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Catheter-directed thrombolysis (CDT) is increasingly performed for acute pulmonary embolism (PE) because it is presumed to provide similar therapeutic benefits to systemic thrombolysis, while decreasing the dose of thrombolytic required and the associated risks. Contemporary suction thrombectomy (ST) devices have entered the market as minimal or no-lytic alternatives, but there is no evidence on their comparative effectiveness. This study aims to compare clinical outcomes of these two interventional alternatives.Consecutive patients who underwent a ST catheter intervention for massive or submassive PE between 2011 and 2017 were identified. For each of these patients, a nearest-neighbor matching was implemented to identify at least three CDT patients who matched as closely as possible on the following six variables: PE type, age, gender, acute deep venous thrombosis, pulmonary disease, and year of procedure. The end point was clinical success defined as meeting all the following criteria: survival to hospital discharge without major bleeding (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries moderate or severe), perioperative stroke or other major adverse procedure-related event, and decompensation for submassive or persistent shock for massive PE.Of 277 patients who received an intervention for acute PE, 54 CDT (63.5 ± 14.2 years of age; 18 massive PE) were matched with 18 ST (64.1 ± 14.1 years of age; 6 massive PE) patients. In the CDT group, 38 (70.4%) received ultrasound-assisted thrombolysis. The ST group had significantly more patients who had a major contraindication for lytics (1 [1.9%] for CDT vs 9 [50%] for ST; P .001). There was no difference in major bleeding (8 [14.8%] for CDT vs 3 [16.7%] for ST; P.999; Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries severe 1 [1.8%] for CDT vs 1 [5.6%] for ST; P.999), stroke (3.7% for CDT vs 0 for ST; P = .408), or death (3.7% for CDT vs 16.7% for ST; P = .096). One patient in the ST group suffered tricuspid valve rupture and two patients in CDT group required surgical thrombectomy. Clinical success was not statistically different between groups (75.9% for CDT vs 61.1% for ST; P = .224). The association was similar when assessing the right/left ventricular ratio improvement (0.30 ± 0.19 for CDT vs 0.17 ± 0.16 for ST; P = .097), or the subgroup of patients with submassive PE (86.1% for CDT vs 66.7% for ST; P = .135).CDT seems to have similar outcomes with ST in the management of acute PE, although larger, more homogenous data are needed. In our experience, ST should be viewed as a complementary alternative for patients with contraindication for thrombolytics or severely compromised hemodynamic profile and can yield good outcomes in an otherwise highly morbid population.

An alternative analgesic to morphine is methadone, which is used to control chronic pain and is used in opioid rehabilitation treatment programs due to methadone having a long half-life and being relatively inexpensive as compared to extended-release forms of morphine. Despite its benefits, methadone accumulates in adipose tissue due to being lipophilic, binds strongly to plasma proteins, and is metabolized in the liver by the cytochrome P450 system causing methadone levels to be variable and subject to influence according to the individual body compositions and concurrent use of cytochrome P450 inhibitors. In addition to methadone being able to cause both respiratory and central nervous system depression, methadone can also prolong the QT interval and cause potentially life-threatening arrhythmias including torsades de pointes. The susceptibility of unintentional overdosing of methadone due to its varied pharmacologic properties and potentially fatal induction of arrhythmias may cause the risks of methadone use to outweigh its benefits and therefore must be closely monitored.

Protein structure refinement is the challenging problem of operating on any protein structure prediction to improve its accuracy with respect to the native structure in a blind fashion. Although many approaches have been developed and tested during the last four CASP experiments, a majority of the methods continue to degrade models rather than improve them. Princeton_TIGRESS (Khoury et al., Proteins 2014;82:794-814) was developed previously and utilizes separate sampling and selection stages involving Monte Carlo and molecular dynamics simulations and classification using an SVM predictor. The initial implementation was shown to consistently refine protein structures 76% of the time in our own internal benchmarking on CASP 7-10 targets. In this work, we improved the sampling and selection stages and tested the method in blind predictions during CASP11. We added a decomposition of physics-based and hybrid energy functions, as well as a coordinate-free representation of the protein structure through distance-binning Cα-Cα distances to capture fine-grained movements. We performed parameter estimation to optimize the adjustable SVM parameters to maximize precision while balancing sensitivity and specificity across all cross-validated data sets, finding enrichment in our ability to select models from the populations of similar decoys generated for targets in CASPs 7-10. The MD stage was enhanced such that larger structures could be further refined. Among refinement methods that are currently implemented as web-servers, Princeton_TIGRESS 2.0 demonstrated the most consistent and most substantial net refinement in blind predictions during CASP11. The enhanced refinement protocol Princeton_TIGRESS 2.0 is freely available as a web server at http://atlas.engr.tamu.edu/refinement/. Proteins 2017; 85:1078-1098. © 2017 Wiley Periodicals, Inc.

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research. Funding Agencies|Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]; U.S. Department of Energy, Office of Science, Office of Workforce Development for Teachers and Scientists (WDTS) under the Science Undergraduate Laboratory Internship (SULI) program; U.S. Department of Energy, Office of Science, Office of Workforce Development for Teachers and Scientists (WDTS) under the Visiting Faculty Program (VFP); United States-Israel Binational Science Foundation (BSF) [2009432]; Israel Science Foundation (ISF) [1122/14]; National Institute of General Medical Sciences [R01GM093123, GM083107, GM116960]; Purdue University start-up funds; Ralph W. and Grace M. Showalter Trust Award; Jim and Diann Robbers Cancer Research Grant for New Investigators Award; Brazilian agency: FAPESP; Brazilian agency: CAPES; Brazilian agency: CNPq; NIH [GM-14312]; NSF [MCB-10-19767]; National Institutes of Medicine [GM11574901]; Swedish Research Council [2012-5270, 2016-05369]; Swedish e-Science Research Center; Polish National Science Center [UMO-2013/10/M/ST4/00640]; IISc Mathematical Initiative Assistantship; National Academy of Sciences, India; National Institutes of Health [R01-GM100701, R01GM052032]; National Science Foundation; National Science Foundation Graduate Research Fellowship [DGE-1148900]; Princeton Institute for Computational Science and Engineering (PICSciE); Princeton University Office of Information Technology; UK Engineering and Physical Sciences Research Council [EP/M020576/1, EP/N031962/1]; National Research Foundation of Korea [2016R1A2A1A05005485]

Iliac vein stenting is recommended to treat venous outflow obstruction after catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis (DVT). Data on the outcome of proximal and distal stent extension are limited. Proximal stent extension to the vena cava may obstruct the contralateral iliac vein, whereas distal extension below the inguinal ligament contradicts common practice for arterial stents. The aim of this retrospective study was to assess outcomes and predictors of failure of iliac vein stents and contralateral iliac vein thrombosis, taking into consideration stent positioning.Consecutive patients who underwent thrombolysis and stenting for DVT between May 2007 and September 2017 were identified from a prospectively maintained database. The intraoperative venograms were reviewed for proximal stent placement (covering50% contralateral iliac vein orifice) and distal placement across the inguinal ligament. End points were ipsilateral DVT recurrence, post-thrombotic syndrome (PTS; Villalta score ≥5), and contralateral DVT. Patients with chronic contralateral DVT or contralateral iliac vein stenting at baseline were excluded from the contralateral DVT outcome evaluation. Survival analysis and Cox regression models were used to determine outcomes.Of 142 patients lysed, 73 patients (12 bilateral DVTs; mean age, 45.8 ± 17.2 years; 46 female patients) were treated with various combinations of thrombolytic techniques and at least one self-expanding iliac stent (77 stented limbs). Thirty-day recurrence developed in nine (12.3%) patients. The 3-year primary patency and secondary patency rates were 75.2% and 82.2%, respectively. The single predictor for loss of primary patency was incomplete thrombolysis (≤50%; hazard ratio [HR], 7.41; P = .002). Overall, 3 of 12 (25%) stents extending below the inguinal ligament occluded at 1 month, 2 months, and 9 months, respectively. The overall rate of PTS (Villalta score ≥5) in the stented cohort was 14.4% at 5 years. This was predicted by incomplete lysis (50%; HR, 7.09; P = .040), stent extension below the inguinal ligament (HR, 6.68; P = .026), and male sex (HR, 6.02; P = .041). Of the 17 stents that extended into the contralateral common iliac vein and 58 stents that did not, there were 1 (5.9%) and 5 (8.6%) contralateral DVTs (P = .588) at an average follow-up of 27.4 ± 33.7 and 22.2 ± 22.3 months (P = .552), respectively.Iliac stenting after thrombolysis for acute DVT guarantees high patency and low PTS rates, provided adequate thrombus resolution has been achieved before stent placement. Stent placement below the inguinal ligament does not affect the patency but may be associated with a higher PTS rate. Stenting proximal to the iliocaval confluence, although a precipitating factor, may not independently increase the likelihood of contralateral DVT.

Objective Retrograde infrageniculate access is an alternative treatment strategy for patients who have failed to respond to antegrade endovascular intervention. This study compares the outcomes of infrageniculate retrograde arterial access with the conventional transfemoral access for the endovascular management of chronic lower extremity ischemia. Methods This was a retrospective single-center review of retrograde endovascular intervention (REI) from 2012 to 2016. Indications for intervention, comorbidities, complications, procedural success, limb outcomes, and mortality were analyzed. Technical failure was defined as the inability to complete the procedure because of failed access or unsuccessful recanalization. Infrageniculate access and transfemoral access were obtained with ultrasound or angiographic roadmap guidance. Patency rates were calculated for technically successful interventions. Results There were 47 patients (85% presenting with critical limb ischemia) who underwent sheathless REI after failed antegrade recanalization of TransAtlantic Inter-Society Consensus class D infrainguinal lesions, whereas 93 patients (83% with critical limb ischemia) underwent standard transfemoral access. There were 16 (34%) femoropopliteal, 14 (30%) tibial, and 17 (36%) multilevel interventions in the retrograde group compared with 41 (41%) femoropopliteal, 20 (20%) tibial, and 39 (39%) multilevel interventions in the transfemoral group. Access sites for the retrograde group included the dorsalis pedis (26%), midcalf peroneal (24%), anterior tibial (22%), posterior tibial (26%), and popliteal (2%) arteries. Overall technical success was achieved in 57% of the retrograde group compared with 78% of the transfemoral group. Mean follow-up was 20 months (range, 1-45 months). There were no significant differences in the primary patency rates between the two groups at 1 year and 2 years. The primary assisted patency rates were significantly better in the transfemoral group at 1 year (66% vs 46%; P = .031) and 2 years (56% vs 29%; P = .031). The secondary patency rates were higher in the transfemoral group at 1 year (93% vs 83%; P = .079) and 2 years (91% vs 76%; P = .079), although this did not reach statistical significance. The rate of reintervention was 41% for the retrograde group vs 40% for the transfemoral group. Most of the reinterventions (70% in the retrograde group and 61% in the transfemoral group) were endovascular interventions for a restenosis or occlusion. Conclusions Infrageniculate access for REI can result in primary patency rates similar to those of antegrade interventions and does not compromise the access site. Technical failure is high in this initial experience and is mostly due to failed recanalization. Limb salvage may be achieved after technical failure with either repeated antegrade intervention or surgical bypass.

In this work, we assess calculated hydration free energies of natural and unnatural amino acids compared to experimental hydration free energies of corresponding side-chain analogs using the ff03 charge model. Fine-grid, explicit water thermodynamic integration calculations using two widely used explicit water models (TIP3P and TIP4P-Ew) were performed on 19 natural amino acids and compared with experimental hydration free energies of corresponding side-chain analogs to establish expected accuracy levels for this charge model. Next, parameters previously derived for 17 unnatural amino acids and several new parameters optimized in this work were assessed using the same methodology. We found that the ff03 charge model is correlated with experimental hydration free energies but underestimates the solubilities of several polar natural and unnatural amino acids. Comparisons are presented with other forcefields and water models recently presented in the literature for both natural and modified amino acids.

Protein structure refinement is the challenging problem of operating on any protein structure prediction to improve its accuracy with respect to the native structure in a blind fashion. Although many approaches have been developed and tested during the last four CASP experiments, a majority of the methods continue to degrade models rather than improve them. Princeton_TIGRESS (Khoury et al., Proteins 2014;82:794-814) was developed previously and utilizes separate sampling and selection stages involving Monte Carlo and molecular dynamics simulations and classification using an SVM predictor. The initial implementation was shown to consistently refine protein structures 76% of the time in our own internal benchmarking on CASP 7-10 targets. In this work, we improved the sampling and selection stages and tested the method in blind predictions during CASP11. We added a decomposition of physics-based and hybrid energy functions, as well as a coordinate-free representation of the protein structure through distance-binning Cα-Cα distances to capture fine-grained movements. We performed parameter estimation to optimize the adjustable SVM parameters to maximize precision while balancing sensitivity and specificity across all cross-validated data sets, finding enrichment in our ability to select models from the populations of similar decoys generated for targets in CASPs 7-10. The MD stage was enhanced such that larger structures could be further refined. Among refinement methods that are currently implemented as web-servers, Princeton_TIGRESS 2.0 demonstrated the most consistent and most substantial net refinement in blind predictions during CASP11. The enhanced refinement protocol Princeton_TIGRESS 2.0 is freely available as a web server at http://atlas.engr.tamu.edu/refinement/. Proteins 2017; 85:1078-1098. © 2017 Wiley Periodicals, Inc.

Inferior vena cava (IVC) thrombosis may occur in patients with iliofemoral deep venous thrombosis (DVT), and its impact on thrombolysis outcomes is poorly defined. This study compared outcomes of patients undergoing thrombolysis for acute iliofemoral DVT with and without IVC involvement.Patients who underwent thrombolysis for iliofemoral DVT between May 2007 and March 2014 were identified from a prospectively maintained database and divided into two groups: those with IVC involvement and those without. End points were technical and clinical success (≥50% lysis or freedom from 30-day DVT recurrence), long-term DVT recurrence, and post-thrombotic syndrome (PTS; Villalta score ≥5). Multivariate regression models were used to determine predictors of anatomic and clinical failures.There were 102 patients (127 limbs) treated with various combinations of catheter-directed or pharmacomechanical thrombolysis. In 46 patients, thrombus extended into the IVC (54.3% extended up to the renal veins; 87% had ≥50% luminal reduction; 50% occurred in association with an indwelling thrombosed IVC filter). The caval group had fewer women and more previous DVTs but otherwise was similar to the noncaval group. Pharmacomechanical thrombolysis was used more frequently in the caval thrombus group (97.8% vs 82.1%; P = .011), and iliac vein stenting was used more often in the noncaval group (41.3% vs 62.5%; P = .033). Clinical success was similar between the two groups (88.7% for caval vs 89.3% for noncaval; P = .921). All failures in the caval group occurred in patients with an indwelling thrombosed IVC filter. Primary patency at 2 years for the caval and noncaval groups was 76.7% and 78.0%, respectively (P = .787). Valve reflux and PTS at 2 years were higher in the noncaval group (50.8% and 34.3% vs 23.3% and 11.5% in the caval group; P = .013 and P = .035). On multivariate analysis, incomplete lysis was predictive of recurrence (hazard ratio [HR], 22.7; P .001) and PTS (HR, 5.59; P = .010), whereas caval involvement (HR, 0.22; P = .005) was protective from PTS.IVC thrombosis does not have an impact on the technical success of thrombolysis in patients with iliofemoral DVT; the presence of a thrombosed IVC filter, though, may make failure more likely. Caval thrombosis may not affect primary patency but is associated with a lower incidence of PTS after successful lysis.

Accurate prediction of protein secondary structure remains a crucial step in most approaches to the protein-folding problem, yet the prediction of ordered secondary structure, specifically beta-strands, remains a challenge. We developed a consensus secondary structure prediction method, conSSert, which is based on support vector machines (SVM) and provides exceptional accuracy for the prediction of beta-strands with QE accuracy of over 0.82 and a Q2-EH of 0.86. conSSert uses as input probabilities for the three types of secondary structure (helix, strand, and coil) that are predicted by four top performing methods: PSSpred, PSIPRED, SPINE-X, and RAPTOR. conSSert was trained/tested using 4261 protein chains from PDBSelect25, and 8632 chains from PISCES. Further validation was performed using targets from CASP9, CASP10, and CASP11. Our data suggest that poor performance in strand prediction is likely a result of training bias and not solely due to the nonlocal nature of beta-sheet contacts. conSSert is freely available for noncommercial use as a webservice: http://ares.tamu.edu/conSSert/.