Citations

Study Design: This was an observational study. Objectives: This study aims to determine the correlation between patient-reported outcomes (PROs) pulled from a national spine registry and physician ratings from physician review websites (PRWs). Summary of Background Data: PRWs are frequently utilized by patients to make health care decisions; however, many PRWs appear to incorporate subjective experiences unrelated to a surgeon’s clinical performance into ratings. As such, their utility as a health care decision-making tool remains unclear. Materials and Methods: This study evaluated 8834 patients from the Quality Outcomes Database (QOD) who underwent 1-level elective lumbar spine surgery. The lumbar module of QOD was queried to rank 124 surgeons using PROs (Oswestry Disability Index, EuroQOL, Numerical Rating Scale—back/leg pain, and patient satisfaction). The QOD PRO-ranking system was compared against PRWs including Healthgrades, Vitals, WebMD, and Google. The Spearman correlation coefficients, Kruskal-Wallis tests, and multiple linear regression models were used for statistical comparison. The primary outcome was the correlation between PRW scores and PROs. Results: Surgeon PRO-derived ranking showed high intercorrelational congruence with coefficients between the 3 PROs (Oswestry Disability Index, EuroQOL, Numerical Rating Scale back/leg) ranging between 0.70 and 0.88. Low correlations were observed between PRO-derived rankings and PRWs, ranging from 0.23 to 0.37. Healthgrades performed most similarly to PRO-derived rankings, correlating best with patient satisfaction, though the correlation was low (ρ=0.37). Conclusions: While PRWs are often used to evaluate surgeon competency, these results demonstrate they poorly correlate with a surgeon’s clinical ability measured by PROs. PRWs should be used with caution when making health care decisions by patients, payers, and administrators. Level of Evidence: Level III.

Abstract Branched-chain amino acid transaminase 1 (BCAT1) is upregulated selectively in human isocitrate dehydrogenase (IDH) wildtype (WT) but not mutant glioblastoma multiforme (GBM) and promotes IDHWT GBM growth. Through a metabolic synthetic lethal screen, we report here that α-ketoglutarate (AKG) kills IDHWT GBM cells when BCAT1 protein is lost, which is reversed by reexpression of BCAT1 or supplementation with branched-chain α-ketoacids (BCKA), downstream metabolic products of BCAT1. In patient-derived IDHWT GBM tumors in vitro and in vivo, cotreatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality. However, AKG failed to evoke a synthetic lethal effect with loss of BCAT2, BCKDHA, or GPT2 in IDHWT GBM cells. Mechanistically, loss of BCAT1 increased the NAD+/NADH ratio but impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis. These metabolic alterations were synergistically augmented by AKG treatment, thereby causing mitochondrial dysfunction and depletion of cellular building blocks, including ATP, nucleotides, and proteins. Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDHWT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable. Significance: Metabolic synthetic lethal screening in IDHWT glioblastoma defines a vulnerability to ΑΚG following BCAT1 loss, uncovering a therapeutic strategy to improve glioblastoma treatment. See related commentary by Meurs and Nagrath, p. 2354

ABSTRACT Background Renal artery stenosis (RAS) is an important cause of chronic kidney disease and secondary hypertension. In animal models, renal ischemia leads to downregulation of growth factor expression and loss of intrarenal microcirculation. However, little is known about the sequelae of large-vessel occlusive disease on the microcirculation within human kidneys. Method This study included five patients who underwent nephrectomy due to renovascular occlusion and seven nonstenotic discarded donor kidneys (four deceased donors). Micro-computed tomography was performed to assess microvascular spatial densities and tortuosity, an index of microvascular immaturity. Renal protein expression, gene expression and histology were studied in vitro using immunoblotting, polymerase chain reaction and staining. Results RAS demonstrated a loss of medium-sized vessels (0.2–0.3 mm) compared with donor kidneys (P = 0.037) and increased microvascular tortuosity. RAS kidneys had greater protein expression of angiopoietin-1, hypoxia-inducible factor-1α and thrombospondin-1 but lower protein expression of vascular endothelial growth factor (VEGF) than donor kidneys. Renal fibrosis, loss of peritubular capillaries (PTCs) and pericyte detachment were greater in RAS, yet they had more newly formed PTCs than donor kidneys. Therefore, our study quantified significant microvascular remodeling in the poststenotic human kidney. RAS induced renal microvascular loss, vascular remodeling and fibrosis. Despite downregulated VEGF, stenotic kidneys upregulated compensatory angiogenic pathways related to angiopoietin-1. Conclusions These observations underscore the nature of human RAS as a microvascular disease distal to main vessel stenosis and support therapeutic strategies directly targeting the poststenotic kidney microcirculation in patients with RAS.

Abstract Objective Leucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with APS. We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis. Methods Two independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic aPL carriers and 150 healthy controls (HCs) from Peking University People’s Hospital. The second included 99 APS patients, 25 aPL carriers and 40 HCs from United States APS centres. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes. Results Both positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort. Conclusion Our study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.

Background and Purpose: The HydroSoft coil was developed to be placed along the aneurysm neck to enhance intracranial aneurysm healing. In order to better understand the safety and efficacy of Hydrosoft coils in treating the aneurysm neck, the GEL THE NEC multicenter registry was developed. We report immediate angiographic and clinical results of this prospective registry. Methods: The GEL THE NEC study was undertaken at 30 centers in 5 countries. Patients aged 21-90 years with a ruptured or unruptured aneurysm 3-15 mm in size were eligible for enrollment. For each patient the following data were obtained: demographics and comorbidities, aneurysm geometry, use of adjunctive devices, immediate angiographic outcomes, and early (<30 days) adverse events. Postoperative anatomic results were graded by on-site neuroradiologists using the Modified Raymond Scale (Raymond 1=complete obliteration of aneurysm including the neck, Raymond 2=contrast filling the neck of the aneurysm without opacification of the aneurysm sac, Raymond 3=contrast filling the sac of the aneurysm). Predictors of good angiographic outcome were studied using chi-squared and t-tests. Results: A total of 571 patients with 571 aneurysms have been treated thus far in the study (196 ruptured, 375 unruptured). HydroSoft coils were successfully deployed in 549 (96.3%) of these patients. Adjunctive devices were used in 307 cases (53.8%) (212 balloon assistance, 89 stent). Aneurysmal occlusion rates were the following: 261 patients (47.3%) exhibited Raymond 1 occlusion, 257 patients (47.0%) had Raymond 2, and 29 patients (5.3%) had Raymond 3. Early post-operative stroke occurred in 10 patients (1.8%). Aneurysm perforation occurred in 11 patients (1.9%). Coil prolapse/migration occurred in 8 patients (1.4%). Early post-operative death occurred in 3 patients, all of whom presented with SAH (0.5%). Small aneurysm neck size was a significant predictor of good angiographic outcome (P=0.0003). Conclusions: Endovascular treatment of intracranial aneurysms with HydroSoft coils resulted in high rates of satisfactory occlusion (94.3%) and low rates of major clinical complications. Aneurysm neck size was a significant predictor of angiographic outcomes.

Background and Objectives: Peroxisome proliferator activated receptor-gamma agonists, such as pioglitazone (PIO) enhanced hematoma resolution and improved functional recovery in our animal model of intracerebral hemorrhage (ICH). We conducted a translational Phase II randomized, controlled clinical trial to determine the maximum tolerated dose (MTD) of PIO in patients with spontaneous ICH and to explore the rate of hematoma resolution and clinical outcome. Methods: Patients with spontaneous ICH within 24 hours of symptom onset were randomly allocated 1:1 to placebo or PIO. Patients received escalating doses of PIO daily for three days, followed by a 30mg maintenance dose for the duration of treatment. Duration of treatment was when 75% of the ICH had resolved as determined by serial MRI or 10 weeks of treatment, whichever occurred first. The primary safety outcome was mortality at Day 14. Secondary measures of safety include any mortality, symptomatic cerebral edema, congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Secondary measures of efficacy include hematoma resolution and clinical outcome. The MTD was determined using the Continual Reassessment Method. Results: From March 2009 to April 2013, 84 patients (42 PIO, 42 control) were enrolled into 11 dose tiers, with a planned range from 0.1-2.0 mg/kg/d. Table 1 demonstrates preliminary baseline and clinical characteristics of patients by treatment group. Overall, 2/84 patients died within 2 weeks after ICH; however mortality rate never exceeded prespecified criteria. The study will be complete in October 2013 and the treatment team remains blinded to treatment allocation. Secondary outcomes by treatment group and the MTD of PIO will be reported. Conclusions: We have completed the treatment phase of the SHRINC Trial. Long term follow-up is on-going. These results will provide the foundation for an efficacy trial evaluating PIO as a potential treatment for patients with spontaneous ICH.

Purpose: Various imaging approaches are utilized for evaluating acute stroke patients. Despite numerous studies, there is no clear evidence that one approach is superior to another for identifying which patients will benefit from mechanical thrombectomy (MT). The PICS registry was established to determine the imaging modalities being employed to triage acute stroke patients for MT and to assess their impact on patient functional outcome. Methods: Patients were enrolled across 35 centers. For each patient, the baseline imaging modality was recorded to determine the utilization rates of noncontrast CT (NCCT), CT perfusion (CT-P), and MRI diffusion weighted imaging (DWI). All patients subsequently treated by the Penumbra System per standard of care were followed for 3 months after the procedure to assess functional outcome using the modified Rankin Scale (mRS). Results: A total of 305 patients were enrolled in this registry, of which 267 had the requisite imaging modalities used for this analysis. Of these, 49.4% were females. Mean age was 66.6 ± 15.9 years; median NIHSS score was 17.0 (IQR 12-21). The median time from stroke onset to presentation was 2.3 hours, from stroke symptom onset to arterial puncture was 4.8 hours, and from arterial puncture to end of thromboaspiration was 73.0 minutes. Post-treatment evaluation revealed that 83.5% of patients were successfully recanalized to TIMI 2/3 (from TIMI 0/1) with 43.5% achieving a 90-day mRS of 0-2. All cause mortality was 19.9% with symptomatic intracranial hemorrhage reported in 4.5% of the patients. The principal imaging modalities used for patient triage were NCCT in 61.8%, CT-P in 27.3% and DWI in 10.9% of the study population. Of the patients selected for NCCT, 42.5% were functionally independent at 90 days, whereas for CT-P and DWI, the rates were 45.9% and 42.9%, respectively. There was no significant difference between groups for patient age, baseline NIHSS, time from onset to presentation, time from arterial puncture to end of thromboaspiration. The time from stroke symptom onset to groin puncture was significantly different in the DWI cohort (p<0.0001) with a median of 4.4 hrs for NCCT, 4.8 hrs for CTP, and 6.5 hrs for DWI. There was a significant difference in % of female patients with CTP 37.0%, DWI 48.3%, and NCCT 55.2% (p=0.034). Conclusion: The type of imaging modality utilized to triage acute ischemic stroke patients for MT varies widely across the US. Based on the present findings, the imaging approach appears to have little impact on patient functional outcome after MT.

Introduction: The metabolic syndrome (MetS) leads to cardiac vascular injury, which may reflect in increased retention of endothelial progenitor cells (EPC). Coronary endothelial cell (EC) mitochondria partly regulate vascular function and structure. We hypothesized that chronic mitoprotection would preserve EC mitochondria and attenuate coronary vascular injury and dysfunction in swine MetS. Methods: Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (ELAM, 0.1mg/kg SC q.d), and lean controls (n=6 each). Coronary artery and sinus blood samples were collected. EC mitochondrial density (electron microscopy), endothelial nitric oxide (eNOS) immunoreactivity (staining), myocardial microvascular density (3D micro-CT), and coronary endothelial function (organ bath) were assessed ex-vivo. The number and arteriovenous gradient of CD34+/KDR+ EPC was calculated by FACS (a negative gradient indicating EPC retention). Results: MetS and MetS+ELAM pigs developed similar MetS (obesity, hyperlipidemia, insulin resistance, and hypertension). EC mitochondrial density decreased in MetS compared to lean, but normalized in MetS+ELAM. ELAM also improved eNOS immunoreactivity, subendocardial microvascular density, and coronary endothelial function. ELAM-induced vasculoprotection was reflected in decreased coronary retention of EPCs. Conclusions: These observations underscore the role of mitochondria in regulating the cardiac circulation in experimental MetS, and the benefits of mitoprotection to preserve EC myocardial microvascular integrity.

Background: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow (RBF) and amplifies regional kidney hypoxia, but their relationship to tissue inflammation and injury markers is poorly understood. We tested the hypothesis that renal injury, reflected by renal vein levels of neutrophil gelatinase associated lipocalin (NGAL) and inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) would be magnified with severe occlusive vascular disease in humans with ARAS. Methods: Inpatient studies performed in patients with ARAS (n=40, 71.3±11% occlusion by CT angiography) or essential hypertension (EH) (n=30), during fixed Na+ intake and ACE/ARB Rx. Single-kidney cortical and medullary perfusion and RBF were measured using multidetector CT, and glomerular filtration rate (GFR) by iothalamate clearance. Tissue deoxyhemoglobin levels (R2*) and fractional kidney hypoxia (% of axial area with R2*>30/s) were measured by BOLD-MRI at 3T. Results: Single kidney RBF, cortical and medullary perfusion were reduced in the post-stenotic kidney, as was GFR. Renal vein NGAL, MCP-1 and fractional hypoxia were higher in patients with ARAS than EH. NGAL and MCP-1 levels correlated directly with cortical R2* and fractional hypoxia (r = 0.52, P <0 .0001 and r = 0.4, P = 0.0006) and with the degree of artey stenosis (r = 0.37, P = 0.04 and r = 0.35, P = 0.05). GFR correlated inversely with NGAL (r= - 0.5, P <0.0001). Conclusions: Our results demonstrate that elevated renal venous markers of kidney inflammation (MCP-1) and injury (NGAL) in ARAS are correlated with the severity of tissue hypoxia as measured by BOLD MR, suggesting a possible link between kidney inflammation and hypoxia.