumab patients were also significantly more likely to achieve a PASI 100 at least once over 52 weeks vs. ustekinumab (76% vs. 52%; P < 0.0001). Once response was achieved, brodalumab patients had a low likelihood of failure or need for rescue. There was significant positive association between PASI response level and DLQI0/1 achievement (P < 0.0001). CONCLUSION: Brodalumab treatment resulted in significantly higher levels of skin clearance, longer sustained response and greater cumulative treatment benefit vs. ustekinumab.

Complete clearance and Psoriasis Area and Severity Index response for brodalumab and ustekinumab by previous treatment history in AMAGINE-2 and AMAGINE-3.

BACKGROUND: The pathway for treatment of psoriasis is partly dependent upon disease severity, and patients may experience inadequate response at any point along the treatment pathway. Patients who repeatedly fail therapy represent a population in whom effective and well-tolerated treatment options are limited. OBJECTIVES: To investigate and describe patients achieving Psoriasis Area and Severity Index (PASI) 100 and cumulative treatment benefit over time in patients with moderate-to-severe psoriasis receiving brodalumab or ustekinumab by prior treatment. METHODS: We conducted a post hoc analysis of data from two phase 3, randomized, controlled, 52-week AMAGINE trials of brodalumab to describe patients who achieved complete clearance as measured by PASI 100 by prior treatment subgroup (naïve to systemic and biologic treatment, systemic-treated but biologic-naïve, biologic-treated without failure, and biologic-treated with failure). A competing risk model was used to assess cumulative incidence over a 52-week period with outcomes of PASI 100 or inadequate response. Cumulative clinical benefit of treatment was determined with an area under the curve analysis. RESULTS: The 52-week cumulative incidence of patients achieving PASI 100 was consistently higher for brodalumab vs. ustekinumab across treatment pathway subgroups (76% vs. 58% in systemic/biologic-naïve patients, 78% vs. 55% in systemic-treated/biologic-naïve patients, 75% vs. 41% in biologic-treated patients without failure, and 70% vs. 30% in biologic-treated patients with failure). Rates of inadequate response were lower with brodalumab compared with ustekinumab across all subgroups. Cumulative treatment benefit was also higher for all subgroups treated with brodalumab compared with those treated with ustekinumab. CONCLUSION: Treatment with brodalumab was associated with higher levels of complete clearance and greater cumulative benefit over time compared with ustekinumab, in patients with moderate-to-severe psoriasis, regardless of prior treatment experience.

Calcipotriol plus betamethasone dipropionate aerosol foam vs. apremilast, methotrexate, acitretin or fumaric acid esters for the treatment of plaque psoriasis: a matching-adjusted indirect comparison.

BACKGROUND: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. OBJECTIVE: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. METHODS: Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included. RESULTS: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451). CONCLUSIONS: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.

Can public health registry data improve Emergency Medical Dispatch?

BACKGROUND: Emergency Medical Dispatchers make decisions based on limited information. We aimed to investigate if adding demographic and hospitalization history information to the dispatch process improved precision. METHODS: This 30-day follow-up study evaluated time-critical emergencies in contact with the emergency phone number 112 in Denmark during 18 months. 'Time-critical' was defined as suspected First Hour Quintet (FHQ) (cardiac arrest, chest pain, stroke, difficulty breathing, trauma). The association of age, sex, and hospitalization history with adverse outcomes was examined using logistic regression. The predictive ability was assessed via area under the curve (AUC) and Hosmer-Lemeshow tests. RESULTS: Of 59,943 patients (median age 63 years, 45% female), 44-45.5% had at least one chronic condition, 3880 (6.47%) died the day or the day after (primary outcome) calling 112. Age 30-59 was associated with increased adjusted odds ratio (OR) of death on day 1 of 3.59 [2.88-4.47]. Male sex was associated with an increased adjusted OR of death on day 1 of 1.37 [1.28-1.47]. Previous hospitalization with nutritional deficiencies (adjusted OR 2.07 [1.47-2.92]) and severe chronic liver disease (adjusted OR 2.02 [1.57-2.59]) was associated with a higher risk of death. For trauma patients, the discriminative ability of the model showed an AUC of 0.74 for death on day 1. CONCLUSION: Increasing age, male sex, and hospitalization history was associated with increased risk of death on day 1 for FHQ 112 callers. Additional efforts are warranted to clarify the role for risk prediction tools in emergency medical dispatch.

The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing.

AIMS/HYPOTHESIS: Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown to be protective against diabetes, although the mechanisms remain largely unknown. The aim of this study was to determine how SIRT1 regulates insulin secretion in the pancreatic beta cell. METHODS: Pancreatic beta cell-specific Sirt1 deletion was induced by tamoxifen injection in 9-week-old Pdx1CreER:floxSirt1 mice (Sirt1BKO). Controls were injected with vehicle. Mice were assessed metabolically via glucose challenge, insulin tolerance tests and physical variables. In parallel, Sirt1 short interfering RNA-treated MIN6 cells (SIRT1KD) and isolated Sirt1BKO islets were used to investigate the effect of SIRT1 inactivation on insulin secretion and gene expression. RESULTS: OGTTs showed impaired glucose disposal in Sirt1BKO mice due to insufficient insulin secretion. Isolated Sirt1BKO islets and SIRT1KD MIN6 cells also exhibited impaired glucose-stimulated insulin secretion. Subsequent analyses revealed impaired α-ketoisocaproic acid-induced insulin secretion and attenuated glucose-induced Ca(2+) influx, but normal insulin granule exocytosis in Sirt1BKO beta cells. Microarray studies revealed a large cluster of mitochondria-related genes, the expression of which was dysregulated in SIRT1KD MIN6 cells. Upon further analysis, we demonstrated an explicit defect in mitochondrial function: the inability to couple nutrient metabolism to mitochondrial membrane hyperpolarisation and reduced oxygen consumption rates. CONCLUSIONS/INTERPRETATION: Taken together, these findings indicate that in beta cells the deacetylase SIRT1 regulates the expression of specific mitochondria-related genes that control metabolic coupling, and that a decrease in beta cell Sirt1 expression impairs glucose sensing and insulin secretion.

A modified clot-based assay to measure negatively charged procoagulant phospholipids.

Growing evidence supports a role for extracellular vesicles (EVs) in haemostasis and thrombosis due to exposure of negatively charged procoagulant phospholipids (PPL). Current commercial PPL-dependent clotting assays use chemically phospholipid depleted plasma to measure PPL activity. The purpose of our study was to modify the PPL assay by substituting the chemically phospholipid depleted plasma with PPL depleted plasma obtained by ultracentrifugation This in order to get readily access to a sensitive and reliable assay to measure PPL activity in human plasma and cell supernatants. The performance of the assay was tested, including the influence of individual coagulation factors and postprandial lipoproteins and compared to a commercial PPL assay (STA-Procoag-PPL). The two PPL assays displayed similar sensitivity to exogenously added standardized phospholipids. The PPL activity measured by the modified assay strongly correlates with the results from the commercial assay. The intraday- and between-days coefficients of variation ranged from 2-4% depending on the PPL activity in the sample. The modified PPL assay was insensitive to postprandial lipoprotein levels in plasma, as well as to tissue factor (TF) positive EVs from stimulated whole blood. Our findings showed that the modified assay performed equal to the comparator, and was insensitive to postprandial lipoproteins and TF+ EVs.

Bone loss in relation to serum levels of osteoprotegerin and nuclear factor-kappaB ligand: the Tromsø Study.

SUMMARY: In this longitudinal study of 4,137 persons, bone mineral density was negatively associated with osteoprotegerin at baseline in both genders. In postmenopausal women not using hormone replacement therapy (HRT), bone-loss increased with increasing osteoprotegerin levels, whereas no relationship was found in men, premenopausal women, or postmenopausal women taking HRT. INTRODUCTION: In a population-based study of 2,003 men and 2,134 women, the relationship between the osteoprotegerin (OPG)/factor-kappaB ligand (RANKL) system and bone mineral density (BMD) and changes in BMD was examined. METHODS: Baseline measurements included height, weight, BMD of the forearm, OPG, RANKL, vitamin D, and serum parathyroid hormone (PTH) and information about lifestyle, prevalent diseases, and use of medication. BMD was remeasured at follow-up 6 years later. RESULTS: BMD was negatively associated with OPG at baseline in both men and women (p trend over OPG levels = 0.01 and 0.007, respectively, after adjustments for age, and other confounders). In postmenopausal women not on hormone replacement therapy, bone loss increased with increasing OPG (p = 0.005), whereas no relationship was found in men, premenopausal women, or postmenopausal women on HRT (p >or= 0.28). BMD at baseline and BMD changes were not related to RANKL levels in any of the groups (p >or= 0.14). CONCLUSIONS: In postmenopausal women not using HRT, bone loss associated positively with OPG. The results indicate that in women deficient in sex steroids, the OPG/RANKL system may play an important counter regulatory role in order to avoid bone loss and maintain BMD. In men and women replete in sex steroids, the OPG/RANKL system was not associated with BMD.

Late sensory function after intraoperative capsaicin wound instillation.

BACKGROUND: Intense capsaicin-induced C-fiber stimulation results in reversible lysis of the nerve soma, thereby making capsaicin wound instillation of potential interest for the treatment of post-operative pain. Clinical histological and short-term sensory studies suggest that the C-fiber function is partly re-established after skin injection of capsaicin. However, no study has evaluated the long-term effects of wound instillation of purified capsaicin on sensory functions. METHODS: Patients included in a double-blind placebo-controlled randomized study of the analgesic effect of capsaicin after groin hernia repair were examined by quantitative sensory testing before, 1 week and 2 years post-operatively. The primary endpoint was occurrence of hyperalgesia/allodynia. The secondary endpoints were acute and late sensory changes between the two patient groups. Patients were blinded to the allocated treatment. RESULTS: Twenty (100%) capsaicin and 16 (76%) placebo-treated patients were seen at the 2 1/2 year follow-up. Hyperalgesia was seen in five capsaicin- vs. one placebo-treated patient (P=0.2). The mechanical detection threshold was significantly increased on the operated side in the capsaicin vs. placebo group at the 1-week follow-up (P<0.05), but was not different at the 2 1/2 year follow-up (P=0.3). There were no other significant differences in sensory function on the operated side between groups at the pre-operative, 1-week or 2 1/2 year post-operative follow-up (P>0.05). The sensory function on the contralateral side was comparable between groups throughout the study (P>0.1). CONCLUSION: This small-volume study calls for further long-term safety studies of wound capsaicin instillation.

Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of long-term budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis. DESIGN: Randomised, placebo-controlled study with a 24-week, blinded follow-up period without any treatment. SETTING: Three gastroenterology clinics in Denmark. PATIENTS: Forty-two patients with histologically confirmed collagenous colitis and diarrhoea (more than three stools/day). INTERVENTIONS: Patients in clinical remission after 6 weeks' open-label therapy with oral budesonide (Entocort CIR capsules, 9 mg/day) received 24 weeks' double-blind maintenance therapy with budesonide 6 mg/day or placebo. Thereafter, patients entered the 24-week, blinded follow-up period. MAIN OUTCOME MEASURE: The proportion of patients in clinical remission (three or fewer stools/day) at the end of maintenance therapy. FINDINGS: A total of 34 patients in remission at week 6 were randomly assigned to budesonide 6 mg/day (n = 17) or placebo (n = 17). After 24 weeks' maintenance treatment, the proportions of patients in clinical remission were 76.5% (13 of 17) with budesonide and 12% (2 of 17) with placebo (p<0.001). At 48 weeks (the end of the follow-up period, without any treatment) these values were 23.5% (4 of 17) and 12% (2 of 17), respectively (p = 0.6). The median times to relapse after stopping active treatment (6 plus 24 weeks in the budesonide group; 6 weeks in the placebo group) were 39 and 38 days, respectively. Long-term treatment with budesonide was well tolerated. CONCLUSIONS: Long-term maintenance therapy with oral budesonide is efficacious and well tolerated for preventing relapse in patients with collagenous colitis. The risk of relapse after 24 weeks' maintenance treatment is similar to that observed after 6 weeks' induction therapy.

Recent advances in solid oxide cell technology for electrolysis.

In a world powered by intermittent renewable energy, electrolyzers will play a central role in converting electrical energy into chemical energy, thereby decoupling the production of transport fuels and chemicals from today's fossil resources and decreasing the reliance on bioenergy. Solid oxide electrolysis cells (SOECs) offer two major advantages over alternative electrolysis technologies. First, their high operating temperatures result in favorable thermodynamics and reaction kinetics, enabling unrivaled conversion efficiencies. Second, SOECs can be thermally integrated with downstream chemical syntheses, such as the production of methanol, dimethyl ether, synthetic fuels, or ammonia. SOEC technology has witnessed tremendous improvements during the past 10 to 15 years and is approaching maturity, driven by advances at the cell, stack, and system levels.

Scaling Behavior of Quasi-One-Dimensional Vortex Avalanches in Superconducting Films.

Scaling behaviour of dynamically driven vortex avalanches in superconducting YBa2Cu3O7-δ films deposited on tilted crystalline substrates has been observed using quantitative magneto-optical imaging. Two films with different tilt angles are characterized by the probability distributions of avalanche size in terms of the number of moving vortices. It is found in both samples that these distributions follow power-laws over up to three decades, and have exponents ranging between 1.0 and 1.4. The distributions also show clear finite-size scaling, when the system size is defined by the depth of the flux penetration front - a signature of self-organized criticality. A scaling relation between the avalanche size exponent and the fractal dimension, previously derived theoretically from conservation of the number of magnetic vortices in the stationary state and shown in numerical simulations, is here shown to be satisfied also experimentally.

Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment.

BACKGROUND: The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment. OBJECTIVES: The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI. PATIENTS/METHODS: In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n=57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n=68) or warfarin (INR 2.8-4.2) (n=61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment. RESULTS: Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r=0.38 and 0.36 respectively, p<0.01 for both) and with F1+2 (r=0.26 and 0.23 respectively, p=0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (-28%+/-5%, p<0.001), and patients treated with aspirin/warfarin (-24%+/-8%, p=0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (-18%+/-7%, p=0.049) and aspirin/warfarin (-19%+/-5%, p=0.029), whereas an increase (12%+/-4%, p=0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p=0.001 for both). CONCLUSIONS: In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.

Switching from NPH insulin to once-daily insulin detemir in basal-bolus-treated patients with diabetes mellitus: data from the European cohort of the PREDICTIVE study.

BACKGROUND: The PREDICTIVE study is a multinational observational study designed to follow up patients with diabetes who started insulin detemir (IDet) in routine care. Recruitment started in June 2004 and is ongoing in some countries. METHODS: We report 12-week follow-up data for patients with type 1 (T1D) or type 2 diabetes (T2D) in the European cohort who, as part of basal-bolus therapy, switched from once- (qd) or twice-daily (bid) neutral protamine Hagedorn insulin (NPH) to qd IDet. End-points - evaluated from patients' records and diaries - were incidence of serious adverse drug reactions, glycaemic parameters, hypoglycaemia and weight change. RESULTS: A total of 3637 patients were included, n = 1500 T1D [mean age 40.9 years, body mass index (BMI) 25.0 kg/m(2), glycosylated haemoglobin (HbA(1c)) 7.9%] and n = 2137 T2D (mean age 60.5 years, BMI 31.9 kg/m(2), HbA(1c) 8.0%). IDet was well tolerated. Lower overall, major and nocturnal rates of hypoglycaemia were observed in T1D and T2D patients switching from NPH to IDet (overall, T1D: 38.2-18.56 episodes/patient year, p < 0.001; T2D: 13.8-3.3 [corrected] episodes/patient year, p < 0.001). Switching from bid NPH to qd IDet resulted in significant 12-week reductions in HbA(1c) (T1D: -0.40%; T2D: -0.56%; both p < 0.001). Switching from qd NPH to qd IDet, resulted in HbA(1c) reductions of: T1D -0.52%; T2D -0.56%; both p < 0.001. Fasting blood glucose levels were also significantly reduced in patients with T1D or T2D. Overall mean weight changes were: T1D: 0.0 kg, T2D: -0.2 kg after 12 weeks. CONCLUSION: In routine care, patients with T1D or T2D may be switched from NPH to IDet qd as part of a basal-bolus regimen.

Insulin detemir improves glycaemic control without weight gain in insulin-naïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study.

OBJECTIVE: Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) is a multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. This post hoc subanalysis evaluates insulin-naïve patients on oral antidiabetic drugs (OADs) who were initiated on insulin detemir as basal therapy (+/- OADs). METHODS: The European cohort of the PREDICTIVE study currently includes 20,531 patients (12,981 with type 2 diabetes) who were prescribed insulin detemir and followed up for 12, 26 or 52 weeks. Here, we report data from a subgroup of 2377 OAD-treated, insulin-naïve type 2 diabetes patients for a mean follow-up of 14.4 weeks. Patients were prescribed insulin detemir as basal therapy (+/- OADs) by their physician, as part of routine clinical care. Results were reported in comparison with baseline observations. RESULTS: One serious adverse drug reaction was reported, which was a major hypoglycaemic episode. Treatment with insulin detemir (+/- OADs) significantly reduced mean haemoglobin A(1c) (HbA(1c)) (-1.3%; p < 0.0001), fasting glucose (-3.7 mmol/l; p < 0.0001), and within-patient fasting glucose variability (-0.5 mmol/l; p < 0.0001). In the majority of patients (82%), these improvements in glycaemic control were achieved with once daily administration of insulin detemir. There was a small reduction in mean body weight (-0.7 kg; p < 0.0001), which was most apparent in patients with a higher body mass index (BMI) at baseline. A significant negative relationship between weight change and baseline BMI was observed (greater the BMI, greater the weight reduction). Multiple regression analysis showed that BMI and HbA(1c) at baseline, and change in HbA(1c), were all predictors for weight change (p < 0.0001 for all), with BMI being the strongest predictor. CONCLUSIONS: Patients with type 2 diabetes naïve to insulin can be effectively treated with once-daily insulin detemir (+/- OADs) to achieve improved glycaemic control with no adverse effect on weight and a low risk of hypoglycaemia. These short-term results are consistent with the findings of clinical trials.

Repeated assessments of physical activity and risk of incident venous thromboembolism.

Essentials It is debated whether physical activity influences the risk of venous thromboembolism. The association was explored accounting for fluctuations in physical activity over time. Overall and in the elderly, physical activity was associated with 23% and 30% lower risk. A moderate proportion of the association (14-36%) was mediated via body mass index. SUMMARY: Background Whether physical activity influences the risk of incident venous thromboembolism (VTE) remains controversial, potentially because of methodological challenges, such as regression dilution bias. Objectives To investigate whether physical activity was associated with VTE risk, and explore the role of body mass index (BMI) as a mediator in a population-based cohort with repeated assessments of physical activity. Methods Participants (n = 30 002) attending one or more surveys of the Tromsø Study 4-6 (1994-1995, 2001-2002, and 2007-2008) were included and categorized on the basis of weekly physical activity. Incident VTE was registered until 31 December 2016. Hazard ratios (HRs) were calculated by the use of time-varying Cox regression models. The Aalen additive hazard model was used to quantify the total, direct and indirect effects of physical activity. Results There were 531 incident VTEs during follow-up. Physical activity (≥ 1 per week) was associated with a lower risk of VTE (HR 0.77, 95% confidence interval [CI] 0.64-0.92) than being inactive. The effect was most pronounced for those aged ≥ 65 years (HR 0.70, 95% CI 0.55-0.88) and for provoked events (HR 0.66, 95% CI 0.50-0.89). The differences in absolute risk between active and inactive individuals were - 0.42 (95% CI - 0.73 to - 0.14) and - 1.59 (95% CI - 2.74 to - 0.52) events annually per 1000 individuals in the total and elderly populations, respectively. A moderate proportion of the association (14-36%) was mediated via BMI. Conclusion Our findings suggest that regular physical activity is associated with a lower risk of VTE, particularly in the elderly. The association occurred at a low weekly amount of physical activity, and was only partly mediated by BMI.

Elevated plasma levels of P-selectin glycoprotein ligand-1-positive microvesicles in patients with unprovoked venous thromboembolism.

Essentials PSGL-1+ microvesicles (MVs) may be important in venous thromboembolism (VTE). We measured plasma levels and parental origin of PSGL-1+ MVs in patients with unprovoked VTE. VTE patients had higher plasma levels of PSGL-1+ MVs than healthy controls. The PSGL-1+ MVs originated mainly from monocytes and endothelial cells. SUMMARY: Background Microvesicles (MVs) express antigens from their parental cells and have a highly procoagulant surface. Animal studies suggest that P-selectin glycoprotein ligand-1-positive (PSGL-1+ ) MVs play a role in the pathogenesis of venous thromboembolism (VTE). Objective The aim of this study was to determine plasma levels, the cellular origin and the morphological characteristics of PSGL-1+ MVs in patients with unprovoked VTE. Methods We conducted a population-based case-control study in 20 patients with a history of unprovoked VTE and 20 age- and sex-matched healthy controls recruited from the general population. Plasma levels, the cellular origin and the morphological characteristics of PSGL-1+ MVs were evaluated using flow cytometry, electron microscopy and confocal microscopy. Results Plasma levels of PSGL-1+ MVs were associated with increased risk of VTE. The odds ratio per one standard deviation increase in PSGL-1+ MVs was 3.11 (95% confidence interval [CI], 1.41-6.88) after adjustment for age and sex, and 2.88 (95% CI, 1.29-6.41) after further adjustment for body mass index. The PSGL-1+ MVs originated mainly from monocytes and endothelial cells determined by double staining with markers of parental cells using flow cytometry and transmission electron microscopy. Scanning electron microscopy of PSGL-1-labeled plasma-derived MVs displayed dominantly spherical vesicles that varied between 50 and 300 nm in diameter. Conclusions Increased plasma levels of PSGL-1+ MVs are associated with the risk of unprovoked VTE. Large population-based prospective studies are required to validate our findings.

Discovery of novel plasma biomarkers for future incident venous thromboembolism by untargeted synchronous precursor selection mass spectrometry proteomics.

Essentials Discovery of predictive biomarkers of venous thromboembolism (VTE) may aid risk stratification. A case-control study where plasma was sampled before the occurrence of VTE was established. We generated untargeted plasma proteomic profiles of 200 individuals by use of mass spectrometry. Assessment of the biomarker potential of 501 proteins yielded 46 biomarker candidates. ABSTRACT: Background Prophylactic anticoagulant treatment may substantially reduce the incidence of venous thromboembolism (VTE) but entails considerable risk of severe bleeding. Identification of individuals at high risk of VTE through the use of predictive biomarkers is desirable in order to achieve a favorable benefit-to-harm ratio. Objective We aimed to identify predictive protein biomarker candidates of VTE. Methods We performed a case-control study of 200 individuals that participated in the Tromsø Study, a population-based cohort, where blood samples were collected before the VTE events occurred. Untargeted tandem mass tag-synchronous precursor selection-mass spectrometry (TMT-SPS-MS3)-based proteomic profiling was used to study the plasma proteomes of each individual. Results Of the 501 proteins detected in a sufficient number of samples to allow multivariate analysis, 46 proteins were associated with VTE case-control status with P-values below the 0.05 significance threshold. The strongest predictive biomarker candidates, assessed by statistical significance, were transthyretin, vitamin K-dependent protein Z and protein/nucleic acid deglycase DJ-1. Conclusions Our untargeted approach of plasma proteome profiling revealed novel predictive biomarker candidates of VTE and confirmed previously reported candidates, thereby providing conceptual support for the validity of the study. A larger nested case-control study will be conducted to validate our findings.

Joint effects of prothrombotic genotypes and body height on the risk of venous thromboembolism: the Tromsø study.

Essentials Body height and prothrombotic genotypes are associated with risk of venous thromboembolism (VTE). The joint effect of prothrombotic genotypes and tall stature on VTE risk is scarcely investigated. We investigated the joint effect of prothrombotic genotypes and tall stature on VTE risk. Prothrombotic genotypes did not yield excess risk of VTE in subjects with a tall stature. SUMMARY: Background Studies have reported synergistic effects of prothrombotic single-nucleotide polymorphisms (SNPs) and obesity on the risk of venous thromboembolism (VTE). Tall stature is associated with an increased VTE risk, but the joint effect of prothrombotic genotypes and tall stature on the VTE risk is unknown. Aims To investigate the joint effects of prothrombotic genotypes and tall stature on the VTE risk. Methods Cases with incident VTE (n = 676) and a randomly selected age-weighted subcohort (n = 1842) were sampled from the Tromsø study (cohort follow-up: 1994-2012). DNA was genotyped for rs6025 (factor V Leiden), rs1799963 (FII), rs8176719 (ABO blood group), rs2066865 (fibrinogen-γ), and rs2036914 (FIX). Age-adjusted and sex-adjusted hazard ratios (HRs) of VTE were calculated by categories of risk alleles (de Haan 5-SNP score: 0-1, 2-3, and ≥ 4) and body height (< 40th, 40th-80th and > 80th percentiles). Results The VTE risk increased by increasing category of body height, and subjects with height ≥ 178 cm had a two-fold higher VTE risk (HR 2.03; 95% confidence interval [CI] 1.51-2.73) than those with height ≤ 165 cm. The VTE risk also increased across categories of risk alleles. However, the combination of a tall stature and risk alleles, either individual SNPs or risk score, did not result in an excess VTE risk. Subjects with four or more risk alleles and height ≥ 178 cm had a two-fold (HR 2.08; 95% CI 1.24-3.52) higher VTE risk than subjects ≤ 165 cm with no risk allele or one risk allele. Conclusions In contrast to obesity, the presence of prothrombotic genotypes did not result in an excess VTE risk in subjects with a tall stature.

Impact of time since diagnosis and mortality rate on cancer-associated venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) cohort.

Essentials Competing risk by death may lead to overestimation of venous thromboembolism (VTE) risk in cancers. We assessed the risk of VTE in cancer with and without accounting for competing risk by death. The risk of VTE was influenced by the mortality rate and the time since cancer diagnosis. Competing risk by death should be taken into account when exploring VTE risk in cancer. SUMMARY: Background Venous thromboembolism (VTE) is a common complication in cancer, and studies have suggested that aggressive cancers create the highest risk of VTE. However, competing risk by death may result in overestimation of VTE risk in patients with cancers associated with high mortality. Therefore, we estimated the risk of VTE by cancer site, accounting for the differential mortality between cancers. Methods The Scandinavian Thrombosis and Cancer cohort included 144 952 participants followed from 1993-1997 to 2008-2012. Incidence rates, cause-specific hazard ratios (HRs) and subdistribution HRs (SHRs) were assessed for overall cancer and by cancer site according to time intervals since cancer diagnosis. Results During follow-up, 14 272 subjects developed cancer, and 567 had cancer-related VTE. In cause-specific analyses, the VTE risk was highest in the first 6 months after cancer diagnosis (HR 17.5, 95% confidence interval [CI] 15.1-20.3), and declined rapidly thereafter. However, when mortality was taken into account, the risk was similar in the periods 6 months before (SHR 4.8, 95% CI 3.6-6.4) and 6 months after (SHR 4.6, 95% CI 3.9-5.4) cancer diagnosis. The range of the 2-year cumulative VTE incidence rates was substantially narrowed for all cancer sites after competing risk by death was taken into account (from 1-10% to 1-4%). Conclusion VTE risk by cancer site was influenced by the mortality rate and the time since cancer diagnosis. Our findings suggest that the cancer itself is a major contributor to VTE risk, and that competing risk by death should be taken into account when VTE risk in cancer is explored.

D-dimer at venous thrombosis diagnosis is associated with risk of recurrence.

Essentials Whether D-dimer at incident venous thromboembolism (VTE) can predict recurrence-risk is unknown. We explored this association in 454 cancer-free patients with a first lifetime VTE. A low D-dimer at first VTE diagnosis was associated with a low recurrence risk. The association was predominant in patients with deep vein thrombosis and unprovoked VTE. Click to hear Dr Cannegieter's presentation on venous thrombosis: prediction of recurrence SUMMARY: Background Venous thromboembolism (VTE) is a common disease with a high recurrence rate. D-dimer measured after cessation of anticoagulant therapy predicts recurrence, and is used to decide on treatment prolongation. However, whether D-dimer measured at first VTE diagnosis can be used to assess recurrence-risk is unknown. Aims To investigate the association between D-dimer, measured at first VTE diagnosis and risk of recurrent VTE. Methods Information on clinical risk factors and laboratory markers were collected in 454 cancer-free patients with a first VTE. Recurrent VTEs and deaths during follow-up (1994-2012) were recorded. Results During a median follow-up of 3.9 years, 84 patients experienced a recurrent VTE. The crude recurrence rate was 1.7 (95% confidence interval [CI], 1.0-2.9) per 100 person-years in the lower quartile of D-dimer (≤ 1500 ng mL-1 ), and 4.9 (95% CI, 3.9-6.1) per 100 person-years in the upper three quartiles combined, yielding an absolute risk difference of 3.2 per 100 person-years. Patients with D-dimer ≤ 1500 ng mL-1 had 54% lower recurrence-risk than patients with D-dimer > 1500 ng mL-1 (HR, 0.46; 95% CI, 0.25-0.82). The association was particularly pronounced among patients with unprovoked events and deep vein thrombosis, showing a 66% (HR, 0.34; 95% CI, 0.15-0.74) and 68% (HR, 0.32; 95% CI, 0.14-0.71) lower recurrence risk among patients with D-dimer ≤ 1500 ng mL-1 , respectively. Conclusions A low D-dimer (≤ 1500 ng mL-1 ) measured at first VTE diagnosis was associated with a low recurrence risk, particularly among patients with DVT and unprovoked events. Our findings suggest that a clinical decision to avoid prolonged anticoagulant treatment could be considered based on low D-dimer at the time of VTE diagnosis.