To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).
A randomized, placebo-controlled, blinded study evaluated ibudilast at a ...dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.
A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (
= 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (
= 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo (
= 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (
= 0.08).
Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.
This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.
Study objective We derive a prediction rule to identify children at very low risk for intra-abdominal injuries undergoing acute intervention and for whom computed tomography (CT) could be obviated. ...Methods We prospectively enrolled children with blunt torso trauma in 20 emergency departments. We used binary recursive partitioning to create a prediction rule to identify children at very low risk of intra-abdominal injuries undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion for abdominal hemorrhage, or intravenous fluid for ≥2 nights for pancreatic/gastrointestinal injuries). We considered only historical and physical examination variables with acceptable interrater reliability. Results We enrolled 12,044 children with a median age of 11.1 years (interquartile range 5.8, 15.1 years). Of the 761 (6.3%) children with intra-abdominal injuries, 203 (26.7%) received acute interventions. The prediction rule consisted of (in descending order of importance) no evidence of abdominal wall trauma or seat belt sign, Glasgow Coma Scale score greater than 13, no abdominal tenderness, no evidence of thoracic wall trauma, no complaints of abdominal pain, no decreased breath sounds, and no vomiting. The rule had a negative predictive value of 5,028 of 5,034 (99.9%; 95% confidence interval CI 99.7% to 100%), sensitivity of 197 of 203 (97%; 95% CI 94% to 99%), specificity of 5,028 of 11,841 (42.5%; 95% CI 41.6% to 43.4%), and negative likelihood ratio of 0.07 (95% CI 0.03 to 0.15). Conclusion A prediction rule consisting of 7 patient history and physical examination findings, and without laboratory or ultrasonographic information, identifies children with blunt torso trauma who are at very low risk for intra-abdominal injury undergoing acute intervention. These findings require external validation before implementation.
Abstract Background In patients with severe aortic stenosis at increased risk for surgery, self-expanding transcatheter aortic valve replacement (TAVR) is associated with improved 2-year survival ...compared with surgery. Objectives This study sought to determine whether this clinical benefit was sustained over time. Methods Patients with severe aortic stenosis deemed at increased risk for surgery by a multidisciplinary heart team were randomized 1:1 to TAVR or open surgical valve replacement (SAVR). Three-year clinical and echocardiographic outcomes were obtained in those patients with an attempted procedure. Results A total of 797 patients underwent randomization at 45 U.S. centers; 750 patients underwent an attempted procedure. Three-year all-cause mortality or stroke was significantly lower in TAVR patients (37.3% vs. 46.7% in SAVR; p = 0.006). Adverse clinical outcome components were also reduced in TAVR patients compared with SAVR patients, including all-cause mortality (32.9% vs. 39.1%, respectively; p = 0.068), all stroke (12.6% vs. 19.0%, respectively; p = 0.034), and major adverse cardiovascular or cerebrovascular events (40.2% vs. 47.9%, respectively; p = 0.025). At 3 years aortic valve hemodynamics were better with TAVR patients (mean aortic valve gradient 7.62 ± 3.57 mm Hg vs. 11.40 ± 6.81 mm Hg in SAVR; p < 0.001), although moderate or severe residual aortic regurgitation was higher in TAVR patients (6.8% vs. 0.0% in SAVR; p < 0.001). There was no clinical evidence of valve thrombosis in either group. Conclusions Patients with severe aortic stenosis at increased risk for surgery had improved 3-year clinical outcomes after TAVR compared with surgery. Aortic valve hemodynamics were more favorable in TAVR patients without differences in structural valve deterioration. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Objective The purpose of this study was to test the hypothesis that a standardized multidisciplinary treatment approach in patients with morbidly adherent placenta, which includes accreta, increta, ...and percreta, is associated with less maternal morbidity than when such an approach is not used (nonmultidisciplinary approach). Study Design A retrospective cohort study was conducted with patients from 3 tertiary care hospitals from July 2000 to September 2013. Patients with histologically confirmed placenta accreta, increta, and percreta were included in this study. A formal program that used a standardized multidisciplinary management approach was introduced in 2011. Before 2011, patients were treated on a case-by-case basis by individual physicians without a specific protocol (nonmultidisciplinary group). Estimated blood loss, transfusion of packed red blood cells, intraoperative complications (eg, vascular, bladder, ureteral, and bowel injury), neonatal outcome, and maternal postoperative length of hospital stay were compared between the 2 groups. Results Of 90 patients with placenta accreta, 57 women (63%) were in the multidisciplinary group, and 33 women (37%) were in the nonmultidisciplinary group. The multidisciplinary group had more cases with percreta ( P = .008) but experienced less estimated blood loss ( P = .025), with a trend to fewer blood transfusions ( P = .06), and were less likely to be delivered emergently ( P = .001) compared with the nonmultidisciplinary group. Despite an approach of indicated preterm delivery at 34-35 weeks of gestation, neonatal outcomes were similar between the 2 groups. Conclusion The institution of a standardized approach for patients with morbidly adherent placentation by a specific multidisciplinary team was associated with improved maternal outcomes, particularly in cases with more aggressive placental invasion (increta or percreta), compared with a historic nonmultidisciplinary approach. Our standardized approach was associated with fewer emergency deliveries.
Abstract Background The U.S. pivotal trial for the self-expanding valve found that among patients with severe aortic stenosis at increased risk for surgery, the 1-year survival rate was 4.9 ...percentage points higher in patients treated with a self-expanding transcatheter aortic valve bioprosthesis than in those treated with a surgical bioprosthesis. Objectives Longer-term clinical outcomes were examined to confirm if this mortality benefit is sustained. Methods Patients with severe aortic stenosis who were at increased surgical risk were recruited. Eligible patients were randomly assigned in a 1:1 ratio to transcatheter aortic valve replacement with the self-expanding transcatheter valve (transcatheter aortic valve replacement TAVR group) or to aortic valve replacement with a surgical bioprosthesis (surgical group). The 2-year clinical and echocardiographic outcomes were evaluated in these patients. Results A total of 797 patients underwent randomization at 45 centers in the United States. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points. Similar results were found in the intention-to-treat cohort (log-rank test p < 0.05). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01). Conclusions In patients with severe aortic stenosis who are at increased surgical risk, the higher rate of survival with a self-expanding TAVR compared with surgery was sustained at 2 years. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Objectives The CoreValve Extreme Risk US Pivotal Trial enrolled patients with symptomatic severe aortic stenosis deemed unsuitable for surgical aortic valve replacement. Implants were attempted using ...transfemoral access (n = 489) or an alternative access (n = 150). In present analysis, we sought to examine the safety and efficacy of CoreValve transcatheter aortic valve replacement using alternative access. Methods The present study included 150 patients with prohibitive iliofemoral anatomy who were treated with the CoreValve transcatheter heart valve delivered by way of the subclavian artery (n = 70) or a direct aortic approach (n = 80). The echocardiograms were read by an independent core laboratory. The primary endpoint was all-cause mortality or major stroke at 12 months. Results The preoperative aortic valve area was 0.72 ± 0.27 cm2 and mean aortic valve gradient was 49.5 ± 17.0 mm Hg. After the transcatheter aortic valve replacement, the effective aortic valve area was 1.82 ± 0.64 cm2 at 1 month and 1.85 ± 0.51 cm2 at 12 months. The mean aortic valve gradient was 9.7 ± 5.8 mm Hg at 30 days and 9.5 ± 5.7 mm Hg at 12 months. The death or major stroke rate was 15.3% at 30 days and 39.4% at 12 months. The individual rate of all-cause mortality and major stroke was 11.3% and 7.5% at 30 days and 36.0% and 9.1% at 12 months. Conclusions These data demonstrate that the CoreValve transcatheter heart valve delivered by an alternative access provides a suitable alternative for treatment of extreme risk patients with symptomatic severe aortic stenosis, who have prohibitive iliofemoral anatomy and no surgical options.
Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, ...we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma.
173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection.
Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis.
High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.
Abstract Background Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire ...for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function. Methods and Results The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). Conclusions Treating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.
Abstract Background Health care–associated infections (HAIs) are the most common noncardiac complications after cardiac surgery and are associated with increased morbidity and mortality. Current ...information about their economic burden is limited. Objectives This research was designed to determine the cost associated with major types of HAIs during the first 2 months after cardiac surgery. Methods Prospectively collected data from a multicenter, observational study of the Cardiothoracic Surgery Clinical Trials Network, in which patients were monitored for infections for 65 days after surgery, were merged with related financial data routinely collected by the University HealthSystem Consortium. Incremental length of stay (LOS) and cost associated with HAIs were estimated using generalized linear models, with adjustments for patient demographics, clinical history, baseline laboratory values, and surgery type. Results Among 4,320 cardiac surgery patients (mean age: 64 ± 13 years), 119 (2.8%) experienced a major HAI during the index hospitalization. The most common HAIs were pneumonia (48%), sepsis (20%), and Clostridium difficile colitis (18%). On average, the estimated incremental cost associated with a major HAI was nearly $38,000, of which 47% was related to intensive care unit services. The incremental LOS was 14 days. Overall, there were 849 readmissions; among these, 8.7% were attributed to major HAIs. The cost of readmissions due to major HAIs was, on average, nearly threefold that of readmissions not related to HAIs. Conclusions Hospital cost, LOS, and readmissions are strongly associated with HAIs. These associations suggest the potential for large reductions in costs if HAIs following cardiac surgery can be reduced. (Management Practices and the Risk of Infections Following Cardiac Surgery; NCT01089712 ).
PDF
