Functional Clustering of Periodic Transcriptional Profiles through ARMA(p,q)

Background: Gene clustering of periodic transcriptional profiles provides an opportunity to shed light on a variety of biological processes, but this technique relies critically upon the robust modeling of longitudinal covariance structure over time. Methodology: We propose a statistical method for functional clustering of periodic gene expression by modeling the covariance matrix of serial measurements through a general autoregressive moving-average process of order (p,q), the socalled ARMA(p,q). We derive a sophisticated EM algorithm to estimate the proportions of each gene cluster, the Fourier series parameters that define gene-specific differences in periodic expression trajectories, and the ARMA parameters that model the covariance structure within a mixture model framework. The orders p and q of the ARMA process that provide the best fit are identified by model selection criteria. Conclusions: Through simulated data we show that whenever it is necessary, employment of sophisticated covariance structures such as ARMA is crucial in order to obtain unbiased estimates of the mean structure parameters and increased precision of estimation. The methods were implemented on recently published time-course gene expression data in yeast and the procedure was shown to effectively identify interesting periodic clusters in the dataset. The new approach wil

3D modelling of drug-coated balloons for the treatment of calcified superficial femoral arteries

Background/Objectives: Drug-coated balloon therapy for diseased superficial femoral arteries remains controversial. Despite its clinical relevance, only a few computational studies based on simplistic two-dimensional models have been proposed to investigate this endovascular therapy to date. This work addresses the aforementioned limitation by analyzing the drug transport and kinetics occurring during drug-coated balloon deployment in a three-dimensional geometry. Methods: An idealized three-dimensional model of a superficial femoral artery presenting with a calcific plaque and treated with a drug-coated balloon was created to perform transient mass transport simulations. To account for the transport of drug (i.e. paclitaxel) released by the device, a diffusion-reaction equation was implemented by describing the drug bound to specific intracellular receptors through a non-linear, reversible reaction. The following features concerning procedural aspects, pathologies and modelling assumptions were investigated: (i) balloon application time (60–180 seconds); (ii) vessel wall composition (healthy vs. calcified wall); (iii) sequential balloon application; and (iv) drug wash-out by the blood stream vs. coating retention, modeled as exponential decay. Results: The balloon inflation time impacted both the free and specifically-bound drug concentrations in the vessel wall. The vessel wall composition highly affected the drug concentrations. In particular, the specifically-bound drug concentration was four orders of magnitude lower in the calcific compared with healthy vessel wall portions, primarily as a result of reduced drug diffusion. The sequential application of two drug-coated balloons led to modest differences (~15%) in drug concentration immediately after inflation, which became negligible within 10 minutes. The retention of the balloon coating increased the drug concentration in the vessel wall fourfold. Conclusions: The overall findings suggest that paclitaxel kinetics may be affected not only by the geometrical and compositional features of the vessel treated with the drug-coated balloon, but also by balloon design characteristics and procedural aspects that should be carefully considered

Superficial femoral artery stenting: Impact of stent design and overlapping on the local hemodynamics

Background: Superficial femoral arteries (SFAs) treated with self-expanding stents are widely affected by in-stent restenosis (ISR), especially in case of long lesions and multiple overlapping devices. The altered hemodynamics provoked by the stent is considered as a promoting factor of ISR. In this context, this work aims to analyze the impact of stent design and stent overlapping on patient-specific SFA hemodynamics.Methods: Through a morphing technique, single or multiple stents were virtually implanted within two patient specific, post-operative SFA models reconstructed from computed tomography. The stented domains were used to perform computational fluid dynamics simulations, quantifying wall shear stress (WSS) based descriptors including time-averaged WSS (TAWSS), oscillatory shear index (OSI), transverse WSS (transWSS), and WSS ratio (WSSRATIO). Four stent designs (three laser-cut - EverFlex, Zilver and S.M.A.R.T. - and one prototype braided stent), and three typical clinical scenarios accounting for different order of stent implantation and overlapping length were compared.Results: The main hemodynamic differences were found between the two types of stent designs (i.e. laser-cut vs. braided stents). The braided stent presented lower median transWSS and higher median WSS(RATIO )than the laser cut stents (p < 0.0001). The laser-cut stents presented comparable WSS-based descriptor values, except for the Zilver, exhibiting a median TAWSS ~30% higher than the other stents. Stent overlapping provoked an abrupt alteration of the WSS-based descriptors. The overlapping length, rather than the order of stent implantation, highly and negatively impacted the hemodynamics.Conclusion: The proposed computational workflow compared different SFA stent designs and stent overlapping configurations, highlighting those providing the most favorable hemodynamic conditions

Prediction of graft patency and mortality after distal revascularization and interval ligation for hemodialysis access-related hand ischemia

ObjectiveThe treatment goals of access-related hand ischemia (ARHI) are to reverse symptoms and salvage the access. Many procedures have been described, but the optimal treatment strategy remains unresolved. In an effort to guide clinical decision making, this study was undertaken to document our outcomes for distal revascularization and interval ligation (DRIL) and to identify predictors of bypass patency and patient mortality.MethodsA retrospective review was performed of all patients who underwent DRIL at the University of Florida from 2002 to 2011. Diagnosis of ARHI was based primarily upon clinical symptoms with noninvasive studies used to corroborate in equivocal cases. Patient demographics, procedure-outcome variables, and reinterventions were recorded. Bypass patency and mortality were estimated using cumulative incidence and Kaplan-Meier methodology, respectively. Cumulative incidence and Cox regression analysis were performed to determine predictors of bypass patency and mortality, respectively.ResultsA total of 134 DRILs were performed in 126 patients (mean [standard deviation] age, 57 [12] years) following brachial artery-based access. The postoperative complication rate was 27% (19% wound), and 30-day mortality was 2%. The wrist-brachial index and digital brachial index increased 0.31 (0.25) and 0.25 (0.29), respectively. Symptoms resolved in 82% of patients, and 85% continued to use their access. Cumulative incidences (± standard error of the mean) of loss of primary and primary-assisted patency rates were 5% ± 2% and 4% ± 2% at 1 year and 22% ± 5% and 18% ± 5% at 5 years, respectively, with mean follow-up of 14.8 months. Univariate predictors of primary patency failure were DRIL complications (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.2-8.9; P = .02), configuration other than brachiobasilic/brachiocephalic autogenous access (OR, 3.4; 95% CI, 1.4-8.3; P = .009), and two or more prior access attempts (OR, 4.1; 95% CI, 1.6-10.4; P = .004). Brachiocephalic access configuration (OR, 0.2; 95% CI, 0.04-0.8; P = .02) and autogenous vein conduit (OR, 0.2; 95% CI, 0.06-0.58; P = .004) were predictors of improved bypass patency. All-cause mortality was 28% and 79% at 1 and 5 years, respectively. Multivariable predictors of mortality were age >40 (hazard ratio [HR], 8.3; 95% CI, 2.5-33.3; P = .0004), grade 3 ischemia (HR, 2.6; 95% CI, 1.5-4.6; P = .0008), complication from DRIL (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and smoking history (HR, 2.2; 95% CI, 1.3-4; P = .007). Patients with no prior access attempts had lower predicted mortality (HR, 0.5; 95% CI, 0.3-0.9; P = .02).ConclusionsThe DRIL procedure effectively improves distal perfusion and reverses the symptoms of ARHI while salvaging the access, but the long-term survival of these patients is poor. Given the poor survival, preoperative risk stratification is critical. Patients at high risk for DRIL failure and mortality may be best served with alternate remedial procedures

Outcomes after redo aortobifemoral bypass for aortoiliac occlusive disease

ObjectivePatients presenting with occluded aortobifemoral (ABF) bypass grafts are managed with a variety of techniques. Redo ABF (rABF) bypass procedures are infrequently performed because of concerns about procedural complexity and morbidity. The purpose of this analysis was to compare midterm results of rABF bypass with those of primary ABF (pABF) bypass for aortoiliac occlusive disease to determine if there are significant differences in outcomes.MethodsA retrospective review was performed of all patients undergoing ABF bypass for occlusive disease between January 2002 and March 2012. A total of 19 patients underwent rABF bypass and 194 received pABF bypass during that period. Data for an indication- and comorbidity-matched case-control cohort of 19 elective pABF bypass patients were collected for comparison to the rABF bypass group. Primary end points included rate of major complications as well as 30-day and all-cause mortality. Secondary end points were amputation-free survival and freedom from major adverse limb events.ResultsThe rABF bypass patients more frequently underwent prior extra-anatomic or lower extremity bypass operations compared with pABF bypass patients (P = .02); however, no difference was found in the incidence of prior failed endovascular iliac intervention (P = .4). By design, indications for the rABF and pABF bypass groups were the same (claudication, n = 6/6 [31.6%]; P = 1; critical limb ischemia, n = 13/13 [78.4%]; P = 1). Aortic access was more frequently by retroperitoneal exposure in the rABF bypass group (n = 13 vs n = 1; P < .0001), and a significantly higher proportion of the rABF bypass patients required concomitant infrainguinal bypass or intraprocedural adjuncts such as profundaplasty (n = 14 vs n = 5; P = .01). The rABF bypass patients experienced greater blood loss (1097 ± 983 mL vs 580 ± 457 mL; P = .02), received more intraoperative fluids (3400 ± 1422 mL vs 2279 ± 993 mL; P = .01), and had longer overall procedure times (408 ± 102 minutes vs 270 ± 48 minutes; P < .0001). Length of stay (days ± standard deviation) was similar (pABF bypass, 11.2 ± 10.4; rABF bypass, 9.1 ± 4.5; P = .7), and no 30-day or in-hospital deaths occurred in either group. Similar rates of major complications occurred in the two groups (pABF bypass, n = 6 [31.6%]; rABF bypass, n = 4 [21.1%]; observed difference, 9.5%; 95% confidence interval, −17.6% to 36.7%; P = .7). Two-year freedom from major adverse limb events (±standard error mean) was 82% ± 9% vs 78% ± 10% for pABF and rABF bypass patients (log-rank, P = .6). Two-year amputation-free survival was 90 ± 9% vs 89 ± 8% between pABF and rABF bypass patients (P = .5). Two-year survival was 91% ± 9% and 90% ± 9% for pABF and rABF bypass patients (P = .8).ConclusionsPatients undergoing rABF bypass have higher procedural complexity compared with pABF bypass as evidenced by greater operative time, blood loss, and need for adjunctive procedures. However, similar perioperative morbidity, mortality, and midterm survival occurred in comparison to pABF bypass patients. These results support a role for rABF bypass in selected patients

Efficacy of dorsal pedal artery bypass in limb salvage for ischemic heel ulcers

AbstractPurpose: Although pedal artery bypass has been established as an effective and durable limb salvage procedure, the utility of these bypass grafts in limb salvage, specifically for the difficult problem of heel ulceration, remains undefined. Methods: We retrospectively reviewed 432 pedal bypass grafts placed for indications of ischemic gangrene or ulceration isolated to either the forefoot (n = 336) or heel (n = 96). Lesion-healing rates and life-table analysis of survival, patency, and limb salvage were compared for forefoot versus heel lesions. Preoperative angiograms were reviewed to evaluate the influence of an intact pedal arch on heel lesion healing. Results: Complete healing rates for forefoot and heel lesions were similar (90.5% vs 86.5%, P = .26), with comparable rates of major lower extremity amputation (9.8% vs 9.3%, P = .87). Time to complete healing in the heel lesion group ranged from 13 to 716 days, with a mean of 139 days. Preoperative angiography demonstrated an intact pedal arch in 48.8% of the patients with heel lesions. Healing and graft patency rates in these patients with heel lesions were independent of the presence of an intact arch, with healing rates of 90.2% and 83.7% (P = .38) and 2-year patency rates of 73.4% and 67.0% in complete and incomplete pedal arches, respectively. Comparison of 5-year primary and secondary patency rates between the forefoot and heel lesion groups were essentially identical, with primary rates of 56.9% versus 62.1% (P = .57) and secondary rates of 67.2% versus 60.3% (P = .50), respectively. Conclusion: Bypass grafts to the dorsalis pedis artery provide substantial perfusion to the posterior foot such that the resulting limb salvage and healing rates for revascularized heel lesions is excellent and comparable with those observed for ischemic forefoot pathology. (J Vasc Surg 1999;30:499-508.

Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial

Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option

Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs).A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10 total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing.There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, = .038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls ( = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months.Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options