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Purpose The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. Patients and Methods A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini–Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. Results Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. Conclusion The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.

Various endovascular intraarterial approaches are available for treating patients with acute ischemic stroke who present with severe neurological deficits. Three recent randomized trials—Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)—evaluated the efficacy of endovascular treatment of acute ischemic stroke and, after failing to demonstrate any significant clinical benefit of endovascular therapies, raised concerns and questions in the medical community regarding the future of endovascular treatment for acute ischemic stroke. In this paper, the authors review the evolution of endovascular treatment strategies for the treatment of acute stroke and provide their interpretation of findings and potential limitations of the three recently published randomized trials. The authors discuss the advantage of stent-retriever technology over earlier endovascular approaches and review the current status and future directions of endovascular acute stroke studies based on lessons learned from previous trials.

BackgroundThe MitraClip® system is a newer percutaneous device that has shown promising results but data on its safety and efficacy in low‐ and high‐surgical risk populations continues to evolve. We performed a systematic review of the published studies reporting the safety and efficacy of MitraClip® implantation for treatment of moderate to severe and severe mitral regurgitation (MR).MethodsReviewers independently searched for relevant articles in Medline and abstracted clinical information based on pre‐defined criteria and end‐points. Patients were classified as low‐ or high‐surgical risk for conventional mitral valve (MV) surgery based on Society of Thoracic Surgeons score, EuroSCORE, or surgeon discretion. Primary safety outcome was 30‐day mortality and primary efficacy outcomes were freedom from death, ≥3+ MR, and requirement for MV surgery during follow‐up.ResultsImmediate and long‐term outcomes of 16 studies, including 2980 patients (age 73.7 ± 0.6 years; 63.3% males) receiving the MitraClip®, were analyzed. Acute procedural success rate was 91.4% with a procedural mortality of 0.1%. Mortality at 30 days and long‐term (310 days) follow‐up was 4.2 and 15.8%, respectively and was significantly higher in the high‐risk group (P = 0.003 and 0.019, respectively). Incidence of major procedural adverse outcomes was relatively low with blood transfusion accounting for most events. At follow‐up, the number of patients with ≥3+ MR reduced from 96.3% to 14.7% (P < 0.001), and those with NYHA class III/IV reduced from 83.2% to 23.4% (P < 0.001).ConclusionMitraClip® implantation for moderate to severe or severe MR appears to be safe with a very low procedural mortality. There is significant improvement in functional outcomes although long‐term mortality is high, especially in high surgical risk patients. © 2013 Wiley Periodicals, Inc.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P <0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (−29±2 versus −9±2 mm Hg; P <0.01) and total peripheral resistance (−10±1 versus −5±1 mm Hg/L per minute; P <0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan ( r =−0.74; P <0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.

ABSTRACTGenes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene‐environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P‐values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P &lt; 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P &lt; 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P &lt; 10−8. Results from the second analytic approach were consistent with those from the first (P &gt; 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Bladder compliance is defined as bladder’s ability to expand in volume without a significant change in pressure. The bladder wall is a multi-layered structure including a muscular layer and fibrous connective tissue. As the percent of connective tissue in the bladder interstitium increases compared to smooth muscle, the bladder becomes more rigid and less capable of expanding during filling. Currently, urodynamic studies (UDS) are considered as the clinical gold standard for bladder compliance assessment. This procedure is invasive and is associated with patient discomfort and is expensive. Ultrasound bladder vibrometry (UBV) is a novel acoustic-radiation-forced-based method for noninvasive assessment of bladder compliance. In UBV, an impulsive acoustic radiation force is focused on the bladder wall (under B-mode ultrasound image guidance) to induce vibrations which may be modeled by as a Lamb wave. High frame rate ultrasound is then utilized to detect the induced waves. This wave motion is then used to estimate the viscoelastic properties and the compliance of the bladder wall. Our results reveal a remarkable agreement between UBV and UDS cystometry measures, suggesting the potential of UBV as a viable clinical tool for the assessment of bladder compliance.