Showing papers by "Sunnybrook Health Sciences Centre published in 2008"

Improving the reporting of pragmatic trials: an extension of the CONSORT statement.

Abstract: Background The CONSORT statement is intended to improve reporting of randomised controlled trials and focuses on minimising the risk of bias (internal validity). The applicability of a trial’s results (generalisability or external validity) is also important, particularly for pragmatic trials. A pragmatic trial (a term first used in 1967 by Schwartz and Lellouch) can be broadly defined as a randomised controlled trial whose purpose is to inform decisions about practice. This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability. Methods At two, two-day meetings held in Toronto in 2005 and 2008, we reviewed the CONSORT statement and its extensions, the literature on pragmatic trials and applicability, and our experiences in conducting pragmatic trials. Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials: the background, participants, interventions, outcomes, sample size, blinding, participant flow, and generalisability of the findings. These extensions are presented, along with illustrative examples of reporting, and an explanation of each extension. Adherence to these reporting criteria will make it easier for decision makers to judge how applicable the results of randomised controlled trials are to their own conditions. Empirical studies are needed to ascertain the usefulness and comprehensiveness of these CONSORT checklist item extensions. In the meantime we recommend that those who support, conduct, and report pragmatic trials should use this extension of the CONSORT statement to facilitate the use of trial results in decisions about health care.

Critically appraising qualitative research

Abstract: Six key questions will help readers to assess qualitative research #### Summary points Over the past decade, readers of medical journals have gained skills in critically appraising studies to determine whether the results can be trusted and applied to their own practice settings. Criteria have been designed to assess studies that use quantitative methods, and these are now in common use. In this article we offer guidance for readers on how to assess a study that uses qualitative research methods by providing six key questions to ask when reading qualitative research (box 1). However, the thorough assessment of qualitative research is an interpretive act and requires informed reflective thought rather than the simple application of a scoring system. #### Box 1 Key questions to ask when reading qualitative research studies One of the critical decisions in a qualitative study is whom or what to include in the sample—whom to interview, whom to observe, what texts to analyse. An understanding that qualitative research is based in experience and in the construction of meaning, combined with the specific research question, should guide the sampling process. For example, a study of the experience of survivors of domestic violence that examined their reasons for not seeking help from healthcare providers might focus on interviewing a …

A Multicenter Randomized Trial of Breast Intensity-Modulated Radiation Therapy to Reduce Acute Radiation Dermatitis

Abstract: Purpose Dermatitis is a frequent adverse effect of adjuvant breast radiotherapy. It is more likely in full-breasted women and when the radiation is distributed nonhomogeneously in the breast. Breast intensity-modulated radiation therapy (IMRT) is a technique that ensures a more homogeneous dose distribution. Patients and Methods A multicenter, double-blind, randomized clinical trial was performed to test if breast IMRT would reduce the rate of acute skin reaction (notably moist desquamation), decrease pain, and improve quality of life compared with standard radiotherapy using wedges. Patients were assessed each week during and up to 6 weeks after radiotherapy. Results A total of 358 patients were randomly assigned between July 2003 and March 2005 in two Canadian centers, and 331 were included in the analysis. Breast IMRT significantly improved the dose distribution compared with standard radiation. This translated into a lower proportion of patients experiencing moist desquamation during or up to 6 weeks after their radiation treatment; 31.2% with IMRT compared with 47.8% with standard treatment (P .002). A multivariate analysis found the use of breast IMRT (P .003) and smaller breast size (P .001) were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain (P .002) and a reduced quality of life (P .003). Conclusion Breast IMRT significantly reduced the occurrence of moist desquamation compared with a standard wedged technique. Moist desquamation was correlated with increased pain and reduction in the quality of life. J Clin Oncol 26:2085-2092. © 2008 by American Society of Clinical Oncology

Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Abstract: Purpose To compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP Patients and Methods Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n 159) or CVP alone (n 162) The median follow-up period was 53 months Results The primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P 0001) Improvements in all other end points, including overall and complete response rates (P 0001), time to progression (TTP; P 0001), response duration (P 0001), time to next antilymphoma treatment (P 0001), and overall survival (OS; P 029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect Conclusion Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL J Clin Oncol 26:4579-4586 © 2008 by American Society of Clinical Oncology

Single-Step Coating of Mesoporous Silica on Cetyltrimethyl Ammonium Bromide-Capped Nanoparticles

Abstract: A generalized, single-step synthesis procedure to coat individual cetyltrimethyl ammonium bromide- (CTAB) capped nanoparticles with a thin layer of mesoporous silica is outlined. This coating method was demonstrated on CTAB-capped Au nanorods and CTAB-transferred CdSe/ZnS quantum dots with silica coatings ∼15 nm thick containing pores ∼4 nm in diameter. This porous silica coating can serve as a platform for further surface modification to facilitate the rapid translation of nanoparticles to a wide range of end applications.

Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.

Abstract: Women at high risk for breast cancer need a highly sensitive screening test. This review summarizes data from 11 prospective studies that screened very high-risk women with mammography plus magneti...

An introduction to reading and appraising qualitative research

Abstract: This article explores the difference between qualitative and quantitative research and the need for doctors to be able to interpret and appraise qualitative research

Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium

Abstract: Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. Ultrasound bursts (1.5-MHz) in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJ-specific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of i.v. administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La3+, m.w. ∼ 139 Da). Leakage of these agents was observed at 1 and 2 h and, in a few vessels, at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain. (E-mail: njm@bwh.harvard.edu)

Effect of local anaesthetic volume (20 vs 5 ml) on the efficacy and respiratory consequences of ultrasound-guided interscalene brachial plexus block

Abstract: Background Interscalene brachial plexus block (ISBPB) is an effective nerve block for shoulder surgery. However, a 100% incidence of phrenic nerve palsy limits the application of ISBPB for patients with limited pulmonary reserve. We examined the incidence of phrenic nerve palsy with a low-volume ISBPB compared with a standard-volume technique both guided by ultrasound. Methods Forty patients undergoing shoulder surgery were randomized to receive an ultrasound-guided ISBPB of either 5 or 20 ml ropivacaine 0.5%. General anaesthesia was standardized. Both groups were assessed for respiratory function by sonographic diaphragmatic assessment and spirometry before and after receiving ISBPB, and after surgery. Motor and sensory block, pain, sleep quality, and analgesic consumption were additional outcomes. Statistical comparison of continuous variables was analysed using one-way analysis of variance and Student's t -test. Non-continuous variables were analysed using χ 2 tests. Statistical significance was assumed at P Results The incidence of diaphragmatic paralysis was significantly lower in the low-volume group compared with the standard-volume group (45% vs 100%). Reduction in forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow at 30 min after the block was also significantly less in the low-volume group. In addition, there was a significantly greater decrease in postoperative oxygen saturation in the standard-volume group (−5.85 vs −1.50, P =0.004) after surgery. There were no significant differences in pain scores, sleep quality, and total morphine consumption up to 24 h after surgery. Conclusions The use of low-volume ultrasound-guided ISBPB is associated with fewer respiratory and other complications with no change in postoperative analgesia compared with the standard-volume technique.

Microvascular Obstruction and the No-Reflow Phenomenon After Percutaneous Coronary Intervention

Abstract: C ase presentation A: A 50-year-old diabetic man presented to the hospital after 8 hours of continuous chest pain. Because of acute myocardial infarction of the anterior wall, he underwent direct stenting to an occlusion in the left anterior descending coronary artery. Despite revascularization, suboptimal coronary flow was achieved, and he subsequently developed heart failure. Case presentation B: A 77-year-old man underwent elective stenting of a significant stenosis in a degenerated saphenous vein coronary bypass graft. After the procedure, coronary flow in the graft was severely reduced, and he sustained a myocardial infarction in the subtended myocardial territory. The concept of “no reflow” refers to a state of myocardial tissue hypoperfusion in the presence of a patent epicardial coronary artery. The underlying cause of no reflow is microvascular obstruction, which may be produced by various mechanisms. No reflow can be classified according to the duration of the preceding myocardial ischemia (Figure 1). “Reperfusion no reflow” occurs after primary percutaneous coronary intervention (PCI) for reperfusion of an infarct artery in the setting of acute myocardial infarction (AMI) and may be asymptomatic or may present clinically with continued chest pain and ST-segment elevation. Reperfusion no reflow is preceded by ischemic cell injury, is confined to the irreversibly damaged necrotic zone, and may be exacerbated at the time of reperfusion. Reperfusion no reflow is an independent predictor of adverse clinical outcome after AMI regardless of infarct size and is associated with heart failure and increased mortality.1 Figure 1. Schematic illustrating the effect of duration of preceding myocardial ischemia on mechanism of no reflow (NR). “Interventional no reflow” follows noninfarct PCI and affects myocardium that was not subjected to prolonged ischemia before the procedure. Clinically recognized interventional no reflow that complicates PCI is typically sudden in onset, presenting as acute ischemia with chest …

Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index.

Abstract: This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using pulsed sonications at 2.04 MHz with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared with data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42 to 0.50). Histologic examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.

Update in antifungal therapy of dermatophytosis.

Abstract: Treatment of dermatophyte infection involves primarily oral and/or topical formulations of azoles or allylamines, particularly itraconazole and terbinafine. Topical medications applied once or twice daily are the primary treatment indicated for tinea corporis/cruris, and tinea pedis/manuum. Use of oral antifungals may be practical where the tinea involvement is extensive or chronic, or where application of a topical is not feasible. For tinea unguium (onychomycosis) and tinea capitis, oral therapies are the primary treatments provided. Recently, topical amorolfine and ciclopirox formulations have been approved for use in milder onychomycosis cases, and their role in the treatment of the different clinical forms of onychomycosis is currently being defined. Relapse of infection remains a problem, particularly with tinea pedis/unguium. Appropriate follow-up duration and education of patients on proper foot hygiene are also important components in providing effective therapy.

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial

Abstract: Summary Background The amyloid-β peptide Aβ 42 has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Aβ 42 -lowering agent (SALA), on cognition and function in patients with mild to moderate AD. Methods 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15–26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). Findings A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20–26) and moderate AD (baseline MMSE 15–19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p≥0·10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3·98 [95% CI 0·33 to 7·62] points per year, effect size [reduction from placebo decline rate] 46·4%, Cohen's d 0·45; p=0·033) and global function (CDR-sb difference −0·80 [−1·57 to −0·03] points per year, effect size 35·7%, Cohen's d 0·42; p=0·042); slowing of cognitive decline did not differ significantly (ADAS-cog difference −1·36 [−4·07 to 1·36] points per year, effect size 33·7%, Cohen's d 0·20; p=0·327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (−52%, Cohen's d −1·08; p=0·003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0–12 and a tarenflurbil group for months 12–24 (all p Interpretation 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. Funding Myriad Pharmaceuticals.

Scanning mechanisms for imaging probe

Abstract: The present invention provides scanning mechanisms for imaging probes using for imaging mammalian tissues and structures using high resolution imaging, including high frequency ultrasound and/or optical coherence tomography. The imaging probes include adjustable rotational drive mechanism for imparting rotational motion to an imaging assembly containing either optical or ultrasound transducers which emit energy into the surrounding area. The imaging assembly includes a scanning mechanism having including a movable member configured to deliver the energy beam along a path out of said elongate hollow shaft at a variable angle with respect to said longitudinal axis to give forward and side viewing capability of the imaging assembly. The movable member is mounted in such a way that the variable angle is a function of the angular velocity of the imaging assembly.

Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study.

Abstract: Background Microbleeds are hemosiderin deposits around small vessels and are well visualized with T2*-weighted gradient-recalled echo (GRE) imaging. Objectives To determine frequency and topography of microbleeds in Alzheimer disease (AD) and to assess their association with leukoaraiosis and cognition. Design Case-control cross-sectional analysis. Microbleeds were counted using GRE imaging. Leukoaraiosis was rated on T2-weighted and proton density–weighted scans using the Age-Related White Matter Changes Rating Scale (ARWMC). Neuropsychological tests indexed cognition. Setting The Cognitive Neurology Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Patients Individuals with probable AD (n = 80) and healthy controls (n = 25) from a longitudinal cohort with GRE sequences as part of standard imaging protocol (2002-2006). Results Microbleeds occurred in 29% of patients with AD and 12% of controls and were multiple (> 1) in 48% of patients with AD and 33% of controls. There was lobar (vs centrencephalic) predominance in 92% of AD patients, with occipital lobes accounting for 57% of these microbleeds. The ARWMC scores ( P r = 0.39, P = .01) and parietooccipital ( r = 0.28, P Conclusions Occipital predominance of microbleeds with corresponding parietooccipital leukoaraiosis has not been well described in prior imaging studies of AD. Microbleeds were frequent, often multiple, and predicted greater leukoaraiosis. These findings illustrate the complexity of AD vasculopathy and the need for additional studies in dementia and stroke populations.

Early Neutrophilia Is Associated With Volume of Ischemic Tissue in Acute Stroke

Abstract: Background and Purpose— Few data exist on the relationship between differential subpopulations of peripheral leukocytes and early cerebral infarct size in ischemic stroke. Using diffusion-weighted MR imaging (DWI), we assessed the relationship of early total and differential peripheral leukocyte counts and volume of ischemic tissue in acute stroke. Methods— All included patents had laboratory investigations and neuroimaging collected within 24 hours of stroke onset. Total peripheral leukocyte counts and differential counts were analyzed individually and by quartiles. DWI lesions were outlined using a semiautomated threshold technique. The relationship between leukocyte quartiles and DWI infarct volumes was examined using multivariate quartile regression. Results— 173 patients met study inclusion criteria. Median age was 73 years. Total leukocyte counts and DWI volumes showed a strong correlation (Spearman rho=0.371, P<000.1). Median DWI volumes (mL) for successive neutrophil quartiles were: 1.3, 1.3, 3.2,...

Imaging probe with combined ultrasound and optical means of imaging

Abstract: The present invention provides an imaging probe for imaging mammalian tissues and structures using high resolution imaging, including high frequency ultrasound and optical coherence tomography. The imaging probes structures using high resolution imaging use combined high frequency ultrasound (IVUS) and optical imaging methods such as optical coherence tomography (OCT) and to accurate co-registering of images obtained from ultrasound image signals and optical image signals during scanning a region of interest.

1-year follow-up of autologous muscle-derived stem cell injection pilot study to treat stress urinary incontinence

Abstract: We hereby report a 1-year follow-up on eight women in the first North America trial in which stress urinary incontinence (SUI) was treated with muscle-derived stem cell injections. Mean and median follow-up in this group was 16.5 and 17 months (range 3–24 months). Improvement in SUI was seen in five of eight women, with one achieving total continence. Onset of improvement was between 3 and 8 months after injection. Cure or improvement continued at a median of 10 months. No serious adverse events were reported.

Mammographic density. Measurement of mammographic density.

Abstract: Mammographic density has been strongly associated with increased risk of breast cancer. Furthermore, density is inversely correlated with the accuracy of mammography and, therefore, a measurement of density conveys information about the difficulty of detecting cancer in a mammogram. Initial methods for assessing mammographic density were entirely subjective and qualitative; however, in the past few years methods have been developed to provide more objective and quantitative density measurements. Research is now underway to create and validate techniques for volumetric measurement of density. It is also possible to measure breast density with other imaging modalities, such as ultrasound and MRI, which do not require the use of ionizing radiation and may, therefore, be more suitable for use in young women or where it is desirable to perform measurements more frequently. In this article, the techniques for measurement of density are reviewed and some consideration is given to their strengths and limitations.

DWI of the spinal cord with reduced FOV single-shot EPI

Abstract: Single-shot echo-planar imaging (ss-EPI) has not been used widely for diffusion-weighted imaging (DWI) of the spinal cord, because of the magnetic field inhomogeneities around the spine, the small cross-sectional size of the spinal cord, and the increased motion in that area due to breathing, swallowing, and cerebrospinal fluid (CSF) pulsation. These result in artifacts with the usually long readout duration of the ss-EPI method. Reduced field-of-view (FOV) methods decrease the required readout duration for ss-EPI, thereby enabling its practical application to imaging of the spine. In this work, a reduced FOV single-shot diffusion-weighted echo-planar imaging (ss-DWEPI) method is proposed, in which a 2D spatially selective echo-planar RF excitation pulse and a 180 degrees refocusing pulse reduce the FOV in the phase-encode (PE) direction, while suppressing the signal from fat simultaneously. With this method, multi slice images with higher in-plane resolutions (0.94 x 0.94 mm(2) for sagittal and 0.62 x 0.62 mm(2) for axial images) are achieved at 1.5 T, without the need for a longer readout.

Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption

Abstract: Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred nonoverlapping brain locations were sonicated through a craniotomy in experiments in 26 rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20 s, peak negative pressure amplitude: 0.1 to 1.5 MPa, Optison dosage 50, 100, 250 microl/kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption (p > 0.05), reducing the burst length resulted in significantly less contrast enhancement (p < 0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47 and 0.36 MPa for 0.1, 1 and 10 ms bursts, respectively. No difference was detected in histology between any experimental groups. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length.