OBJECTIVEOne of the goals in this study was to set up a semiautomatic method to estimate blood-brain barrier disruption obtained in patients with glioblastoma by using an implantable, unfocused, ultrasound device. Another goal was to correlate the probability of significant ultrasound-induced signal enhancement (SUISE) with local acoustic pressure in the brain.METHODSGd-enhanced MR images acquired before and after ultrasound treatments were analyzed prospectively. The image sets were segmented, normalized, and coregistered to evaluate contrast enhancement. The volume of SUISE was calculated with voxels labeled as gray or white matter, in a cylindrical region of interest, and with enhancement above a given threshold. To validate the method, the resulting volumes of SUISE were compared to qualitative grades previously assigned by 3 clinicians for 40 ultrasound treatments in 15 patients. A parametric study was performed to optimize the algorithm prediction of the qualitative grades. The 3D acoustic field in the brain was estimated from measurements in water combined with simulations accounting for ultrasound attenuation in brain and overlaid on each MR image to correlate local acoustic pressure with the probability of SUISE (defined as enhancement > 10%).RESULTSThe algorithm predicted grade 2 or 3 and grade 3 openings with areas under the receiver operating characteristic curve of 0.831 and 0.995, respectively. The probability of SUISE was correlated with local acoustic pressure (R2 = 0.98) and was 3.33 times higher for gray matter than for white matter.CONCLUSIONSAn algorithm for evaluating blood-brain barrier disruption was validated and can be used for future clinical trials to further understand and quantify this technique in humans.Clinical trial registration no.: NCT02253212 (clinicaltrials.gov)

Background Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer’s disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device. Methods An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of − 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial. Conclusions These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed. Trial registration ClinicalTrials.gov, NCT03119961

Purpose. To assess the effect of pretrial publicity on mock jurors' post‐trial opinions and verdicts, and to investigate the role of the judge's admonition to ignore information obtained outside the trial and the role of asking jurors for their opinions before the trial. Methods. In two studies, university students were exposed to pretrial publicity that was either negative or neutral towards the defendant, a week or more later were shown a videotape of a trial, and asked for their opinions about guilt and their verdicts. In Study 1, with 99 participants, the judge's instruction either did or did not contain a specific admonition to ignore information outside the trial. In Study 2, with 78 participants, pretrial opinions either were or were not solicited. Results. Neither study found any main effect of pretrial publicity. In Study 1, jurors given the specific admonition were less likely to think the defendant was guilty. In Study 2, only when participants were asked for their pretrial opinions of guilt were their post‐trial opinions and verdicts significantly affected by negative pretrial publicity. Conclusions. The post‐trial effects of pretrial publicity are not strong and robust, but rather appear to depend on other factors in the situation. We interpret the effect of the specific admonition as being due to a leaning‐over‐backwards phenomenon. We interpret the effect of soliciting pretrial opinions as magnifying the effects of pretrial publicity and producing an overestimate of their strength.

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Background : The Occluded Artery Trial (OAT) randomized 2201 patients (up to 28 days post MI) with an occluded infarct-related artery to either percutaneous coronary intervention (PCI) or medical treatment alone (MED). There was no difference in five-year life table event rates for the primary end point of death, reinfarction (ReMI) or heart failure. However in patients randomized to PCI there was a trend for an increase in adjudicated ReMI: 7.0% vs. 5.1%, HR 1.35 (95% CI: 0.92–1.99, p=0.12) and investigator-reported ReMI: 10.9% PCI vs 7.9% MED, HR 1.36, (95% CI: 0.98 –1.86, p=0.05). Aim : To determine independent predictors of ReMI. Methods : ReMIs were adjudicated and required two of the following: ischemic symptoms ≥30 min, ECG changes and marker elevation [creatinine kinase elevation 2x upper limit of normal (ULN), CKMB >ULN or troponin 2x ULN; after PCI, CK or CK-MB 3x ULN and after surgery, CK or CK-MB 5x ULN]. Cox multivariable regression models were developed including baseline demographics, angiographic data, and discharge medications. P<0.01 was considered significant for this secondary analysis. Results: Conclusions : In the OAT trial predictors of adjudicated ReMI were prior MI (before qualifying MI) and diabetes. The predictors were similar for both treatment groups and no single angiographic factor or effect of medication was identified. Adjudicated ReMI