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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Repeated measurements of carotid atherosclerosis and future risk of venous thromboembolism: the Tromsø Study.

Essentials The relationship between atherosclerosis and venous thromboembolism (VTE) is controversial. In total, 10 426 participants recruited from the general population were included. Carotid intima media thickness and total plaque area was not associated with VTE. There was no association between plaque initiation or plaque progression and subsequent VTE. SUMMARY: Background Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial. Objective To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population. Methods Participants were recruited from the fourth (1994-1995), fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time-varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index. Results There were 368 incident VTE events during a median follow-up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time-varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval [CI] 0.86-1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98-1.02; and HR 0.96, 95% CI 0.84-1.11). Conclusion Carotid IMT and TPA were not associated with an increased risk of VTE in time-varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.

The impact of initial cancer stage on the incidence of venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) Cohort.

Essentials Impact of cancer stage on venous thromboembolism (VTE) risk is not well-known in all cancers. The Scandinavian Thrombosis and Cancer Cohort provides person-time data and validated VTEs. Impact of cancer stage on VTE incidence tended to vary with cancer type. Cancer stage may not per se be a risk factor for VTE in all cancer types. SUMMARY: Background Absolute measures of the impact of cancer stage on the incidence of venous thromboembolism (VTE) in patients with distinct cancer types have not been investigated in a large population-based cohort study. Objectives To investigate differences in the incidence rates of objectively confirmed VTE according to the development of cancer in a large population-based cohort study. Cancer type and stage at the time of diagnosis were taken into account. Patients and Methods The Scandinavian Thrombosis and Cancer Cohort includes data regarding cancer types, stages and objectively confirmed VTE diagnoses among 144 952 participants followed from 1993 to 2012. We studied stage-specific incidence rates of VTE, and calculated incidence rate differences (IRDs) for VTE according to stages in patients with 10 types of solid cancer. Results During the entire follow-up, 335 VTEs occurred, of which 293 occurred within 5 years. The IRD of VTE in patients with distant metastasis as compared with those with localized disease indicated large variation depending on cancer type. The highest IRD was observed for pancreatic cancer (IRD of 187.0 × 10-3 person-years [p-y]; 95% confidence interval [CI] - 6.7 to 380.8), and the lowest IRD was observed for prostate cancer (IRD of 3.7 × 10-3 p-y; 95% CI - 7 to 15.2). Regional spread as compared with localized disease also indicated large variation depending on cancer type; the highest IRD was observed for uterine cancer (IRD of 37.6 × 10-3 p-y; 95% CI - 23.7 to 99), and the IRDs for breast and prostate cancer were close to zero. Conclusion More advanced cancer at the time of diagnosis was associated with a higher risk of VTE, but the strength of the associations differed substantially between cancer types.

Occult cancer-related first venous thromboembolism is associated with an increased risk of recurrent venous thromboembolism.

Essentials Recurrence risk after an occult cancer-related incident venous thromboembolism (VTE) is unknown. We compared the risk of VTE recurrence in occult-, overt- and non-cancer related first VTE. Patients with occult-cancer related first VTE had the highest risk of VTE recurrence. The high recurrence risk in occult cancer is likely due to the advanced cancers. SUMMARY: Background Although venous thromboembolism (VTE) is associated with a high recurrence rate, the absolute recurrence rates for cancer-related VTE, particularly occult cancer, are not well known. Objectives To investigate the risk of VTE recurrence in patients with occult and overt cancer-related VTE. Methods Incident VTE events among participants of the first to sixth Tromsø surveys occurring in the period 1994-2012 were included. Occult cancer was defined as cancer diagnosed within a year following a VTE, and overt cancer was defined as cancer diagnosed within the 2 years before a VTE. Results Among 733 patients with incident VTE, 110 had overt cancer and 40 had occult cancer. There were 95 recurrent VTE events during a median of 3.2 years of follow-up. The 1-year cumulative incidence of VTE recurrence was 38.6% in subjects with occult cancer, 15.5% in subjects with overt cancer, and 3.8% in non-cancer subjects. The 1-year risk of recurrence was 12-fold (hazard ratio [HR] 12.4, 95% confidence interval [CI] 5.9-26.3) higher in subjects with occult cancer and four-fold (HR 4.3, 95% CI 2.0-9.2) higher in subjects with overt cancer than in non-cancer subjects. The occult cancers associated with VTE recurrence were typically located at prothrombotic sites (i.e. lung and gastrointestinal) and presented at advanced stages. The majority (69%) of recurrences in subjects with occult cancer occurred before or shortly after cancer diagnosis, and were therefore not treatment-related. Conclusion Our findings suggest that the increased risk of recurrence in patients with occult cancer is mainly attributable to the advanced cancers in these patients.

Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle.

AIM: To assess the effect of elevated basal shear stress on angiogenesis in humans and the role of enhanced skeletal muscle capillarization on blood flow and O2 extraction. METHODS: Limb haemodynamics and O2 extraction were measured at rest and during one-leg knee-extensor exercise (12 and 24 W) in 10 healthy untrained young men before and after 4-week treatment with an α1 receptor-antagonist (Terazosin, 1-2 mg day-1 ). Corresponding biopsies were taken from the m. vastus lateralis. RESULTS: Resting leg blood flow was increased by 57% 6 h following Terazosin treatment (P < 0.05), while basal capillary-to-fibre ratio was 1.69 ± 0.08 and increased to 1.90 ± 0.08 after treatment (P < 0.05). Leg O2 extraction during knee-extensor exercise was higher (4-5%; P < 0.05), leg blood flow and venous lactate levels lower (6-7%; P < 0.05), while leg VO2 was not different after Terazosin treatment. CONCLUSIONS: These results demonstrate that daily treatment with an α-adrenergic receptor blocker induces capillary growth in human skeletal muscle, likely due to increased shear stress. The increase in capillarization resulted in an increased fractional O2 extraction, a lower blood flow and venous lactate levels in the exercising leg. The increase in capillarization, and concomitant functional readouts in the exercising leg, may provide a basis for novel angiotherapy.

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.

Recurrence and mortality after first venous thromboembolism in a large population-based cohort.

Essentials Reports on recurrence and mortality after a first venous thromboembolism (VTE) vary considerably. We describe rates of recurrence and mortality in patients with a first VTE from the Tromsø study. The overall recurrence rate was 3.9 per 100 person-years, but this varied widely with time. Despite advances in VTE management, the rates of adverse events are still fairly high. SUMMARY: Background Previous reports on recurrence and mortality rates after a first episode of venous thromboembolism (VTE) vary considerably. Advances in the management and treatment of VTE during the last 15 years may have influenced the rates of clinical outcomes. Aim To estimate the rates of recurrence and mortality after a first VTE in patients recruited from a large population-based cohort. Method From the Tromsø study, patients (n = 710) with a first, symptomatic, objectively confirmed VTE were included and followed in the period 1994-2012. Recurrent episodes of VTE were identified from multiple sources and carefully validated by review of medical records. Incidence rates and cumulative incidence rates with 95% confidence intervals (CIs) of VTE recurrence and mortality were calculated. Results The mean age of the patients was 68 years (range 28-102 years), and 166 (23.4%) had cancer at the time of first VTE. There were 114 VTE recurrences and 333 deaths during a median study period of 7.7 years (range 0.04-18.2 years). The risk of recurrence was highest during the first year. The overall 1-year recurrence rate was 7.8 (95% CI 5.8-10.6) per 100 person-years (PY), whereas the recurrence rate in the remaining follow-up period (1-18 years) was 3.0 (95% CI 2.4-3.8) per 100 PY. The overall 1-year all-cause mortality rate was 29.9 (95% CI 25.7-34.8) per 100 PY, and in those without cancer the corresponding rate was 23.6 (95% CI 17.8-31.3) per 100 PY. Conclusion Despite advances in VTE management, the rates of adverse events remained fairly high, particularly in the first year following a first VTE.

A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells.

BACKGROUND: Bone morphogenetic protein (BMP) 7 is abundant in atherosclerotic plaques and increases monocyte pro-coagulant activity by enhancing tissue factor (TF) expression. While several members of the BMP superfamily are able to serve as chemotactic agents for monocytes, the role of BMP-7 in regulation of monocyte motility is not known. AIMS: To assess the effect of BMP-7 on adhesive and migratory properties of human monocytes. METHODS: Chemokinesis, adhesion, and transendothelial migration of BMP-7-treated THP-1 cells and human monocytes were analysed using live-cell imaging, orbital shear, and Boyden chamber assays. Surface presentation of ß2 integrins and phosphorylation status of Akt & focal adhesion kinase (FAK) were studied by flow cytometry and Western blot. RESULTS: High levels of BMP-7 protein were detectable in intimal regions of atherosclerotic plaques; BMP-7 significantly enhanced THP-1 and monocyte chemokinetic properties in vitro (1.21+0.01 and 1.76+0.21 fold increase in crawling distance, respectively). Under orbital shear, adhesion of monocytic cells to microvascular endothelial cell (MVEC) monolayers was also significantly increased by BMP-7 (3.89+1.56 and 2.57+0.97 fold over vehicle). Moreover, BMP-7 accelerated transendothelial migration of THP-1 cells and monocytes towards MCP-1 (5.91+0.88 and 2.96±0.65 fold increase, respectively). BMP-7 enhanced cell surface presentation of ß2 integrins in the active conformation. Observed effects were determined to be Akt and FAK dependent, as shown by pharmacological inhibition. CONCLUSION: BMP-7 directly upregulates adhesion and migration of human monocytic cells via activation of ß2 integrins, Akt, and FAK. Our findings suggest that BMP-7 may serve as a novel contributor to atherogenesis.