Surveillance and risk factors for early restenosis following transcarotid artery revascularization.

OBJECTIVE: Restenosis after transcarotid artery revascularization (TCAR) is a known complication. When identified in the early postoperative period, it may be related to technique. We evaluated our TCAR experience to identify potentially modifiable factors impacting restenosis. METHODS: This is a single-institution, retrospective review of patients undergoing TCAR from November 2017 to July 2022. Restenosis was defined as >50% stenosis on duplex ultrasound (DUS) examination or computed tomographic angiography (CTA). Continuous variables were compared using Kruskal-Wallis's test. Categorical variables were compared using the Fisher's exact test. RESULTS: Of 61 interventions, 11 (18%) developed restenosis within the median follow-up of 345 days (interquartile range, 103-623 days). Among these patients, 82% (9/11) had >50% stenosis, and 18% (2/11) had >80% stenosis. Both patients with high-grade restenosis were symptomatic and underwent revascularization. Diagnosis of post-TCAR restenosis was via DUS examination in 45% (5/11), CTA in 18% (2/11), or both CTA/DUS examination in 36% (4/11). Restenosis occurred within 1 month in 54% (6/11) and 6 months in 72% (8/11) of patients. However, three of the six patients with restenosis within 1 month had discordant findings on CTA vs DUS imaging. Patient comorbidities, degree of preoperative stenosis, medical management, balloon size, stent size, lesion characteristics, and predilatation angioplasty did not differ. Patients with restenosis were younger (P = .02), had prior ipsilateral endarterectomy (odds ratio [OR], 6.5; P = .02), had history of neck radiation (OR, 18.3; P = .01), and lower rate of postdilatation angioplasty (OR, 0.11; P = .04), without an increased risk of neurological events. CONCLUSIONS: Although post-TCAR restenosis occurred in 18% of patients, only 3% of patients had critical restenosis and required reintervention. Patient factors associated with restenosis were younger age, prior endarterectomy, and history of neck radiation. Although early restenosis may be mitigated by improved technique, the only technical factor associated with restenosis was less use of postdilatation angioplasty. Balancing neurological risk, this factor may have increased application in appropriate patients. Diagnosis of restenosis was inconsistent between imaging modalities; current surveillance paradigms and diagnostic thresholds may warrant reconsideration.

Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD.

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Readmission after early thoracic endovascular aortic repair versus medical management of acute type B aortic dissection.

BACKGROUND: The use of thoracic endovascular aortic repair (TEVAR) for the management of acute uncomplicated type B aortic dissection (TBAD) has increased. Although the results from early studies were promising, larger randomized trials evaluating TEVAR are lacking. It is also unclear where sufficient equipoise exists for such trials. In the present study, we evaluated the number of readmissions and unplanned operations after TEVAR vs those after medical management as the initial treatment of acute uncomplicated TBAD and the frequency of each treatment in this population. METHODS: We performed a multi-institutional retrospective review of patients with acute TBAD from 2015 to 2020 with the 1-year outcomes available, excluding patients with prior aortic intervention or chronic, iatrogenic or traumatic etiologies. The primary exposure was TEVAR vs medical management at the index admission. The patient demographics, clinical presentation, and imaging findings were analyzed using bivariate and multivariate logistic regression for the primary outcomes of unplanned readmission and/or operation after the initial admission. The secondary outcomes were mortality, myocardial infarction, stroke, renal failure requiring dialysis, retrograde type A dissection, and length of stay. We hypothesized that the readmissions would be higher with medical management. RESULTS: A total of 216 patients with TBAD (47 with complicated and 169 with uncomplicated) from two large academic centers were identified. Of the 169 patients with uncomplicated TBAD, 83 (49%) had been treated medically and 86 (51%) had undergone TEVAR at the initial admission. No differences were found in the demographics or high-risk imaging features at presentation. The medically managed patients had had higher rates of unplanned readmission (34% vs 9%; P = .0001) and operation (28% vs 8%; P = .0007) but shorter lengths of stay (6.3 vs 13.1 days; P < .0001). No differences were found in mortality, although the rate of myocardial infarction was higher in the medically managed group (10.8% vs 2.3%; P = .02). Although 28% of the medically managed patients had later required operation, they had had morbidity and mortality similar to those of patients who had undergone initial TEVAR. Initial medical management was associated with unplanned readmission (odds ratio, 8.3; P = .02) and the need for operation (odds ratio, 4.56; P = .006). No differences were found in the outcomes according to the involved aortic zones. CONCLUSIONS: In the present study, medical management of acute uncomplicated TBAD was associated with higher rates of readmission and the need for unplanned operation compared with TEVAR. However, no differences were found in the 1-year mortality for the patients for whom medical management had failed. Because one half of the patients had undergone medical management and one half had undergone early TEVAR, this finding suggests clinical equipoise for the treatment of acute uncomplicated TBAD. Therefore, a larger randomized trial appears warranted to determine whether a clear benefit exists for early TEVAR.

Comparison Study of Iliac Branch Endoprosthesis when Used on and off Label.

BACKGROUND: The aim of this study is to compare how instructions for use (IFU) affected perioperative and intermediate term outcomes for common iliac artery aneurysms (CIAA) treated with the Gore Excluder iliac branch endoprosthesis (IBE). METHODS: A retrospective analysis was performed of all patients treated at two affiliated academic centers from September 2016 to May 2020. Outcomes were compared between IFU and nonIFU IBE cases. Criteria for nonIFU included: (1) use with a nonGore aortic endoprosthesis (n = 10), (2) isolated IBE (n = 3), and (3) requiring nondedicated covered stents for additional extension into a more suitable landing zone in the ipsilateral internal iliac artery or one of its branches (n = 11). Perioperative and intermediate term data were collected for both groups. The primary end points were free from the major adverse event (MAE) at 30 days and primary effectiveness at 1 year. RESULTS: A total of 51 CIAA (39 patients) were treated with an IBE. Overall, 15 patients were treated under IFU and 24 under nonIFU. The IFU group mean age was older (72 vs. 67 years, P = 0.03), and males (97%) were primarily treated. Comorbidities were similar except nonIFU had more patients with previous endovascular abdominal aortic aneurysm repair on presentation (0 vs. 4 cases, P = 0.04). Procedure (178 vs. 264 min, P = 0.02) and fluoroscopy (52 vs. 74 min, P = 0.04) times were longer in the nonIFU group. Technical success was 100% for both groups, and there was no difference in device related reintervention at 30 days (0 vs. 1, P = 0.44). There was no MAE in either group at 30 days. Intervention for any endoleak was similar between the groups (2 vs. 3, P = 0.94). Percent CIAA sac regression was similar between the groups (19% vs. 18%, P = 0.21). There was no difference for primary effectiveness at 1 year (93% vs. 92%, P = 0.85). There was one death per group at one year not related to an aortic or iliac cause. CONCLUSIONS: In properly selected patients with complex anatomy, IBE can be used with nondedicated aortic and internal iliac components with good early term outcomes.

Critical appraisal of the contemporary use of atherectomy to treat femoropopliteal atherosclerotic disease.

OBJECTIVE: Atherectomy has become increasingly used as an endovascular treatment of lower extremity atherosclerotic disease in the United States. However, concerns and controversies about its indications and outcomes exist. The goal of the present systematic review and meta-analysis was to investigate the outcomes and complications related to atherectomy to treat femoropopliteal atherosclerotic disease. METHODS: A systematic review in accordance with the recommendations from the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement was performed. Four major scientific repositories (MEDLINE, Embase, the Cochrane Library, and Thompson Web of Sciences) were queried from their inception to April 5, 2020. We reviewed and entered the data in a dedicated dataset. The outcomes included the patency rates, clinical and hemodynamic improvement, and morbidity and mortality associated with atherectomy interventions. RESULTS: Twenty-four studies encompassing 1900 patients met the inclusion criteria for the present study. Of the 1900 patients, 74.3% had presented with Rutherford class 1 to 3 and 25.7% presented with Rutherford class 4 to 6; 1445 patients had undergone atherectomy, and 455 patients had been treated without atherectomy. The atherectomy group had undergone directional atherectomy (n = 851), rotational atherectomy (n = 851), laser atherectomy (n = 201), and orbital atherectomy (n = 78). Most of these patients had also received adjunct treatments, which varied across the studies and included a combination of stenting, balloon angioplasty, or drug-coated balloon angioplasty. Technical success was achieved in 92.3% of the cases. Distal embolization, vessel perforation, and dissection occurred in 3.4%, 1.9%, and 4% of the cases, respectively. The initial patency was 95.4%. At the 12-month median follow-up, the primary patency was 72.6%. The ankle brachial index had improved from a preoperative mean of 0.6 to a postoperative mean of 0.84. The incidence of major amputation and mortality during the follow-up period was 2.2% and 3.4%, respectively. CONCLUSIONS: The results from our review of the reported data suggest that femoropopliteal atherectomy can be completed safely, modestly improving the ankle brachial index and maintaining the 1-year patency in nearly three of four patients. However, these findings were based on heterogeneous studies that skewed the generalizable conclusions about atherectomy's efficacy. Atherectomy places a high cost burden on the healthcare system and is used in the United States at a higher rate than in other countries. Our review of the literature did not demonstrate clear atherectomy superiority to alternatives that would warrant the pervasive and increasing use of this costly technology. Future work should focus on developing high-quality randomized controlled trials to determine the specific patient and lesion characteristics for which atherectomy can add value.

Functional Dynamics of Substrate Recognition in TEM Beta-Lactamase.

The beta-lactamase enzyme provides effective resistance to beta-lactam antibiotics due to substrate recognition controlled by point mutations. Recently, extended-spectrum and inhibitor-resistant mutants have become a global health problem. Here, the functional dynamics that control substrate recognition in TEM beta-lactamase are investigated using all-atom molecular dynamics simulations. Comparisons are made between wild-type TEM-1 and TEM-2 and the extended-spectrum mutants TEM-10 and TEM-52, both in apo form and in complex with four different antibiotics (ampicillin, amoxicillin, cefotaxime and ceftazidime). Dynamic allostery is predicted based on a quasi-harmonic normal mode analysis using a perturbation scan. An allosteric mechanism known to inhibit enzymatic function in TEM beta-lactamase is identified, along with other allosteric binding targets. Mechanisms for substrate recognition are elucidated using multivariate comparative analysis of molecular dynamics trajectories to identify changes in dynamics resulting from point mutations and ligand binding, and the conserved dynamics, which are functionally important, are extracted as well. The results suggest that the H10-H11 loop (residues 214-221) is a secondary anchor for larger extended spectrum ligands, while the H9-H10 loop (residues 194-202) is distal from the active site and stabilizes the protein against structural changes. These secondary non-catalytically-active loops offer attractive targets for novel noncompetitive inhibitors of TEM beta-lactamase.

JEDi: java essential dynamics inspector - a molecular trajectory analysis toolkit.

BACKGROUND: Principal component analysis (PCA) is commonly applied to the atomic trajectories of biopolymers to extract essential dynamics that describe biologically relevant motions. Although application of PCA is straightforward, specialized software to facilitate workflows and analysis of molecular dynamics simulation data to fully harness the power of PCA is lacking. The Java Essential Dynamics inspector (JEDi) software is a major upgrade from the previous JED software. RESULTS: Employing multi-threading, JEDi features a user-friendly interface to control rapid workflows for interrogating conformational motions of biopolymers at various spatial resolutions and within subregions, including multiple chain proteins. JEDi has options for Cartesian-based coordinates (cPCA) and internal distance pair coordinates (dpPCA) to construct covariance (Q), correlation (R), and partial correlation (P) matrices. Shrinkage and outlier thresholding are implemented for the accurate estimation of covariance. The effect of rare events is quantified using outlier and inlier filters. Applying sparsity thresholds in statistical models identifies latent correlated motions. Within a hierarchical approach, small-scale atomic motion is first calculated with a separate local cPCA calculation per residue to obtain eigenresidues. Then PCA on the eigenresidues yields rapid and accurate description of large-scale motions. Local cPCA on all residue pairs creates a map of all residue-residue dynamical couplings. Additionally, kernel PCA is implemented. JEDi output gives high quality PNG images by default, with options for text files that include aligned coordinates, several metrics that quantify mobility, PCA modes with their eigenvalues, and displacement vector projections onto the top principal modes. JEDi provides PyMol scripts together with PDB files to visualize individual cPCA modes and the essential dynamics occurring within user-selected time scales. Subspace comparisons performed on the most relevant eigenvectors using several statistical metrics quantify similarity/overlap of high dimensional vector spaces. Free energy landscapes are available for both cPCA and dpPCA. CONCLUSION: JEDi is a convenient toolkit that applies best practices in multivariate statistics for comparative studies on the essential dynamics of similar biopolymers. JEDi helps identify functional mechanisms through many integrated tools and visual aids for inspecting and quantifying similarity/differences in mobility and dynamic correlations.

A systematic review and meta-analysis of outcomes after acute limb ischemia in patients with cancer.

BACKGROUND: Cancer results in a hypercoagulable state that is associated with both venous and arterial thromboses. However, little is known about the effects of acute limb ischemia (ALI) in this cohort of patients. In the present systematic review and meta-analysis, we analyzed the available clinical data on cancer and its association with ALI and evaluated the outcomes in these patients after a diagnosis of ALI. METHODS: Three databases, including PubMed, EMBASE, and the Cochrane Library, were queried. Studies that met the inclusion criteria were included regardless of the publication year, language, sample size, or follow-up length. All the steps of the meta-analysis were conducted in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) and MOOSE (meta-analysis of observational studies in epidemiology) guidelines. RESULTS: Seven studies from 6222 references with a total of 2899 patients were included. Of the 2899 patients, 1195 (41%) had had a diagnosis of ALI before their cancer diagnosis, and 1704 (59%) had presented with ALI after a cancer diagnosis. Nearly three quarters of ALI events were among patients with cancer of the skin and soft tissue (19%), genitourinary (18%), lung (17%), and gastrointestinal (16%) systems. ALI recurrence was similar between the two groups, and major amputation was more likely in patients with a diagnosis of ALI after a cancer diagnosis (7.4% vs 4.6%; P < .01). The incidence of mortality at 1 year was significantly greater for patients with established cancer who had presented with ALI compared with the patients who had presented with ALI before a cancer diagnosis (50.6% vs 29.9%; P < .01). After adjusting for study variability using the random effects model, the mortality at 1 year for all patients was 52.3% (95% confidence interval, 37.7%-66.5%). No significant heterogeneity (P = .73) was found between the two groups of patients, which varied by the timing of the ALI diagnosis in relation to the cancer diagnosis. CONCLUSIONS: The 1-year mortality after the development of ALI in patients with cancer was >50%. For patients presenting with ALI of unclear etiology, the presence of an underlying cancer should be considered.

Iliac Conduits for Endovascular Treatment of Aortic Pathologies: A Systematic Review and Meta-analysis.

PURPOSE: The treatment of thoracoabdominal aortic aneurysm has largely shifted to endovascular techniques. However, severe iliofemoral arterial disease often presents a challenge during these interventions. As a result, iliac conduits have been introduced to facilitate aortic endovascular therapy. The goal of the current study was to gauge utilization and to analyze iliac artery conduit outcomes to facilitate endovascular therapy to treat aortic pathologies. MATERIALS AND METHODS: A meta-analysis of 14 studies was conducted with the use of random effects modeling. The incidence of periprocedural adverse events was gauged based on iliac conduit vs nonconduit cases and planned vs unplanned iliac conduit placement. Outcomes of interest included length of hospital stay, morbidity and mortality associated to conduits, and all-cause mortality. RESULTS: Iliac conduits, either open or endo-conduits, were utilized in 17% (95% CI: 9%-27%) of 16,855 cases, with technical successful rate of 94% (95% CI: 80%-100%). Periprocedural complications occurred in 32% (95% CI: 22%-42%) of the cases, with overall bleeding complication rate being 10% (95% CI: 5%-16%). Female patients, positive history for smoking, pulmonary disease, and peripheral artery disease at baseline were associated with more frequent utilization of iliac conduits. Conduit use was associated with longer hospitalization, higher periprocedural all-cause mortality (OR: 2.85; 95% CI: 1.75-4.64; p<0.001), and bleeding complication rate (OR: 2.38; 95% CI: 1.58-3.58; p<0.001). Sensitivity analysis among conduit cases showed that planned conduits were associated with fewer periprocedural complications compared to unplanned conduits (OR: 0.38; 95% CI: 0.20-0.73; p=0.004). CONCLUSION: Iliac conduit placement is a feasible strategy, associated with high technical success to facilitate complex aortic endovascular repair. However, periprocedural adverse event rate, including bleeding complications is not negligible. All-cause mortality and morbidity rates among cases that require iliac conduits should be strongly considered during clinical decision making. High-quality comparative analyses between iliac conduit vs nonconduit cases and between several types of iliac conduit grafts aiming at facilitating endovascular aortic repair are still needed to determine the best strategy to address challenging iliac artery accesses.

Massive Pulmonary Embolism with Cardiac Arrest during Routine Tibial Bypass Surgery.

We report the case of a massive pulmonary embolism with intraoperative cardiac arrest in a 48-year-old male during routine surgical tibial bypass successfully managed by catheter-based interventions. Our experience supports the trending shift in pulmonary embolism therapy guidelines to include endovascular approaches and emphasizes the need for vascular surgeons to adapt their training protocols.

Sharp Recanalization with the Upstream GoBack Catheter for Chronic Occlusive Ilio-Caval Thrombosis.

Recanalization of chronic iliofemoral deep vein thrombosis is indicated to reduce symptoms and improve quality of life. However, recanalization is dependent on the ability to cross chronic obstructions. We present a case of chronically thrombosed inferior vena cava and common iliac veins that failed conventional crossing techniques but were successfully recanalized using the recently approved Upstream GoBack Crossing Catheter.

Victory Tax: A Holistic Income Tax System.

How can an income tax system be designed to exploit human nature and a free market to create a poverty free society, while balancing budgets without disproportional tax burdens? Such a tax system, with universal character, is deduced from the following guiding principles: (1) a single tax rate applies to all income types and levels; (2) the tax rate adjusts to satisfy budget projections; (3) government transfer only supplements the income of households with self-generated income below the poverty line; (4) deductions for basic living expenses, itemized investments and capital losses are allowed; (5) deductions cannot be applied to government transfer. A general framework emerges with three parameters that determine a minimum allowed tax deduction, a maximum allowed itemized deduction, and a maximum deduction defined by income percentage. An income distribution that mimics the United States, and a series of log-normal distributions are considered to quantitatively compare detailed characteristics of this tax system to progressive and flat tax systems. To minimize government dependency while maximizing after-tax income, the effective tax rate (ETR) as a function of income percentile takes the shape of the letter, V, inspiring the name victory tax, where the middle class has the lowest ETR.

A systematic review of diagnosis and treatment of acute limb ischemia during pregnancy and postpartum period.

BACKGROUND: Acute limb ischemia (ALI) carries significant overall morbidity and mortality. Pregnant and postpartum women are physiologically hypercoagulable, but little is known about the impact of ALI in this cohort of patients. The goal of this systematic review was to gather available data on diagnosis and treatment of ALI during pregnancy and the postpartum period. METHODS: A systematic review of studies on patients with ALI during pregnancy and the puerperium was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Three databases including PubMed MEDLINE, Embase, and Cochrane Library were queried. Manuscripts that provided data on diagnosis and treatment of ALI in pregnant and postpartum patients were included regardless of language or study design. Outcomes of interest included type of treatment for ALI (open and endovascular), morbidity, and mortality. RESULTS: Fourteen manuscripts of 6222 references were included with a total of 14 patients. The median age of patients was 31.5 years. Embolism, present in eight (57%) patients, was slightly more common than thrombosis. All patients had a pregnancy complication or concomitant medical condition that might have predisposed to arterial occlusion either directly or indirectly by leading to iatrogenic arterial injury; peripartum cardiomyopathy, the most common, occurred in six (43%) patients. Open surgery was the preferred treatment option in 11 (79%) patients, followed by anticoagulation alone. No endovascular procedures were described. One patient underwent major amputation on presentation, and an additional patient required major amputation for recurrent ALI. No deaths occurred. Twelve (86%) patients had complete recovery with no other ALI-associated sequelae. CONCLUSIONS: ALI is rare in pregnant and postpartum women despite their transient physiologic hypercoagulability and is almost uniformly associated with pregnancy complications. Open surgical revascularization or anticoagulation alone appears to have acceptable outcomes as most patients present with embolism or thrombosis without underlying systemic arterial disease.

Percutaneous Endovascular Repair of a Ruptured Extent III Thoracoabdominal Aortic Aneurysm with Bilateral Large Common Iliac Aneurysms and Aortocaval Fistula.

Ruptured thoracoabdominal aneurysms (rTAAAs) are rare and carry a significant rate of morbidity and mortality. Aortocaval fistula secondary to rTAAA is even more infrequent. We describe an urgent and staged endovascular treatment of a ruptured extent III thoracoabdominal aortic aneurysm with an aortocaval fistula by performing vena cava stenting to treat aortocaval fistula as a damage control maneuver prior to transfer and subsequent TAAA repair with a physician-modified endograft at a quaternary level hospital.

Rigidity and flexibility characteristics of DD[E/D]-transposases Mos1 and Sleeping Beauty.

DD[E/D]-transposases catalyze the multistep reaction of cut-and-paste DNA transposition. Structurally, several DD[E/D]-transposases have been characterized, revealing a multi-domain structure with the catalytic domain possessing the RNase H-like structural motif that brings three catalytic residues (D, D, and E or D) into close proximity for the catalysis. However, the dynamic behavior of DD[E/D]-transposases during transposition remains poorly understood. Here, we analyze the rigidity and flexibility characteristics of two representative DD[E/D]-transposases Mos1 and Sleeping Beauty (SB) using the minimal distance constraint model (mDCM). We find that the catalytic domain of both transposases is globally rigid, with the notable exception of the clamp loop being flexible in the DNA-unbound form. Within this globally rigid structure, the central ß-sheet of the RNase H-like motif is much less rigid in comparison to its surrounding α-helices, forming a cage-like structure. The comparison of the original SB transposase to its hyperactive version SB100X reveals the region where the change in flexibility/rigidity correlates with increased activity. This region is found to be within the RNase H-like structural motif and comprise the loop leading from beta-strand B3 to helix H1, helices H1 and H2, which are located on the same side of the central beta-sheet, and the loop between helix H3 and beta-strand B5. We further identify the RKEN214-217DAVQ mutations of the set of hyperactive mutations within the catalytic domain of SB transposase to be the driving factor that induces change in residue-pair rigidity correlations within SB transposase. Given that a signature RNase H-like structural motif is found in DD[E/D]-transposases and, more broadly, in a large superfamily of polynucleotidyl transferases, our results are relevant to these proteins as well.

Stent-Graft Length Is Associated with Decreased Patency in Treatment of Central Venous Stenosis in Hemodialysis Patients.

BACKGROUND: Central venous occlusion may occur in hemodialysis patients, resulting in arm or facial swelling and failure of dialysis access. Endovascular management with balloon angioplasty or stenting has been described, but there are minimal data on the use of covered stents in this pathology. We sought to review a single institution's experience with the use of covered stents for central venous occlusive disease in hemodialysis patients. METHODS: A retrospective review of all patients undergoing placement of covered stents between April 2014 and December 2016 for central venous occlusive disease to preserve a failing dialysis access was performed. Patients' records were reviewed to identify demographics, medical comorbidities, operative variables, primary patency rates, and secondary interventions. RESULTS: A total of 29 patients were included in the analysis. Viabahn (W.L. Gore and Associates, Flagstaff, AZ) stent grafts were exclusively used in all patients. Technical success rate was 100%. The patients were predominantly female (65.5%), with a mean age of 67.9 ± 12.1 and medical comorbidities of hypertension (86%), diabetes (76%), and tobacco use (7%). The majority (86%) had prior angioplasty and 17 of 29 (59%) patients had previous central venous catheters. The right brachiocephalic vein was the most commonly stented vessel (28%). The median stent length and diameter used were 50 millimeters (range 25-100 millimeters) and 13 millimeters (range: 9-13 millimeters), respectively. The majority of patients (83%) received a single stent, with only 2 patients requiring more than one. Median follow-up was 24 months (range: 6-41 months). Four of 29 (13.8%) patients developed symptomatic stent restenosis requiring secondary intervention, all of which occurred in patients with primary stenosis between 50% and 75%. When compared to the patients without restenosis, longer stents were found to be significantly associated with restenosis (62.5 centimeters, interquartile range [IQR]: 0] vs. 50 centimeter, IQR: 0, P = 0.002). Primary patency rates were 92.9%, 91.7%, and 80.0% at 6, 12, and 24 months respectively. Secondary patency rates were 96.4%, 95.8%, and 93.3% at 6 months, 12 months, and 24 months, respectively. The overall primary patency rate was estimated at 86.2% using Kaplan-Meier analysis at 30.5 months (95% confidence interval: 26.5-34.5 months). CONCLUSIONS: Covered stent grafts have reasonable primary patency and excellent secondary patency when used for central venous stenosis in dialysis patients. Stent-graft length is associated with poorer long-term patency rates.

Molecular clustering and percolation characteristics near the glass transition in aqueous trehalose and choline dihydrogen phosphate solutions.

Spatial and temporal characteristics of molecular structure in ternary solutions of trehalose and choline dihydrogen phosphate (CDHP) are studied using molecular dynamics simulations at 300 K for a range of solute concentrations with a 2 : 1 stoichiometric ratio of trehalose to CDHP. For a given molecular configuration, water molecules are classified as interior (only neighboring other water molecules) or interfacial (at least one solute neighbor). As a tagged water molecule diffuses, it dynamically exchanges between interior and interfacial type as its local environment changes, with differences in hydrogen-bond strength between different molecular species creating a persistent preference for interfacial water. At high solute concentrations, interfacial and interior water have similar diffusivity, which allows for water to collectively act as a plasticizer. The percolation threshold for water, defined as the maximum solute concentration at which there still exists a water cluster that spans the simulation box, was found to be slightly under the liquid-glass transition, estimated to be near 84.5% solute concentration based on the onset of a volume hysteresis effect, which was not previously studied in the computational literature. The systems were observed to be highly inhomogeneous, with interlaced percolating networks of water and solute coexisting at intermediate concentrations. The density of interior water was found to decrease with increasing solute concentration, creating low-density regions within the matrix.

JED: a Java Essential Dynamics Program for comparative analysis of protein trajectories.

BACKGROUND: Essential Dynamics (ED) is a common application of principal component analysis (PCA) to extract biologically relevant motions from atomic trajectories of proteins. Covariance and correlation based PCA are two common approaches to determine PCA modes (eigenvectors) and their eigenvalues. Protein dynamics can be characterized in terms of Cartesian coordinates or internal distance pairs. In understanding protein dynamics, a comparison of trajectories taken from a set of proteins for similarity assessment provides insight into conserved mechanisms. Comprehensive software is needed to facilitate comparative-analysis with user-friendly features that are rooted in best practices from multivariate statistics. RESULTS: We developed a Java based Essential Dynamics toolkit called JED to compare the ED from multiple protein trajectories. Trajectories from different simulations and different proteins can be pooled for comparative studies. JED implements Cartesian-based coordinates (cPCA) and internal distance pair coordinates (dpPCA) as options to construct covariance (Q) or correlation (R) matrices. Statistical methods are implemented for treating outliers, benchmarking sampling adequacy, characterizing the precision of Q and R, and reporting partial correlations. JED output results as text files that include transformed coordinates for aligned structures, several metrics that quantify protein mobility, PCA modes with their eigenvalues, and displacement vector (DV) projections onto the top principal modes. Pymol scripts together with PDB files allow movies of individual Q- and R-cPCA modes to be visualized, and the essential dynamics occurring within user-selected time scales. Subspaces defined by the top eigenvectors are compared using several statistical metrics to quantify similarity/overlap of high dimensional vector spaces. Free energy landscapes can be generated for both cPCA and dpPCA. CONCLUSIONS: JED offers a convenient toolkit that encourages best practices in applying multivariate statistics methods to perform comparative studies of essential dynamics over multiple proteins. For each protein, Cartesian coordinates or internal distance pairs can be employed over the entire structure or user-selected parts to quantify similarity/differences in mobility and correlations in dynamics to develop insight into protein structure/function relationships.

Decomposing Dynamical Couplings in Mutated scFv Antibody Fragments into Stabilizing and Destabilizing Effects.

Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried, the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies.