Active networks must balance the flexibility of a programmable network infrastructure against the safety and security requirements inherent in sharing that infrastructure. Furthermore, this balance ...must be achieved while maintaining the usability of the network. The SwitchWare active network architecture is a novel approach to achieving this balance using three layers: active packets, which contain mobile programs that replace traditional packets; active extensions, which provide services on the network elements and can be dynamically loaded; and a secure active router infrastructure, which forms a high-integrity base on which the security of the other layers depends. In addition to integrity checking and cryptography-based authentication, security in our architecture depends heavily on verification techniques from programming languages, such as strong type checking.
Objectives
The Movember Foundation launched the Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative to create a global consensus on the selection and monitoring of men with ...low‐risk prostate cancer (PCa) on active surveillance (AS). The aim of this study is to present data on inclusion and follow‐up for AS in this unique global AS database.
Patients and Methods
Between 2014 and 2016, the database was created by combining patient data from 25 established AS cohorts worldwide (USA, Canada, Australasia, UK and Europe). Data on a total of 15 101 patients were included. Descriptive statistics were used to report patients' clinical and demographic characteristics at the time of PCa diagnosis, clinical follow‐up, discontinuation of AS and subsequent treatment. Cumulative incidence curves were used to report discontinuation rates over time.
Results
At diagnosis, the median (interquartile range IQR) patient age was 65 (60–70) years and the median prostate‐specific antigen level was 5.4 (4.0–7.3) ng/mL. Most patients had clinical stage T1 disease (71.8%), a biopsy Gleason score of 6 (88.8%) and one tumour‐positive biopsy core (60.3%). Patients on AS had a median follow‐up time of 2.2 (1.0–5.0) years. After 5, 10 and 15 years of follow‐up, respectively, 58%, 39% and 23% of patients were still on AS. The current version of GAP3 has limited data on magnetic resonance imaging (MRI), quality of life and genomic testing.
Conclusions
GAP3 is the largest worldwide collaboration integrating patient data from men with PCa on AS. The results will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Longer follow‐up and the evaluation of MRI, new genomic markers and patient‐related outcomes will result in even more valuable data and eventually in better patient outcomes.
Background Blacks have more severe endothelial dysfunction and aortic stiffening as compared with whites. We aimed to investigate the association between aortic stiffness and microvascular function ...in the black community. Methods and Results We assessed the association between forearm vascular reactive hyperemia (an indicator of microvascular function) and aortic stiffness in 1458 black participants (N=965 66% women; mean age: 66±11 years) in the Jackson Heart Study. We evaluated 2 measures of aortic stiffness: brachial pulse pressure and carotid-femoral pulse wave velocity. Using high-resolution ultrasound and Doppler, we evaluated brachial blood flow at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. Multiple cardiovascular risk factors were significantly related to baseline and hyperemic brachial flow velocity. Women had lower baseline flow across the entire age spectrum. During hyperemia, we observed a significant age-sex interaction for flow velocity ( P=0.02). Female sex was protective against microvascular dysfunction among younger participants, but older women exhibited a greater attenuation of the hyperemic flow reserve. In multivariable models that adjusted for cardiovascular disease risk factors and mean arterial pressure, higher carotid-femoral pulse wave velocity (β=-0.106±0.033; P=0.001 was related to lower baseline flow. However, during reactive hyperemia, elevated brachial pulse pressure (β=-0.070±0.031; P=0.03) and carotid-femoral pulse wave velocity (β=-0.128±0.030; P<0.001) were both related to attenuated brachial flow velocity. Conclusions In a sample of blacks, higher aortic stiffness and pressure pulsatility were associated with lower flow reserve during reactive hyperemia, beyond changes attributable to traditional cardiovascular disease risk factors alone.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant ...evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
To report the 1-year clinical outcomes from the GORE EXCLUDER Conformable AAA Endoprosthesis system in the US regulatory trial.
The study is a prospective, multicenter, investigational device ...exemption clinical trial at 31 US sites with core laboratory assessment of imaging and independent event adjudication. The primary safety (incidence of major adverse events at 30 days) and effectiveness end points (successful aneurysm treatment at 1 year) were assessed in a cohort of patients with abdominal aortic aneurysms (AAAs).
We enrolled 80 patients between December 19, 2017, and February, 27, 2019. The mean maximum aortic diameter was 57.7 ± 7.95 mm (range, 42.5-82.7 mm) with an average patient age of 73.5 ± 8.14 years (range, 56-96 years). Overall technical success was 100% (80/80). The mean hospital length stay was 1.2 ± 0.6 days (range, 1-4 days). No primary safety end point events were observed, including no death, stroke, myocardial infarction, bowel ischemia, paraplegia, respiratory failure, renal failure, procedural blood loss of more than 1000 mL, or thromboembolic events including limb occlusion or distal emboli. There were no type I or III endoleaks detected on the 1-, 6-, or 12-month follow-up computed tomography scans. There were no stent fractures, device migrations (≥10 mm), AAA ruptures, or conversions to open surgical repair observed. Two patients had AAA sac growth of more than 5 mm at 1 year owing to type II endoleaks. There were no aneurysm-related deaths within the 12-month follow-up, and freedom from aneurysm-related mortality was 100% through 1 year.
The safety and effectiveness of the GORE EXCLUDER Conformable AAA Endoprosthesis system has been demonstrated with 98.5% freedom from primary effectiveness end point events at 1 year and 100% freedom from primary safety end point events assessed through 30 days.
Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists ...that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.
Fraser et al. (Reports, 17 July 2015, p. 302) report a unimodal relationship between productivity and species richness at regional and global scales, which they contrast with the results of Adler et ...al. (Reports, 23 September 2011, p. 1750). However, both data sets, when analyzed correctly, show clearly and consistently that productivity is a poor predictor of local species richness.
Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
We performed an ...analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval CI:=1.70–2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36–2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50–2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01–3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78–7.17, p=0.13).
Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
This large Mendelian randomization study utilizes a risk score of telomere length associated genetic variants to demonstrate a strong association between longer predicted leukocyte telomere length and increased risk of developing common subtypes of renal cell carcinoma.
Deep venous thrombosis (DVT) confers vein wall injury associated with fibrosis and extracellular matrix (ECM) turnover, likely mediated by matrix proteases. This study investigated the expression of ...proteases and collagen involved in early vein wall remodeling.
In the mouse, DVT was produced by ligation of the infrarenal inferior vena cava (IVC) or sham operation, and tissue was harvested at 4, 8, and 12 days. The vein wall tissue was processed for real-time reverse transcriptase-polymerase chain reaction (6 to 8 per time point), Western immunoblotting (5 per time point), and gelatin zymography (5 per time point). Analysis of variance was used for multiple comparisons, and a P < .05 was significant.
Thrombus resolution was documented by a 38% decrease in the thrombosed IVC weight from day 4 to day 12 (P = .007). Total vein wall collagen increased over time, with a corresponding increase in procollagen I and III, and expression peaked at 12 days (24-fold and 6.1-fold, respectively, P < .02). Matrix metalloproteinase-2 (MMP-2) gene expression was 23-fold greater at 12 days after thrombus formation compared with sham or 4 days after thrombosis (P < .05). Total MMP-2 activity was also significantly elevated at 12 days compared with sham (P < .05). MMP-9 expression was 19-fold and 27-fold higher at days 4 and 8, respectively, relative to sham (P < .05), with no difference in activity. MMP-14 expression was twofold to 3.6-fold greater at day 12 compared with earlier time points and shams (P < .001), but no differences in protein levels were found. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) protein levels were not significantly different from sham over time; however, the ratio of uPA to PAI-1 was decreased through 8 days.
Vein wall remodeling after DVT is similar to wound healing and is associated with increased procollagen gene expression and total collagen. It is also associated with increased early MMP-9 expression, followed by MMP-2 expression and activity after DVT resolution.
Deep vein thrombosis is an often neglected problem that long term is associated with the postphlebitic syndrome of limb swelling, pain, and often ulceration. The basic mechanisms of the vein wall damage that results have not been delineated. The following study describes the vein wall matrix metalloproteinase gene and activity response induced over time in the vein wall after DVT. Additionally, the corresponding collagen upregulation and proximate plasmin system mediators are determined. With this knowledge, potential therapies to reduce vein wall injury directly might be possible.
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