BTN3A3 evasion promotes the zoonotic potential of influenza A viruses.

Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

Targeted Protein Localization by Covalent 14-3-3 Recruitment.

14-3-3 proteins have a unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that interactions of 14-3-3 with specific phosphorylated substrate proteins can be enhanced through small-molecule natural products or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates and potential neo-substrates to sequester and inhibit their function remains elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has cysteine C38 at the substrate-binding interface, near the sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screen a fully synthetic cysteine-reactive covalent ligand library to identify molecular glues that enhance the interaction of 14-3-3σ with not only druggable transcription factors such as estrogen receptor (ERα) but also challenging oncogenic transcription factors such as YAP and TAZ, which are part of the Hippo transducer pathway. We identify a hit EN171 that covalently targets both C38 and C96 on 14-3-3 to enhance 14-3-3 interactions with ERα, YAP, and TAZ, leading to impaired estrogen receptor and Hippo pathway transcriptional activity. We further demonstrate that EN171 could not only be used as a molecular glue to enhance native protein interactions but could also be used as a covalent 14-3-3 recruiter in heterobifunctional molecules to sequester nuclear neo-substrates such as BRD4 and BLC6 into the cytosol. Overall, our study reveals a covalent ligand that acts as a novel 14-3-3 molecular glue for challenging transcription factors such as YAP and TAZ and demonstrates that these glues can be potentially utilized in heterobifunctional molecules to sequester nuclear neo-substrates out of the nucleus and into the cytosol to enable targeted protein localization.

Standardization of thyroid ultrasound reporting in the community setting decreases biopsy rates.

OBJECTIVE: With the rising incidence of thyroid cancer, a standardized approach to the evaluation of thyroid nodules is essential. Despite the presence of multiple national guidelines detailing evaluation and management of these nodules, significant variability exists in the information that is collected and reported to clinicians from diagnostic imaging. The aim of this study was to evaluate the impact of thyroid ultrasound standardization on thyroid cancer detection in a community practice setting. DESIGN: As part of a physician-driven quality improvement project, a multidisciplinary team created an electronic worksheet to be utilized by sonographers to capture suspicious findings based on societal guidelines and agreed on institutional criteria for recommending fine needle aspiration (FNA) of thyroid nodules. PATIENTS: For a one-year period prior to and after the intervention, all ultrasounds performed for suspected thyroid pathology, excluding patients undergoing follow-up imaging, were reviewed at two affiliated community hospitals served by a single radiology and pathology group. MEASUREMENTS: The number of fine needle biopsies recommended and performed, as well as the percentage of FNAs positive for malignancy were evaluated. RESULTS: A total of 608 and 675 ultrasounds were reviewed in pre- and post-standardization periods, respectively. Following standardization, there was a similar percentage of FNAs recommended (35% vs. 37%, p = .68), fewer FNAs per total ultrasounds performed (36% vs. 31%, p = .03), fewer FNAs performed when FNA was not explicitly recommended (9.9% vs. 2.8%, p = .000046) and an increased detection of cytology consistent with, or suspicious for, malignancy (5% vs. 11.5%, p = .0028). CONCLUSIONS: Standardization of thyroid imaging protocol and management recommendations can reduce the number of FNAs performed and increase the percentage of positive tests in a community setting.

Combination of Foley and prostaglandins versus Foley and oxytocin for cervical ripening: a network meta-analysis.

BACKGROUND: Trial and meta-analysis data revealed a reduction in time to delivery for Foley and prostaglandins or Foley and oxytocin vs Foley alone. However, there are limited data for the comparison of the 2 combination methods against each other. OBJECTIVE: This study aimed to determine whether Foley and prostaglandins or Foley and oxytocin decrease the time to vaginal delivery using a network meta-analysis. STUDY DESIGN: A network meta-analysis (PROSPERO CRD42018081948) was performed comparing Foley and prostaglandins (prostaglandin E1 or prostaglandin E2) vs Foley and oxytocin for cervical ripening. Foley alone and prostaglandins alone were used as nodes for indirect comparison. Database searches were performed from inception to March 2020 with data abstracted from published manuscripts. Eligibility criteria included randomized trials comparing Foley and oxytocin with Foley and prostaglandins (misoprostol or dinoprostone). Trials that compared Foley catheter or prostaglandins with a combination of Foley and prostaglandins or Foley and concurrent oxytocin were also included. Nulliparous and multiparous women were analyzed together. Foley catheters of any catheter material or size and >24 weeks' gestational age with a live fetus were included. Quasi-randomized, cohorts, and other combination methods for cervical ripening were not included. Prostaglandin E1 and prostaglandin E2 combined methods were analyzed separately in a planned subanalysis. The primary outcome was the mean time from induction to vaginal delivery in hours. Secondary outcomes included time from induction to delivery, delivery within 24 hours, cesarean delivery, chorioamnionitis, endometritis, epidural use, tachysystole, postpartum hemorrhage, meconium, neonatal intensive care unit admission, and 5-minute appearance, pulse, grimace, activity, and respiration score of <7. Data were analyzed as a network meta-analysis using multivariate meta-regression. RESULTS: A total of 30 randomized controlled trials with a total of 6465 women were considered eligible for inclusion in this network meta-analysis. When compared with Foley alone, the use of Foley-oxytocin reduced the time to vaginal delivery by 4.2 hours (mean duration, -4.2 hours; 95% confidence interval, -6.5 to -1.9). Foley-prostaglandins reduced the time to vaginal delivery compared with Foley but did not meet statistical significance (mean duration, -2.9 hours; 95% confidence interval, -5.7 to 0.0; P=.05). When compared head-to-head, there was no difference in the time to vaginal delivery between Foley-prostaglandins and Foley-oxytocin (mean duration, 1.3 hours; 95% confidence interval, -2.0 to 4.7). There was no difference in the rate of cesarean delivery, chorioamnionitis, epidural, tachysystole, postpartum hemorrhage, meconium, neonatal intensive care unit admissions, or 5-minute appearance, pulse, grimace, activity, and respiration score of <7 for Foley-prostaglandins vs Foley-oxytocin, although the rate of endometritis was high for Foley-prostaglandins. In the subanalysis by prostaglandin type, there was no difference in the time to vaginal delivery for Foley-misoprostol vs Foley-dinoprostone vs Foley-oxytocin. However, Foley-dinoprostone had a definite trend toward longer time to all deliveries compared with that of both Foley-misoprostol and Foley-oxytocin (P=.05). CONCLUSION: Time to vaginal delivery was similar when comparing Foley with combined misoprostol, combined dinoprostone, and combined oxytocin. Dinoprostone comparisons are limited by small sample size but suggest longer time to delivery compared with Foley and misoprostol or oxytocin. No significant differences were observed in maternal or neonatal adverse events except for endometritis, but this was limited by the sample size, varied reporting of studies used in the indirect comparisons, and definitions of infectious morbidity use in the studies.

Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful.

BACKGROUND: Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. METHODS: A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. RESULTS: In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p < 0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p = 0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p < 0.001). Average follow-up was 24 months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p = 0.02). Among patients with normal PTH, those with PTH ≤ 55 pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p = 0.12). CONCLUSIONS: Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are > 55 pg/mL.

Induction of labor versus expectant management in patients with idiopathic polyhydramnios.

OBJECTIVE: To evaluate whether induction of labor is associated with lower risk of cesarean section compared to expectant management in patients with isolated polyhydramnios. STUDY DESIGN: This is a single-center, retrospective cohort study of patients with pregnancies complicated by idiopathic polyhydramnios, documented between 34 and 38 weeks gestation, who were delivered between July 2012 and February 2020. The primary outcome was cesarean delivery. Secondary outcomes included chorioamnionitis, endometritis, postpartum hemorrhage, preeclampsia/gestational hypertension, and composite neonatal morbidity. RESULTS: There were 194 patients included with idiopathic polyhydramnios - 115 underwent induction and 79 patients were expectantly managed. Planned induction was associated with a lower rate of CD compared with expectant management but did not meet statistical significance (19.1 % vs 30.4 %, aOR 0.51, 95 % CI 0.24, 1.05). A similar effect was seen when stratifying for parity: both nulliparous (9.1 % vs 16.3 %, aOR 0.59, 95 % CI 0.17, 1.98) and multiparous (32.7 % vs 47.2 %, aOR 0.45, 95 % CI 0.18, 1.15) patients had a lower CD rate when there was a planned induction, though neither group met statistical significance. No differences in maternal or fetal secondary outcomes were identified (chorioamnionitis, endometritis, postpartum hemorrhage, preeclampsia/gestational hypertension, composite neonatal morbidity). CONCLUSION: Lower rates of cesarean section were associated with labor induction for patients with isolated polyhydramnios, but confidence intervals did not reach statistical significance.

DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders.

Targeted protein degradation with monovalent molecular glue degraders is a powerful therapeutic modality for eliminating disease causing proteins. However, rational design of molecular glue degraders remains challenging. In this study, we sought to identify a transplantable and linker-less covalent handle that could be appended onto the exit vector of various protein-targeting ligands to induce the degradation of their respective targets. Using the BET family inhibitor JQ1 as a testbed, we synthesized and screened a series of covalent JQ1 analogs and identified a vinylsulfonyl piperazine handle that led to the potent and selective degradation of BRD4 in cells. Through chemoproteomic profiling, we identified DCAF16 as the E3 ligase responsible for BRD4 degradation-an E3 ligase substrate receptor that has been previously covalently targeted for molecular glue-based degradation of BRD4. Interestingly, we demonstrated that this covalent handle can be transplanted across a diverse array of protein-targeting ligands spanning many different protein classes to induce the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. Our study reveals a DCAF16-based covalent degradative and linker-less chemical handle that can be attached to protein-targeting ligands to induce the degradation of several different classes of protein targets.

Daxx mediated histone H3.3 deposition on HSV-1 DNA restricts genome decompaction and the progression of immediate-early transcription.

Herpesviruses are ubiquitous pathogens that cause a wide range of disease. Upon nuclear entry, their genomes associate with histones and chromatin modifying enzymes that regulate the progression of viral transcription and outcome of infection. While the composition and modification of viral chromatin has been extensively studied on bulk populations of infected cells by chromatin immunoprecipitation, this key regulatory process remains poorly defined at single-genome resolution. Here we use high-resolution quantitative imaging to investigate the spatial proximity of canonical and variant histones at individual Herpes Simplex Virus 1 (HSV-1) genomes within the first 90 minutes of infection. We identify significant population heterogeneity in the stable enrichment and spatial proximity of canonical histones (H2A, H2B, H3.1) at viral DNA (vDNA) relative to established promyelocytic leukaemia nuclear body (PML-NB) host factors that are actively recruited to viral genomes upon nuclear entry. We show the replication-independent histone H3.3/H4 chaperone Daxx to cooperate with PML to mediate the enrichment and spatial localization of variant histone H3.3 at vDNA that limits the rate of HSV-1 genome decompaction to restrict the progress of immediate-early (IE) transcription. This host response is counteracted by the viral ubiquitin ligase ICP0, which degrades PML to disperse Daxx and variant histone H3.3 from vDNA to stimulate the progression of viral genome expansion, IE transcription, and onset of HSV-1 replication. Our data support a model of intermediate and sequential histone assembly initiated by Daxx that limits the rate of HSV-1 genome decompaction independently of the stable enrichment of histones H2A and H2B at vDNA required to facilitate canonical nucleosome assembly. We identify HSV-1 genome decompaction upon nuclear infection to play a key role in the initiation and functional outcome of HSV-1 lytic infection, findings pertinent to the transcriptional regulation of many nuclear replicating herpesvirus pathogens.

Detection of tactile inputs in the rat vibrissa pathway.

The rapid detection of sensory inputs is crucial for survival. Sensory detection explicitly requires the integration of incoming sensory information and the ability to distinguish between relevant information and ongoing neural activity. In this study, head-fixed rats were trained to detect the presence of a brief deflection of their whiskers resulting from a focused puff of air. The animals showed a monotonic increase in response probability and a decrease in reaction time with increased stimulus strength. High-speed video analysis of whisker motion revealed that animals were more likely to detect the stimulus during periods of reduced self-induced motion of the whiskers, thereby allowing the stimulus-induced whisker motion to exceed the ongoing noise. In parallel, we used voltage-sensitive dye (VSD) imaging of barrel cortex in anesthetized rats receiving the same stimulus set as those in the behavioral portion of this study to assess candidate codes that make use of the full spatiotemporal representation and to compare variability in the trial-by-trial nature of the cortical response and the corresponding variability in the behavioral response. By application of an accumulating evidence framework to the population cortical activity measured in separate animals, a strong correspondence was made between the behavioral output and the neural signaling, in terms of both the response probabilities and the reaction times. Taken together, the results here provide evidence for detection performance that is strongly reliant on the relative strength of signal versus noise, with strong correspondence between behavior and parallel electrophysiological findings.

Comparison of intrapartum glycemic management strategies in pregnant women with type 1 diabetes mellitus.

BACKGROUND: Achieving intrapartum maternal euglycemia in women with type 1 diabetes mellitus (T1DM) is critical to reducing the risk of neonatal hypoglycemia. OBJECTIVE: This study sought to compare the maternal and neonatal outcomes among women with T1DM by different intrapartum glycemic control strategies of continuation of subcutaneous insulin pumps versus intravenous insulin infusion. METHODS: A retrospective cohort study was performed to identify all women with type 1 diabetes mellitus in pregnancy between 1 October 2017 and 1 August 2020 at our tertiary medical center. Medical records were reviewed for sociodemographic, clinical characteristics, and perinatal outcomes. A composite neonatal outcome was created to include one or more of the following outcomes: 5-minute APGAR less than 7, neonatal intensive care unit admission, neonatal hypoglycemia, or respiratory distress. RESULTS: We identified 75 women with T1DM that met inclusion criteria, 27(36%) who remained on their subcutaneous insulin pump and 48(64%) who were transitioned to intravenous insulin infusion intrapartum. Women that continued subcutaneous insulin were more likely to be older (30.5 vs. 28.1, p = .04), multiparous (74% vs. 50%, p = .042), and have a continuous glucose monitor (CGM) (93% vs. 43%, p < .001). There was no difference in maternal hypoglycemic events (14.8% vs. 18.8%, p = .76) or severe hyperglycemia (greater than 250 mg/dL)/development of diabetic ketoacidosis (3.7% vs. 4.2%, p = .99) in labor between both groups. There was no difference in neonatal composite outcome when adjusted for gestational age at delivery, maternal age, parity, and CGM use for both groups (aOR 0.73, 95% CI 0.12-4.43, p = .728). CONCLUSION: Continuation of subcutaneous insulin in the intrapartum period appears to be a reasonable option in women with T1DM, however future, larger studies are needed to confirm this. Both patient and provider must be comfortable with this intrapartum strategy for effective glycemic control.

Prefrontal neurons predict choices during an auditory same-different task.

The detection of stimuli is critical for an animal's survival [1]. However, it is not adaptive for an animal to respond automatically to every stimulus that is present in the environment [2-5]. Given that the prefrontal cortex (PFC) plays a key role in executive function [6-8], we hypothesized that PFC activity should be involved in context-dependent responses to uncommon stimuli. As a test of this hypothesis, monkeys participated in a same-different task, a variant of an oddball task [2]. During this task, a monkey heard multiple presentations of a "reference" stimulus that were followed by a "test" stimulus and reported whether these stimuli were the same or different. While they participated in this task, we recorded from neurons in the ventrolateral prefrontal cortex (vPFC; a cortical area involved in aspects of nonspatial auditory processing [9, 10]). We found that vPFC activity was correlated with the monkeys' choices. This finding demonstrates a direct link between single neurons and behavioral choices in the PFC on a nonspatial auditory task.

Management of acute limb ischemia related to underlying pheochromocytoma.

Acute limb ischemia (ALI) related to pheochromocytoma is rare. We describe a 69-year-old woman who presented with ALI due to a thromboembolic phenomenon from new-onset atrial fibrillation that was successfully treated with intra-arterial catheter-directed lysis and systemic anticoagulation. Further workup revealed a left adrenal mass and biochemical test results consistent with pheochromocytoma. The patient underwent a retroperitoneoscopic converted to open left adrenalectomy, splenectomy, and distal pancreatectomy because of severe inflammation in the retroperitoneum, probably from an adrenal or subcapsular renal hematoma secondary to systemic anticoagulation. Interval imaging before adrenalectomy for pheochromocytoma should be considered after thrombolysis and anticoagulation for ALI.

Skeletal effects of combined medical and surgical management of primary hyperparathyroidism.

BACKGROUND: Parathyroidectomy (PTX) increases bone mineral density and decreases fracture risk in patients with primary hyperparathyroidism. This study examined the effect of adding bisphosphonates either before or after PTX on skeletal outcomes. METHODS: A retrospective cohort study of bisphosphonate-naïve patients (1995-2016) with osteoporosis and primary hyperparathyroidism (calcium >10.5 mg/dL; PTH >65) was performed. Time-varying Cox regression was used to estimate an adjusted risk of any fracture in 5 comparison groups: observation, bisphosphonates alone, PTX alone, bisphosphonates then PTX, and PTX then bisphosphonates. The secondary outcome was change in bone mineral density of the hip. RESULTS: The cohort comprised 1,737 patients, of whom 303 underwent PTX (17%), 433 received bisphosphonates only (25%), 125 had bisphosphonates then PTX (7%), and 69 had PTX then bisphosphonates (4%). PTX was associated with a decrease in fracture risk (HR 0.55, 95% CI 0.35-0.84), as was bisphosphonates then PTX (HR 0.46, 95% CI 0.25-0.83). In contrast, the fracture risks associated with PTX then bisphosphonates (HR 1.09, 95% CI 0.65-1.81) and bisphosphonates alone (HR 0.82, 95% CI 0.62-1.08) were similar to observation. Hip bone mineral density increased after both PTX (5.50%, 95% CI 3.39-7.61) and PTX then bisphosphonates (6.30%, 95% CI 2.53-10.07). CONCLUSION: Bisphosphonate initiation after PTX may interfere with the beneficial effects of PTX on fracture risk in osteoporotic patients with primary hyperparathyroidism.

Trends in the Surgical Management of Known or Suspected Differentiated Thyroid Cancer at a Single Institution, 2010-2018.

Background: The surgical management of nodular thyroid disease has been influenced by the advent of molecular diagnostics and recent guidelines recommending a more conservative approach to low-risk thyroid tumors. The purpose of this study was to assess practice changes arising from the early adoption of current literature within a single high-volume center. Methods: A retrospective cohort study of all patients evaluated or surgically treated for known or suspected thyroid cancer at a single institution was performed (2010-2018). We analyzed the yield of diagnostic thyroidectomy for indeterminate (Bethesda III and IV) nodules, the choice of initial operation for likely malignant (Bethesda V and VI) nodules, and the rate of completion thyroidectomy. The Cochran-Armitage test was used to assess the significance of any observed trends. Results: Of 2497 patients who underwent initial thyroidectomy from 2010 to 2018, 1791 patients had a tissue diagnosis of suspected or known thyroid cancer by cytopathology (Bethesda III-VI) or surgical pathology (differentiated thyroid cancer). In patients with likely malignant nodules but no clinical evidence of invasive or metastatic disease, the proportion managed with total thyroidectomy plus prophylactic neck dissection fell from 50% to 10% (p = 0.007). The proportion with likely malignant nodules managed definitively with thyroid lobectomy rose from 2% to 19% (p < 0.001). The rate of completion thyroidectomy for thyroid cancer found in the initial lobectomy specimen declined from 73% to 26% (p < 0.001). Among all patients with cytologically indeterminate nodules (n = 1036), we observed a decrease in the rate of diagnostic thyroidectomy from 67% to 35% over the study period (p = 0.015). Conclusions: The early adoption of new diagnostic technology and management guidelines has manifested in a less aggressive surgical approach to known or suspected thyroid cancer. Long-term follow-up will be required to assess oncologic and patient-centered outcomes arising from this modern strategy.

Sex differences in learning and inhibition in spontaneously hypertensive rats.

Few studies have addressed potential differences in the nature of cognitive impairment observed in males and females with ADHD. In Experiment 1, we examined sex differences in conditioned inhibitory behaviour in spontaneously hypertensive rats (SHR strain), a purported animal model of ADHD. Rats were presented with two types of trials during each of the 15 conditioning sessions. On some trials an auditory stimulus (a tone) was presented and followed immediately by delivery of food reward. On the remaining trials the tone was preceded by presentation of a visual stimulus and on those trials food was not delivered after the tone was presented. As training progressed, conditioned responding during presentation of the tone increased on reinforced trials and decreased during the non-reinforced trials, indicative of successful discrimination and inhibition. Overall, female SHR rats exhibited less conditioned overall food cup behaviour compared to male rats. Female SHR rats also required more training sessions until they responded significantly more during presentation of the tone on reinforced trials versus non-reinforced trials. In addition, the magnitude of the discrimination was smaller in female SHR rats compared to males. In contrast, no sex differences were observed in WKY rats (commonly-used control strain) in Experiment 2. Importantly, there were no significant sex differences in baseline activity or motivation during either experiment, indicating that performance differences could not account for the observed results. These results suggest that male and female SHR rats differ in their ability to form conditioned associations and inhibit behavioural responses and may provide a useful model for sex differences in cognitive dysfunction specific to ADHD.

Cognitive and functional status after vein of Galen aneurysmal malformation endovascular occlusion.

AIM: To study the clinical outcomes of treating vein of Galen aneurysmal malformations (VGAM), we assessed our patient cohort using standardized cognitive and functional measures. METHODS: A retrospective review of patients with VGAM treated by a single practitioner between 2003 and 2009 was performed for this study. In addition to routine clinical assessment, all patients were evaluated for cognitive and functional impairment using validated measures including the Neurobehavioral Rating Scale-Revised, the Bicêtre outcome score, and the Barthel index. RESULTS: Five patients underwent combined transarterial and transvenous embolization of their VGAM during the study period. VGAMs were classified based on angioarchitecture as either choroidal (1/5) or mural (4/5) according to the classification scheme of Lasjaunias. In total, 13 embolization procedures were performed consisting of 1 to 3 treatment stages per patient. Complete or near complete occlusion was achieved in 4 patients, while subtotal occlusion was achieved in 1 patient. During follow-up (median 62.6 mo), all patients were either unchanged or cognitively and neurologically intact. CONCLUSION: VGAM can be safely and effectively treated by staged transarterial and transvenous embolization. Using this strategy, excellent long-term cognitive and functional outcomes can be achieved.

Contrast-enhanced sonography as a novel tool for assessment of vascular malformations.

BACKGROUND: Vascular malformations with arteriovenous shunt components can cause significant disability, chronic pain, and functional impairment. Effective treatment may require serial procedures, yet an imaging modality optimized to control cost and reduce radiation exposure in this predominantly pediatric population has not yet been identified. METHODS AND RESULTS: We describe the use of contrast-enhanced sonography as a novel tool to define vascular anatomy and localize arteriovenous shunting in a young patient with a symptomatic vascular malformation. CONCLUSIONS: This method may effectively reduce radiation exposure and cost, and additionally provide unique information about arteriovenous shunting, offering a novel imaging application for patients with these conditions.

Prefrontal activity predicts monkeys' decisions during an auditory category task.

The neural correlates that relate auditory categorization to aspects of goal-directed behavior, such as decision-making, are not well understood. Since the prefrontal cortex (PFC) plays an important role in executive function and the categorization of auditory objects, we hypothesized that neural activity in the PFC should predict an animal's behavioral reports (decisions) during a category task. To test this hypothesis, we tested PFC activity that was recorded while monkeys categorized human spoken words (Russ et al., 2008b). We found that activity in the ventrolateral PFC, on average, correlated best with the monkeys' choices than with the auditory stimuli. This finding demonstrates a direct link between PFC activity and behavioral choices during a non-spatial auditory task.