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Background and Purpose— Because of unique attributes of mechanical thrombectomy performed between 6 and 24 hours after symptom onset in acute ischemic stroke patients, it is not known if predictors of angiographic recanalization and favorable outcome in patients treated with thrombectomy in the late (6–24 hour) time window are similar to those treated in the early time window. Methods— We analyzed data from the DAWN trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) which enrolled patients with symptom onset 6 to 24hours after last known well and occlusion of the intracranial internal carotid artery or proximal middle cerebral artery with a mismatch between severity of clinical deficit and infarct core volume as identified by computed tomography–perfusion or diffusion magnetic resonance imaging. We evaluated the effect of tandem occlusions, periprocedural heparin use, procedural speed (from puncture to procedure completion), general anesthesia, balloon-guide catheters, thrombectomy device size, and number of passes on substantial reperfusion (modified Thrombolysis in Cerebral Infarction 2b/3) and on likelihood of obtaining a modified Rankin Scale at 3 months indicating functional independence. Results— Of 107 patients who underwent MT in the interventional arm of DAWN, substantial reperfusion and modified Rankin Scale score 0 to 2 at 3 months was seen in 90 (84%) and 52 (49%), respectively. In univariate analysis, general anesthesia (odds ratio [OR] 0.27; P =0.042) and ≥3 passes with stent retriever (OR, 0.17; P =0.002) were inversely associated with substantial reperfusion. In multivariate analyses, only ≥3 passes were associated with lack of revascularization (OR, 0.17; P =0.002). in univariate analysis ≥3 passes (OR, 0.24; P =0.003) and baseline National Institutes of Health Stroke Scale score >17 (OR, 0.19; P P =0.003) and National Institutes of Health Stroke Scale score >17 (OR, 0.19; P Conclusions— Patients requiring ≥3 thrombectomy passes had reduced substantial reperfusion and favorable outcome at 3 months in DAWN. Whether or not additional thrombectomy techniques beyond ≥3 thrombectomy passes with the Trevo stent retriever are beneficial for patient outcomes in this patient population remains to be clarified by future studies. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02142283.

Background and Purpose— It is unknown whether noncontrast computed tomography (NCCT) can identify patients who will benefit from intra-arterial treatment (IAT) in the extended time window. We sought to characterize baseline Alberta Stroke Program Early CT Score (ASPECTS) in DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and to assess whether ASPECTS modified IAT effect. Methods— Core lab adjudicated ASPECTS scores were analyzed. The trial cohort was divided into 2 groups by qualifying imaging (computed tomography versus magnetic resonance imaging). ASPECTS-by-treatment interaction was tested for the trial coprimary end points (90-day utility-weighted modified Rankin Scale (mRS) score and mRS, 0–2), mRS 0 to 3, and ordinal mRS. ASPECTS was evaluated separately as an ordinal and a dichotomized (0–6 versus 7–10) variable. Results— Of 205 DAWN subjects, 123 (60%) had NCCT ASPECTS, and 82 (40%) had diffusion weighted imaging ASPECTS. There was a significant ordinal NCCT ASPECTS-by-treatment interaction for 90-day utility-weighted mRS (interaction P =0.04) and mRS 0 to 2 (interaction P =0.02). For both end points, IAT effect was more pronounced at higher NCCT ASPECTS. The dichotomized NCCT ASPECTS-by-treatment interaction was significant only for mRS 0 to 2 (interaction P =0.04), where greater treatment benefit was seen in the ASPECTS 7 to 10 group (odds ratio, 7.50 [2.71–20.77] versus odds ratio, 0.48 [0.04–5.40]). A bidirectional treatment effect was observed in the NCCT ASPECTS 0 to 6 group, with treatment associated with not only more mRS 0 to 3 outcomes (50% versus 25%) but also more mRS 5 to 6 outcomes (40% versus 25%). There was no significant modification of IAT effect by diffusion weighted imaging ASPECTS. Conclusions— Baseline NCCT ASPECTS appears to modify IAT effect in DAWN. Higher NCCT ASPECTS was associated with greater benefit from IAT. No treatment interaction was observed for diffusion weighted imaging ASPECTS.

Background: Two recent trials showed a strong benefit of thrombectomy in the extended window. However, these studies were performed in selected centers and utilized strict inclusion criteria. We aim to evaluate the outcomes of thrombectomy in a large prospective cohort treated outside the rigid clinical trial setting. Methods: Trevo Registry patients with ICA, MCA-M1 or M2 occlusions and pre-morbid mRS0-2 were categorized according to time-from-last-seen-well (TLSW) to puncture as early (0-6hours) vs. late (6-24hours). Uni- and multivariate analyzes were performed to identify good outcome (90-day mRS0-2) predictors. Subgroup analyses were performed for the basic DAWN (age >=18, NIHSS >=10, ICA or M1 occlusion, pre-morbid mRS 0-1) and DEFUSE 3 (age 18-90, NIHSS >=6, ICA or MCA-M1 occlusion, mRS 0-2) trial criteria. Results: As compared to the late (n=430), early patients (n=1173) were older (70 vs 68, p=0.011) and had higher IV tPA use (69 vs 25%, p= 6 (1.37 [1.07-1.75]), DM (0.58 [0.44-0.77]), and time to treatment (0.98 [0.97-1.00]) were independent predictors of good outcomes. Imaging modality did not predict outcomes. Similar findings were observed in the early versus late DAWN-like (n=709 vs 257) and DEFUSE 3-like (n=855 vs 273) cohorts. There was great similarity between the outcomes of the Trevo Registry subsets vs their analogous RCTs: early DAWN-like vs SWIFT Prime (90-day mRS 0-2: 57.5 vs 60%; 90-day mRS 6: 11.% vs 9%), Late DAWN-like vs DAWN (50.2 vs 48.6%; 10.6 vs 18%), and Late DEFUSE 3-like vs DEFUSE 3 (52 vs 45%; 10.3 vs 14%). Conclusions: Our study provides favorable data for the generalizability of the safety and efficacy of thrombectomy in the “real-world” setting.

Perioperative antimicrobial prophylaxis is administered to liver transplant (LTx) recipients to prevent surgical site infections (SSIs), but regimens are not standardized, and there are limited effectiveness data. Prevention and treatment of SSIs have been complicated by the emergence of multidrug-resistant (MDR) pathogens.We retrospectively reviewed SSIs among 331 LTx recipients at our center in 2010 to 2014.Culture-proven superficial and deep SSIs occurred in 3% and 15% of patients, respectively, at median 12.5 and 13.5 days post-LTx. Recipients with superficial SSIs and those without SSIs were similar in demographics, clinical characteristics, length of hospital stay, and mortality. Deep SSIs included abscesses (58%), peritonitis (28%), deep incisional infections (8%), and cholangitis (6%). Rates of deep SSIs were comparable among patients receiving prophylaxis with ampicillin-sulbactam, aztreonam and vancomycin, or tigecycline (P = 0.61). Independent risk factors for deep SSIs were bile leak (P0.001) and operative time (P0.001). Enterobacteriaceae (42%), Enterococcus spp. (24%), and Candida spp. (15%) were predominant pathogens. Fifty-three percent of bacteria were MDR, including 95% of Enterococcus faecium and 55% of Enterobacteriaceae; 82% of deep SSIs were caused by bacteria resistant to antimicrobials used for prophylaxis, and 58% of patients were treated with an inactive empiric regimen. Deep SSIs were associated with longer lengths of stay (P0.001), and higher 90-day and long-term mortality rates (P0.001).Deep SSIs, including those caused by MDR bacteria, were common after LTx despite prophylaxis with broad-spectrum antimicrobials. Rather than altering prophylaxis regimens, programs should devise empiric treatment regimens that are directed against the most common local pathogens.

Background and Aims: Balloon Guide Catheter (BGC) use during thrombectomy treatment in Stroke patients has been reported to have positive effects on revascularization, procedural characteristics, and clinical outcomes. We evaluate the use of BGC in an open-label large prospective TREVO Retriever Registry of real world patients to determine predictors of good ‘clinical’ outcomes. Method: Consecutive Trevo Registry patients that had Balloon Guide Catheter (BGC) used during their thrombectomy procedure were identified; a subset of patients who fulfilled the criteria (ICA and/or MCA-M1/M2 occlusion with pre-morbid mRS 0-1, TLSW ≤6 hrs) within the cohort were also identified. Multivariate analysis was performed to identify the predictors of good outcomes in BGC thrombectomy patients. Results: A total of 1031 BGC treated Trevo Registry patients (overall enrolled, n=2010) qualified for analysis, of which 605 patients fulfilling the subset criteria were identified. The mean age of BGC/stent retriever patients was 67.5 with a median (IQR) baseline NIHSS of 15(11-19). Occlusion location of the BCG group was ICA -20.4%, M1- 57.1%, M2/M3-20.3%, and Posterior 1.8%. In the overall BGC cohort, the median (IQR) time to treatment was (4.2 (3.0,6.5)- hrs.) with conscious/local sedation used in 63.4% and general anesthesia used in 37.3% of cases. The median number of passes with Trevo stent retriever was 1 and revascularization (mTICI ≥ b) was achieved in 92.8% of cases. The sICH rate was low at 1.9% (20/1031) with a low rate of vessel perforation (0.2%). At 90 days post stroke, 56.0% of patients achieved functional independence (mRS 0-2) with 63.7% of the subset of “guidline “ BGC patients achieving functional independence at 90 days. Multivariate logistic regression showed age (aOR 0.97 [0.96, 0.99] P Conclusion: Data from Trevo Registry demonstrate the use of BGC in thrombectomy procedure is safe, and leads to a reduction of disability in ischemic stroke patients.

Background: Endovascular therapy (EVT) effectiveness is established in ischemic strokes with large vessel occlusion (LVO) in the terminal ICA and M1, which was extended up to 24 hrs by recent DAWN trial results. However this benefit is not as well established in more distal (M2) occlusions, especially late presenters (beyond 6 hrs). We evaluated thrombectomy outcomes in M2 occlusions as compared to ICA/M1 across early and late time windows. Methods: In a prospective, multicenter, single arm, international registry (Trevo Retriever Registry), anterior circulation LVOs were stratified on clot location into M2 vs ICA/M1 and dichotimized into early vs late (0-6 vs 6-24 hrs). 90 day mRS (0-1 excellent, 0-2 good) were the primary outcomes; sICH and dissection were the secondary (safety) outcomes. Multivariate analyses identified pre-procedure variables independently correlating with good outcome in M2s. Results: 1581 patients were identified (1265 ICA/M1, 316 M2). The M2 and ICA/M1 groups were similar (age in both 68.4), IV-tPA (69.1 vs 69.7%, p=0.8) and same median/IQR ASPECTS 8 (7-9). M2 patients had lower NIHSS (13 vs 16, p Conclusion: Excellent and good outcomes may be achieved in distal LVO isolated to M2 similar to those with proximal occlusions. A benefit that can be reached up to 24 hrs.

Background and Aims: Intravenous tPA remains the standard of care, with MT currently indicated within 8 hours for IV tPA failures or patients with IV tPA contraindications. Whether LVO patients should receive IV tPA treatment or instead be triaged directly to MT therapy is currently unknown but greatly debated. The Trevo Registry is a real world, multi-center, international study of mechanical thrombectomy (MT) patients treated from 0-24 hours. Evaluation of the Trevo Registry clinical and procedurals outcomes of MT patients treated with or without IV tPA could provide insight into the benefit of IV tPA in MT patients. We hypothesized that in MT patients treated within 8 hours, pretreatment with intravenous tPA would lead to better clinical outcomes compared to patients who did not receive IV tPA. Method: Consecutively enrolled patients treated within 8 hours with ICA, M1, or M2 occlusions were selected for analysis. Univariate and multivariable regressions were conducted to identify clinical and radiographic independent variables that correlate best with the dependent variable of functional outcome: mRS 0-2, with a focus on intravenous tPA treatment. Results: A total of 1183 Trevo Registry patients (overall enrolled, n=2010) qualified for analysis, of whom 380 were not treated with IV tPA. Demographics were similar, however atrial fibrillation (46.3% vs 27.2%) and previous ischemic stroke (14.1% vs 7.5%) were higher in the no IV tPA group. The median time to treatment was similar (3.8 vs. 3.6 hrs). First pass mTICI ≥ 2B (63.6% vs 66.4%) and final revascularization (91.1% vs 92.8%) were similar between no IV tPA and IV tPA groups.Unadjusted, there were similar rates of functional outcome (90 day mRS 0-2; 60.9% vs. 62.5%). After adjustment, patients who did not receive IV-tPA had similar rates of good outcome (aOR 1.08, 95% CI [0.87-1.34]. P=0.58) as well as reduction (shift) in disability (aOR 1.08, 95% CI [0.87-1.34]. P=0.49). Safety outcomes (mortality, sICH) were similar between both groups. Conclusion: In the Trevo Registry of MT patients treated within 8 hours, patients who did not receive IV tPA had similar endovascular and clinical outcomes as patients pretreated with IV tPA. The added benefit of IV tPA for MT patients should be further investigated.

Background: The DAWN trial showed EVT effectiveness in the late time window (6-24 hrs), however, DAWN patients were carefully selected based on advanced perfusion imaging, CTP and MRI. Similar to the early window (0-6 hrs), simple imaging (CT) and other clinical variables may select patients for thrombectomy beyond 6 hours. We evaluated a largescale, real world practice for predictors that could identify patients who may benefit from EVT in the late time window. Methods: Patients with LVO in the anterior circulation (M1, M2, ICA) from a prospective, single arm, multicenter, international registry (Trevo Retriever Registry) treated in the late window LSN to groin puncture (GP) (6-24 hrs) were included. Univariate and multivariate analyses assessed factors independently correlating with good outcome (90 day mRS 0-2). Furthermore, patients outcomes were compared based on their baseline imaging selection CT vs CTP and MRI. Results: 549 patients were treated beyond 6 hours. The average age was 67, median/IQR ASPECTS 8(6-9), median/IQR NIHSS was 15 (9-20), median/IQR time LSN to GP (hr) was 9.7 (7.3-13.6) and IV-tPA rate were 22.8%. CT was the only imaging selection method in 15.9%, while additional advanced imaging was utilized in the remaining patients; CTP (70%), and MRI(14.1%). Good outcomes were observed in 51.4% of late window patients. Age (aOR 0.96, 95% CI 0.94-0.98, p Conclusion: Simple imaging and clinical variables can identify patients that could benefit from thrombectomy in the late window. Importantly, ASPECTS reliably predicted good outcome beyond 6 hours without adjunctive benefit from adding advanced perfusion imaging, a finding that may simplify patients selection to facilitate and generalize the intervention in the late window to wide, real world practice.

We review and offer our clinical perspectives on the emergence of echinocandin-resistant Candida.Candida FKS gene mutations attenuate echinocandin activity, but overall mutation rates among clinical isolates remain low (Candida glabrata, ∼4%; other species,1%). Rates are higher with prior echinocandin exposure, exceeding 50% among C. glabrata or Candida albicans isolates causing breakthrough invasive candidiasis. The median duration of prior echinocandin exposure among FKS mutant isolates is ∼100 days. The clinical usefulness of echinocandin susceptibility testing is limited by the low overall prevalence of resistance, and uncertainties surrounding testing methods and interpretation of minimum inhibitory concentrations (MICs). In single-center studies, caspofungin resistance (defined using institution-specific MIC breakpoints) was 32-53% sensitive and 75-95% specific for predicting treatment outcomes of C. glabrata invasive candidiasis; corresponding values for the presence of an FKS mutation were 35-41% and 90-98%. Results were similar using anidulafungin and micafungin MICs. Clinical data are scarce for non-C. glabrata species.Echinocandins remain preferred agents against invasive Candida infections. Susceptibility testing and FKS genotypic testing do not have roles in routine clinical practice, but may be useful in newly-diagnosed patients who are echinocandin-experienced or those who have not responded to echinocandin treatment.

Background: Endovascular thrombectomy trials established efficacy in acute ischemic stroke, yet real-world data on device effectiveness is warranted. Core lab adjudication of angiography is required to validate reperfusion, providing evidence and detailed data beyond randomized, controlled trials. We report the largest endovascular therapy registry data linking independent core lab data on reperfusion with clinical outcomes. Methods: The Trevo Retriever Registry is a prospective, open-label, consecutive enrollment, multicenter, international registry with more than 65 enrolling sites worldwide. An independent Imaging Core Lab, blind to all other data, evaluates the angiography with a battery of various TICI scores (mTICI, oTICI, oTICI2C) to define reperfusion. Statistical analyses examined TICI reperfusion and association with clinical outcomes considering expansive data collected in the registry. Results: 506 enrolled subjects (mean age 68.2 ± 14.2 yrs; 53% female) had core lab adjudicated angiography as of July 2016, including 21.5% > 80 years old. Baseline NIHSS was median 15.0 (9.0, 20.0) with time from onset to CT of median 4.0 (1.7, 9.7) hrs. Core lab adjudicated arterial occlusion sites were: 53% M1, 24% ICA, 16% M2, 4% Basilar and 2% other. Time to reperfusion (oTICI ≥ 2A) was median 30.0 (19.0, 42.0) min. Core lab adjudicated revascularization was mTICI ≥ 2B in 90.4% (95%CI 87.4, 92.9), oTICI ≥ 2B in 82.3% (95%CI 78.6, 85.6) and oTICI2C ≥ 2C in 45.0% (95%CI 40.5, 49.6). mRS of 0-2 at 90 days was achieved in 57.3% (95%CI 52.5, 62.1). Extensive clinical, laboratory and stroke workflow variables were considered, yet only male sex (OR 0.62 (95% CI 0.38, 0.99) was an independent predictor of successful reperfusion (oTICI ≥ 2B) while age (OR 0.96 (95% CI 0.94, 0.97), NIHSS (OR 0.91 (95% CI 0.88, 0.94) and diabetes (OR 0.54 (95% CI 0.33, 0.88) predicted mRS 0-2 at 90 days. Conclusions: Proven reperfusion rates after endovascular stroke therapy excel in the real-world translation of thrombectomy devices around the globe, leading to good outcomes after stroke.

Background: Most endovascular stroke therapy studies and subsequent guidelines restrict intervention based on ASPECTS. A wide range of ASPECTS scores may be encountered in practice and individual patient benefit may be realized even at low ASPECTS. We examined large-scale data on outcomes after endovascular therapy, stratified by baseline ASPECTS in the Trevo Retriever Registry. Methods: The independent Imaging Core Lab of the Trevo Retriever Registry prospectively determines ASPECTS on baseline imaging acquired immediately prior to endovascular thrombectomy. ASPECTS scores and regional involvement were analyzed with respect to site of arterial occlusion, effect of time from symptom onset, co-morbidities and clinical outcomes, based on ASPECTS strata. Results: Baseline ASPECTS data was reviewed by the Imaging Core Lab in 426 subjects with anterior circulation stroke enrolled in the Trevo Retriever Registry, as of July 2016. Mean age was 68.8 ± 13.7 yrs, with 20.9% > 80 years old. Baseline NIHSS was median 15.0 (10.0, 19.0). Onset to CT was median 3.8 (1.5, 9.0) hrs, with median ASPECTS of 8.0 (7.0, 9.0), ranging from 3-10. Baseline ASPECTS 0-7 occurred in 118/426 (27.7%) subjects, including 39.0% of ICA, 27.1% M1 and 16.9% M2/3 arterial occlusions at angiography. Baseline clinical variables predicting ASPECTS included age and NIHSS, whereas the ASPECTS score was mildly associated with final TICI2C reperfusion (r=0.24, p Conclusions: Discrete ASPECTS strata may influence outcomes of endovascular therapy conducted in routine practice around the world, yet individuals with low ASPECTS may still achieve reasonable outcomes.

Limited information is currently available regarding muscle synergistic patterns and triggered reflex responses during dynamic weight-bearing activities in the presence of muscle fatigue. Purpose: The purpose of this study was to examine the effects of quadriceps muscle fatigue on patterns of muscle activation and performance in response to sudden, unexpected perturbations during a weight-bearing task. Methods: Motion of the knee was measured as subjects were asked to track a visual target as accurately as possible while performing a resisted single leg squat task. Random perturbations were delivered in 20% of the trials by unexpectedly releasing the resistance during the flexion phase of the exercise. Absolute and constant errors were calculated to evaluate target tracking performance. Quadriceps and hamstring muscle activity was recorded during both perturbed and unperturbed trials. Twelve healthy women were tested before and after completing a repetitive submaximal eccentric quadriceps fatigue protocol. A second group of 12 women served as controls. Unexpected perturbations elicited long-latency responses characterized by facilitation of the quadriceps and inhibition of the hamstrings. Results: Muscle fatigue increased the amplitude of the long-latency response in vastus lateralis by 4.3% maximum voluntary isometric contraction (P = 0.004). Changes in tracking error occurred in response to perturbations after fatigue in spite of significantly increased quadriceps muscle activity, especially during the extension phase of the exercise. Conclusion: Quadriceps muscle fatigue alters the patterns of coordinated muscle activity and may render subjects less able to cope with unexpected perturbations during weight-bearing tasks.

Dynamic stability of the knee joint is a research topicof increasing focus after ACL injury, stroke, and incomplete spinal cord injury. Since rehabilitation programs use functional weightbearing tasks to improve neuromuscular control of the knee, it is important to understand the adaptability of muscle control strategies during weight-bearing exercise. The purpose of this study was to compare muscle activation patterns during a single leg squat (SLS) exercise performed before and after feedback-controlled training.This was a cross-sectional comparative study. Fifteen young, healthy individuals performed the SLS exercise while tracking a sinusoidal target with flexion and extension of the knee. The SLS instrument provided bidirectional resistance that was normalized to body weight. Six trials of 10 repetitions of the SLSs were performed to quantify improved performance (learning). Electromyographic activity from five muscles that cross the knee was analyzed. Accuracy of performance was measured by calculating the error between the target and actual knee displacement.Reduction in error measurements verified that individuals increased the accuracy of performance in each trial and retained this improvement across trials (p0.05). Modulation in muscle activity as a result of learning was reflected mainly in the biceps femoris, rectus femoris, and vastus lateralis muscles.Increased accuracy with the SLS exercise was accompanied by a decrease in coactivation of selected musculature around the knee. This study presents a novel approach to quantify the effect of performance on muscle synergistic activation patterns during weight-bearing exercise. Controlled strengthening, as defined in this study, emphasizes accuracy of performance in conjunction with principles of strength training and has implications to knee control.

After spinal cord injury (SCI), paralyzed extremities experience a precipitous loss of bone mineral density (BMD). Shortly after SCI, BMD begins to decline at a rate of 2% to 4% per month,1 reaching equilibrium between 12 and 24 months at a level near fracture threshold.2–4 At this stage, fractures can occur with trivial injuries to the limbs, often during routine transfers and activities of daily living.5 Between 1% and 6% of people with SCI will sustain fractures in their paralyzed extremities,6–8 most often at the distal femur and proximal tibia.8 It remains unknown whether bone loss after SCI is due to insufficient osteogenic loads or if it is the result of neurogenic changes. Rehabilitation strategies to preserve BMD after SCI have been elusive. Strategies that involve loading of the extremities, such as electrically stimulated cycling and suspended treadmill walking, have shown limited effects on BMD.9–11 These methods may not deliver a sufficient load to provide an osteogenic stimulus to the skeletal system. Bone is in a state of activity-dependent flux, and biomechanical stresses help determine the shape, size, and composition of bone.12,13 Moreover, in the neurologically intact human model, bone density responds in a dosage-dependent manner to strain magnitude.14 It is plausible that this principle is still in operation after SCI. However, to our knowledge, no previous report has assessed compressive loads placed on bone as part of a long-term intervention to limit bone loss after SCI in humans. In the paralyzed human model, it is difficult to deliver loads that exceed an osteogenic threshold without the use of electrically elicited muscle contractions. Muscular contractions deliver high compressive loads through bones and across joint surfaces during isometric contractions. Indeed, muscular contraction, not body weight, is responsible for the largest portion of the forces experienced by bone.15 Isometric contractions of muscles that run parallel with the bone (such as soleus) yield high compressive forces, and as such, may be optimal for preventing bone loss.16 Accordingly, the purposes of this study were: 1) to electrically train the plantar flexor muscles in order to optimize compressive loads delivered to the tibia and 2) to determine if these muscle stresses attenuate the normal bone loss after SCI. We hypothesize that tibial compressive forces will increase as a result of the electrical stimulation training program and that tibia BMD decline will be attenuated in the limbs exposed to the muscle training.