Identification of motifs and mechanisms for lipid droplet targeting of the lipolytic inhibitors G0S2 and HIG2.

G0S2 and HIG2 are two selective inhibitors of ATGL (also known as PNPLA2), the key enzyme for intracellular lipolysis. Whereas G0S2 regulates triglyceride (TG) mobilization in adipocytes and hepatocytes, HIG2 functions to enhance intracellular TG accumulation under hypoxic conditions. A homologous hydrophobic domain (HD) is shared by G0S2 and HIG2 (also known as HILPDA) for binding to ATGL. However, the determinants of their lipid droplet (LD) localization are unknown. Here, we study how G0S2 and HIG2 are targeted to LDs, and identify both ATGL-independent and -dependent mechanisms. Structural prediction and studies in cells reveal that ATGL-independent localization of G0S2 to both the endoplasmic reticulum (ER) and LDs is mediated by a hairpin structure consisting of two hydrophobic sequences. Positively charged residues in the hinge region play a crucial role in sorting G0S2, which initially localizes to ER, to LDs. Interestingly, the role of these positive charges becomes dispensable when ATGL is co-expressed. In comparison, HIG2, which lacks a similar hairpin structure, is dependent on ATGL for its full LD targeting. Thus, our studies identify specific structural features and mechanisms for mediating accumulation of these two ATGL inhibitors on LDs.

Measuring CSF shunt flow with MRI using flow enhancement of signal intensity (FENSI).

PURPOSE: To develop and validate a noninvasive imaging technique for accurately assessing very slow CSF flow within shunt tubes in pediatric patients with hydrocephalus, aiming to identify obstructions that might impede CSF drainage. THEORY AND METHODS: A simulation of shunt flow enhancement of signal intensity (shunt-FENSI) signal is used to establish the relationship between signal change and flow rate. The quantification of flow enhancement of signal intensity data involves normalization, curve fitting, and calibration to match simulated data. Additionally, a phase sweep method is introduced to accommodate the impact of magnetic field inhomogeneity on the flow measurement. The method is tested in flow phantoms, healthy adults, intensive care unit patients with external ventricular drains (EVD), and shunt patients. EVDs enable shunt-flow measurements to be acquired with a ground truth measure of CSF drainage. RESULTS: The flow-rate-to-signal simulation establishes signal-flow relationships and takes into account the T1 of draining fluid. The phase sweep method accurately accounts for phase accumulation due to frequency offsets at the shunt. Results in phantom and healthy human participants reveal reliable quantification of flow rates using controlled flows and agreement with the flow simulation. EVD patients display reliable measures of flow rates. Shunt patient results demonstrate feasibility of the method and consistent flow rates for functional shunts. CONCLUSION: The results demonstrate the technique's applicability, accuracy, and potential for diagnosing and noninvasively monitoring hydrocephalus. Limitations of the current approach include a high sensitivity to motion and strict requirement of imaging slice prescription.

Laparoscopic Total Pancreatectomy After Laparoscopic Whipple.

BACKGROUND: The incidence of a second de novo pancreatic ductal adenocarcinoma (PDAC) among patients with prior cancer has been reported to be 6%.1,2 however, as survival increases through improvements in systemic therapy, this incidence of a de novo PDAC after prior PDAC may become more prevalent.3-8 In this context, a structured and stepwise approach to a total pancreatectomy for a second de novo PDAC after a prior PDAC treated with a pancreaticoduodenectomy is detailed. PATIENTS: We present two similar cases. The first patient was a 71-year-old female with de novo body PDAC, and the second was a 50-year-old female with de novo tail PDAC. To rule out recurrence, immunohistochemical staining as well as the review of biopsies by two experienced pathologists were employed. Both patients had undergone a laparoscopic pancreatoduodenectomy for PDAC 4 and 3 years prior. Each patient received four cycles of neoadjuvant chemotherapy and underwent a safe laparoscopic total pancreatectomy. TECHNIQUE: Prior to surgery, three-dimensional anatomic and port site modeling is performed to optimize the understanding of the spatial relationship between the tumor, blood vessels, and adjacent organs involved. The port site modeling (including pneumoperitoneum simulation) focuses on the optimal port set-up for dissecting the biliopancreatic limb off the portal vein. Following complete mobilization of the biliopancreatic limb, the biliopancreatic limb is staple-divided between the hepatico- and pancreaticojejunostomy. Great care must be taken to avoid accidental staple injury to the hepatic artery or celiac trunk. The remainder of the dissection is akin to a standard distal pancreaticosplenectomy. CONCLUSION: Virtual pancreatectomy modeling facilitates an optimal set-up for the critical step of this case, i.e. dissection of the pancreaticojejunostomy off the portal vein. Early division of the biliopancreatic limb between hepatico- and pancreatojejunostomy is crucial to facilitating the remainder of the dissection. Laparoscopic total pancreatectomy for a de novo PDAC after laparoscopic pancreaticoduodenectomy may become more common as survival of patients with prior PDAC improves over time.

A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

SCAT5 baseline values, test-retest reliability, and reliable change metrics in high school athletes.

OBJECTIVE: In the United States, more than 1 million sport-related concussions afflict children annually, with many cases undetected or unreported. The Sport Concussion Assessment Tool (SCAT) is widely used to detect concussions in high school, collegiate, and professional sports. The objective of this study was to establish baseline values for the SCAT version 5 (SCAT5) in high school athletes. METHODS: Baseline SCAT5 evaluations were conducted in students (ages 14-19 years) from 19 high schools in central Illinois who were participating in various school-sponsored sports. The SCAT5 evaluations were retrospectively extracted from the electronic medical record system for analysis. Statistical analyses included the Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables, considering significance at p < 0.05. Test-retest reliability at < 6 months, 10-14 months, and 16-20 months was computed using intraclass correlation and Spearman's rho (ρ). Reliable change indices are provided using the Iverson formula. RESULTS: A total of 2833 unique athletes were included, and the average age was 15.5 ± 1.14 (SD) years. There were 721 female (25.5%) and 2112 male (74.5%) athletes. Students ≥ 15 years old had more prior concussions (p < 0.001), and male athletes were more frequently hospitalized for head injury (p = 0.013). Female athletes exhibited a significantly higher prevalence of mood disorders (14.7% vs 4.6%, p < 0.001), whereas attention-deficit/hyperactivity disorder was more common in male athletes (5.2% vs 13.2%, p < 0.001). Symptom number and severity were significantly greater in female athletes (3.17 ± 4.39 vs 2.08 ± 3.49, p < 0.001; 5.47 ± 9.21 vs 3.52 ± 7.26, p < 0.001, respectively), with mood-related symptoms representing the largest differences. Female athletes and students ≥ 15 years old performed better on most cognitive assessments. Female athletes and students < 15 years old performed better on the modified Balance Error Scoring System (p < 0.001). Test-retest reliability was poor to moderate for most assessment components. Reliable change index cutoff values differed slightly by sex, with female athletes often having a greater cutoff value. CONCLUSIONS: This study underscores the variability of SCAT5 baseline values influenced by age, sex, and medical history among adolescent athletes. It provides a robust dataset, delineating baseline values stratified by sex and age within this demographic. Additionally, the results provide enhanced guidance to clinicians for interpretation of change and reliability of baselines.

Temporal Trends in Public Stroke Knowledge, 1995-2021.

BACKGROUND: Outreach campaigns have sought to reduce the burden of stroke by improving knowledge of stroke risk factors (RF) and warning signs (WS). We describe trends in stroke knowledge from 1995 to 2021. METHODS: From 1995 to 2021, 6 separate surveys were conducted in the Greater Cincinnati Northern Kentucky Region. Temporal trends in RF/WS knowledge were analyzed using logistic regression adjusting for Race, sex, age, and education. RESULTS: In 1995, 28.6% of participants (537/1880) could name ≥2 WS, compared with 50.6% (983/1944) in 2021 (trend P<0.0001 after adjustment). In 1995, 44.5% of participants (836/1880) knew ≥2 RF, compared with 56.7% (1103/1944) in 2021 (trend P<0.0001 after adjustment). Although still improved compared with 1995, fewer participants could identify ≥2 RF in 2021 (1103/1944, 56.7%) when compared with 2011 (1287/2036, 63.2%, pairwise P<0.05). This decline in RF knowledge was disproportionately larger in women (odds ratio of 0.67 for knowledge in 2021 compared with 2011 in females, P=0.047 for the interaction between sex and study year). CONCLUSIONS: Although stroke knowledge has overall improved since 1995, there is evidence for lost gains since 2011, particularly in women. Stroke outreach campaigns need ongoing evaluation.

Apomixis: oh, what a tangled web we have!

MAIN CONCLUSION: Apomixis is a complex evolutionary trait with many possible origins. Here we discuss various clues and causes, ultimately proposing a model harmonizing the three working hypotheses on the topic. Asexual reproduction through seeds, i.e., apomixis, is the holy grail of plant biology. Its implementation in modern breeding could be a game-changer for agriculture. It has the potential to generate clonal crops and maintain valuable complex genotypes and their associated heterotic traits without inbreeding depression. The genetic basis and origins of apomixis are still unclear. There are three central hypothesis for the development of apomixis that could be: i) a deviation from the sexual developmental program caused by an asynchronous development, ii) environmentally triggered through epigenetic regulations (a polyphenism of sex), iii) relying on one or more genes/alleles. Because of the ever-increasing complexity of the topic, the path toward a detailed understanding of the mechanisms underlying apomixis remains unclear. Here, we discuss the most recent advances in the evolution perspective of this multifaceted trait. We incorporated our understanding of the effect of endogenous effectors, such as small RNAs, epigenetic regulation, hormonal pathways, protein turnover, and cell wall modification in response to an upside stress. This can be either endogenous (hybridization or polyploidization) or exogenous environmental stress, mainly due to oxidative stress and the corresponding ROS (Reacting Oxygen Species) effectors. Finally, we graphically represented this tangled web.

Neurosurgical Implant Safety in 7 T MRI: A Scoping Review.

The use of 7 Tesla (T) magnetic resonance imaging (MRI) is expanding across neurosurgical and neurologic specialties. However, few neurosurgical-related implants have been tested for safety at 7 T, limiting its use in patients with cranial fixation, shunt placements, and other implants. Implant safety can be determined via the American Society for Testing Materials International (ASTM) guidelines. To assess the current state of neurosurgical implant safety at 7 T, a systematic search was performed using PubMed, MEDLINE, Web of Knowledge, and citation matching. Studies written in English that included at least one neurosurgical implant and at least one safety outcome were included. Data were extracted for implant studied, implant composition, deflection angle, torque, temperature change, and ASTM guidelines followed. PRISMA reporting guidelines for scoping reviews were followed. Overall, 18 studies consisting of 45 unique implants were included. Implants included cranial fixation devices, aneurysm clips, spinal rods, pedicle screws, ventriculoperitoneal (VP) shunts, deep brain stimulation devices, and electroencephalogram (EEG) caps and electrodes. Cranial fixation devices, deep brain stimulation devices, spinal rods, and pedicle screws are likely 7 T MRI compatible based on outcomes reported. Aneurysm clips and EEG devices had variable safety outcomes. The VP shunts studied lost functionality after 7 T MRI exposure. We identified several implants that are likely compatible with 7 T MRI. Given the growth in 7 T imaging and expansion of the technology, neurosurgical implants should be constructed with the aforementioned considerations. Caution must be taken with all implants, especially aneurysm clips, programmable VP shunts, and EEG recording devices. It is also noteworthy that several implant testing reports did not report following ASTM standards. This scoping review seeks to concisely summarize all neurosurgical-related implants that have been tested for safety in 7 T MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Wild origins and mitochondrial genetic diversity of Angolan Colobus monkeys (Colobus angolensis) in AZA-accredited zoos and its implications for ex situ population management.

Across zoo's accredited by the Association of Zoos and Aquariums (AZA), species are typically managed as a single population to retain 90% of the founding members' gene diversity. Often, little is known about the specific geographic origins of the founders or how representative the ex situ population's genetic diversity is of the wild population. This study uses mitochondrial DNA (mtDNA) sequencing to investigate haplotype diversity and geographic female founder origin of the AZA-managed Angolan colobus (Colobus angolensis) monkey population. We obtained fecal samples from individuals closely related to founder animals at five zoos and found four haplotypes among 23 individuals. Analyzed together with wild C. angolensis haplotypes, we found two haplotypes identical to those found in Tanzanian populations: one haplotype, possessed by 13 individuals (descended from three founders), matched an East Usambara Mountains haplotype, while the other, possessed by seven individuals (from four founders), matched a haplotype found in both the South Pare Mountains and Rufiji River. Two haplotypes were not detected in wild populations but were closely related to haplotypes found in the Rufiji River (one individual descended from one founder) and Shimoni, Kenya (two individuals descended from one founder) populations, suggesting nearby origins. Thus, the AZA-managed population of Angolan colobus likely originated from several localities, but all have mtDNA lineages associated with the subspecies C. a. palliatus, a Vulnerable subspecies. Examining founders' mtDNA haplotypes may be a useful addition to the zoo population management toolkit to help improve breeding recommendations by identifying individuals with rare haplotypes and revealing likely kinship among founders.

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos.

Bi-potential neuromesodermal progenitors (NMPs) produce both neural and paraxial mesodermal progenitors in the trunk and tail during vertebrate body elongation. We show that Sall4, a pluripotency-related transcription factor gene, has multiple roles in regulating NMPs and their descendants in post-gastrulation mouse embryos. Sall4 deletion using TCre caused body/tail truncation, reminiscent of early depletion of NMPs, suggesting a role of Sall4 in NMP maintenance. This phenotype became significant at the time of the trunk-to-tail transition, suggesting that Sall4 maintenance of NMPs enables tail formation. Sall4 mutants exhibit expanded neural and reduced mesodermal tissues, indicating a role of Sall4 in NMP differentiation balance. Mechanistically, we show that Sall4 promotion of WNT/ß-catenin signaling contributes to NMP maintenance and differentiation balance. RNA-Seq and SALL4 ChIP-Seq analyses support the notion that Sall4 regulates both mesodermal and neural development. Furthermore, in the mesodermal compartment, genes regulating presomitic mesoderm differentiation are downregulated in Sall4 mutants. In the neural compartment, we show that differentiation of NMPs towards post-mitotic neuron is accelerated in Sall4 mutants. Our results collectively provide evidence supporting the role of Sall4 in regulating NMPs and their descendants.

Mitochondrial genetic diversity and divergence dating of Angolan colobus monkeys (Colobus angolensis) in the eastern forests of Kenya and Tanzania: Implications for subspeciation and reconstructing historical biogeography.

Whether the Colobus angolensis that reside in the fragmented forests in eastern Kenya and Tanzania represent one subspecies or two has been debated for 50 years. Morphological and more recent genetic and ecological studies suggest that these populations represent two subspecies, C. a. palliatus and C. a. sharpei. However, their distribution of mitochondrial variation remains unresolved since the genetic study only characterized four populations at the range ends. Therefore, we characterized five populations in the area of the hypothesized subspecies divide. We identified eight new haplotypes which, combined with those previously identified, provided 26 haplotypes from nine populations for analysis. Haplotypes found south of the Rufiji River cluster together but separately from northern haplotypes. The largest sequence differences within cytochrome b occur between population pairs representing opposite sides of the river; their mean difference (1.5%) is more than that of other primate subspecies. Analysis of molecular variance attributes most of the variation to that north versus south of the river. These results support the previous subspecies distinction between C. a. palliatus (northern) and C. a. sharpei (southern), divided by the Rufiji River. The estimated time of the most recent common ancestor of all haplotypes indicates that the subspecies have been isolated from each other for approximately 550,000 years. The common ancestor of northern and southern haplogroups was 370,000 and 290,000 years ago, respectively. Nevertheless, the correlation between genetic and geographic distances suggests that isolation-by-distance contributed to population structuring. Significant variation among populations, with only three haplotypes shared between populations, also indicates that an extended period of isolation drove population distinctiveness. Considering these results, we evaluate hypotheses about the founding and differentiation of these subspecies during Pleistocene climatic fluctuations and propose a novel, more direct migration route from Central Africa to their current range navigating Lake Tanganyika, the central Tanzanian corridor, and the Rufiji River.

Cervical Carotid Pseudo-Occlusions and False Dissections: Intracranial Occlusions Masquerading as Extracranial Occlusions.

BACKGROUND AND PURPOSE: Pseudo-occlusion (PO) of the cervical internal carotid artery (ICA) refers to an isolated occlusion of the intracranial ICA that appears as an extracranial ICA occlusion on computed tomography angiography (CTA) or digital subtraction angiography because of blockage of distal contrast penetration by a stagnant column of unopacified blood. We aim to better characterize this poorly recognized entity. METHODS: Retrospective review of an endovascular database (2010-2015; n=898). Only patients with isolated intracranial ICA occlusions as confirmed by angiographic exploration were included. CTA and digital subtraction angiography images were categorized according to their apparent site of occlusion as (1) extracranial ICA PO or (2) discernible intracranial ICA occlusion. RESULTS: Cervical ICA PO occurred in 21/46 (46%) patients on CTA (17 proximal cervical; 4 midcervical). Fifteen (71%) of these patients also had PO on digital subtraction angiography. A flame-shaped PO mimicking a carotid dissection was seen in 7 (33%) patients on CTA and in 6 (29%) patients on digital subtraction angiography. Patients with and without CTA PO had similar age (64.8±17.1 versus 60.2±15.7 years; P=0.35), sex (male, 47% versus 52%; P=1.00), and intravenous tissue-type plasminogen activator use (38% versus 40%; P=1.00). The rates of modified Treatment In Cerebral Ischemia 2b-3 reperfusion were 71.4% in the PO versus 100% in the non-PO cohorts (P<0.01). The rates of parenchymal hematoma, 90-day modified Rankin Scale score 0-2, and 90-day mortality were 4.8% versus 8% (P=0.66), 40% versus 66.7% (P=0.12), and 25% versus 21% (P=0.77) in PO versus non-PO patients, respectively. Multivariate analysis indicated that PO patients had lower chances of modified Treatment In Cerebral Ischemia 3 reperfusion (odds ratio 0.14; 95% confidence interval 0.02-0.70; P=0.01). CONCLUSIONS: Cervical ICA PO is a relatively common entity and may be associated with decreased reperfusion rates.

Large Volumes of Critically Hypoperfused Penumbral Tissue Do Not Preclude Good Outcomes After Complete Endovascular Reperfusion: Redefining Malignant Profile.

BACKGROUND AND PURPOSE: Acute ischemic stroke patients with large volumes of severe hypoperfusion (Tmax>10 s>100 mL) on magnetic resonance imaging have a higher likelihood of intracranial hemorrhage and poor outcomes after reperfusion. We aim to evaluate the impact of the extent of Tmax>10 s CTP lesions in patients undergoing successful treatment. METHODS: Retrospective database review of endovascular acute ischemic stroke treatment between September 2010 and March 2015 for patients with anterior circulation occlusions with baseline RAPID CTP and full reperfusion (mTICI 3). The primary outcome was the impact of the Tmax>10 s lesion spectrum on infarct growth. Secondary safety and efficacy outcomes included parenchymal hematomas and good clinical outcomes (90-day modified Rankin Scale score, 0-2). RESULTS: Of 684 treated patients, 113 patients fit the inclusion criteria. Tmax>10 s>100 mL patients (n=37) had significantly higher baseline National Institutes of Health Stroke Scale (20.7±3.8 versus 17.0±5.9; P<0.01), more internal carotid artery terminus occlusions (29% versus 9%; P=0.02), and larger baseline (38.6±29.6 versus 11.7±15.8 mL; P<0.01) and final (60.7±60.0 versus 29.4±33.9 mL; P<0.01) infarct volumes when compared with patients without Tmax>10 s>100 mL (n=76); however, the 2 groups were otherwise well balanced. There were no significant differences in infarct growth (22.1±51.6 versus 17.8±32.4 mL; P=0.78), severe intracranial hemorrhage (PH2: 2% versus 4%; P=0.73), good outcomes (90-day mRS score, 0-2: 56% versus 59%; P=0.83), or 90-day mortality (16% versus 7%; P=0.28). On multivariate analysis, only baseline National Institutes of Health Stroke Scale (odds ratio, 1.19; 95% confidence interval, 1.06-1.34; P<0.01) and baseline infarct core volume (odds ratio, 1.05; 95% confidence interval, 1.02-1.08; P<0.01) were independently associated with Tmax>10 s>100 mL. There was no association between Tmax>10 s>100 mL with any PH, good outcome, or infarct growth. CONCLUSIONS: In the setting of limited baseline ischemic cores, large Tmax>10 s lesions on computed tomographic perfusion do not seem to be associated with a higher risk of parenchymal hematomas and do not preclude good outcomes in patients undergoing endovascular reperfusion with contemporary technology.

Early Endovascular Treatment in Intravenous Tissue Plasminogen Activator-Ineligible Patients.

BACKGROUND AND PURPOSE: Intravenous tissue-type plasminogen activator (tPA) treatment in acute stroke has many exclusion criteria. We aimed to assess the safety and efficacy of endovascular therapy (ET) in intravenous (IV) tPA-ineligible patients. METHODS: Retrospective analysis of a prospectively collected database of consecutive patients treated with ET within 6 hours of stroke onset between September 2010 and April 2015. Patients treated with IV-tPA followed by ET were compared with those treated with ET alone because of IV-tPA ineligibility. Efficacy and safety end points included the rates of good outcome (90-day modified Rankin scale score ≤2), successful reperfusion (modified Treatment in Cerebral Ischemia 2b-3), parenchymal hematoma (PH-1 and PH-2), and 90-day mortality. Univariate and logistic regression were performed to identify the predictors of outcomes. RESULTS: A total of 422 patients were included. Two hundred and fifty-three (59%) patients received IV-tPA+ET, and 169 (41%), ET alone. Combined IV-tPA+ET patients were slightly younger (64.9±15.2 versus 67.9±14.9 years; P=0.05), more often males (56% versus 44%; P=0.01), and had less hypertension (70% versus 81%; P=0.02) and vertebrobasilar occlusions (3% versus 8%; P=0.02). The remaining baseline characteristics, including National Institutes of Health Stroke Scale score (20 [15-23] versus 19 [15-24]; P=0.85), Alberta Stroke Program Early CT Score (ASPECTS; 8 [7-9] versus 8 [7-9]; P=0.24), and stroke onset to puncture times (235±70 versus 240±81 minutes; P=0.27), were similar across both groups. There were no significant differences in the rates of modified Treatment in Cerebral Ischemia 2b-3 (83% versus 80%; P=0.52), 90-day modified Rankin scale score ≤2 (45% versus 38%; P=0.21), or any PH (3% versus 5%; P=0.21). Unadjusted 90-day mortality was higher with ET alone (21% versus 34%; P<0.01); however, IV-tPA ineligibility was not associated with modified Treatment in Cerebral Ischemia 2b-3, any PH, good outcome, or 90-day mortality on logistic regression. CONCLUSIONS: IV-tPA-eligible and -ineligible patients seem to have similar outcomes after early ET.

Automated CT Perfusion Ischemic Core Volume and Noncontrast CT ASPECTS (Alberta Stroke Program Early CT Score): Correlation and Clinical Outcome Prediction in Large Vessel Stroke.

BACKGROUND AND PURPOSE: The semiquantitative noncontrast CT Alberta Stroke Program Early CT Score (ASPECTS) and RAPID automated computed tomography (CT) perfusion (CTP) ischemic core volumetric measurements have been used to quantify infarct extent. We aim to determine the correlation between ASPECTS and CTP ischemic core, evaluate the variability of core volumes within ASPECTS strata, and assess the strength of their association with clinical outcomes. METHODS: Review of a prospective, single-center database of consecutive thrombectomies of middle cerebral or intracranial internal carotid artery occlusions with pretreatment CTP between September 2010 and September 2015. CTP was processed with RAPID software to identify ischemic core (relative cerebral blood flow<30% of normal tissue). RESULTS: Three hundred and thirty-two patients fulfilled inclusion criteria. Median age was 66 years (55-75), median ASPECTS was 8 (7-9), whereas median CTP ischemic core was 11 cc (2-27). Median time from last normal to groin puncture was 5.8 hours (3.9-8.8), and 90-day modified Rankin scale score 0 to 2 was observed in 54%. The correlation between CTP ischemic core and ASPECTS was fair (R=-0.36; P<0.01). Twenty-six patients (8%) had ASPECTS <6 and CTP core ≤50 cc (37% had modified Rankin scale score 0-2, whereas 29% were deceased at 90 days). Conversely, 27 patients (8%) had CTP core >50 cc and ASPECTS ≥6 (29% had modified Rankin scale 0-2, whereas 21% were deceased at 90 days). Moderate correlations between ASPECTS and final infarct volume (R=-0.42; P<0.01) and between CTP ischemic core and final infarct volume (R=0.50; P<0.01) were observed; coefficients were not significantly influenced by the time from stroke onset to presentation. Multivariable regression indicated ASPECTS ≥6 (odds ratio 4.10; 95% confidence interval, 1.47-11.46; P=0.01) and CTP core ≤50 cc (odds ratio 3.86; 95% confidence interval, 1.22-12.15; P=0.02) independently and comparably predictive of good outcome. CONCLUSIONS: There is wide variability of CTP-derived core volumes within ASPECTS strata. Patient selection may be affected by the imaging selection method.

Viscoelasticity of subcortical gray matter structures.

Viscoelastic mechanical properties of the brain assessed with magnetic resonance elastography (MRE) are sensitive measures of microstructural tissue health in neurodegenerative conditions. Recent efforts have targeted measurements localized to specific neuroanatomical regions differentially affected in disease. In this work, we present a method for measuring the viscoelasticity in subcortical gray matter (SGM) structures, including the amygdala, hippocampus, caudate, putamen, pallidum, and thalamus. The method is based on incorporating high spatial resolution MRE imaging (1.6 mm isotropic voxels) with a mechanical inversion scheme designed to improve local measures in pre-defined regions (soft prior regularization [SPR]). We find that in 21 healthy, young volunteers SGM structures differ from each other in viscoelasticity, quantified as the shear stiffness and damping ratio, but also differ from the global viscoelasticity of the cerebrum. Through repeated examinations on a single volunteer, we estimate the uncertainty to be between 3 and 7% for each SGM measure. Furthermore, we demonstrate that the use of specific methodological considerations-higher spatial resolution and SPR-both decrease uncertainty and increase sensitivity of the SGM measures. The proposed method allows for reliable MRE measures of SGM viscoelasticity for future studies of neurodegenerative conditions. Hum Brain Mapp 37:4221-4233, 2016. © 2016 Wiley Periodicals, Inc.

Flavanone Intake Is Inversely Associated with Risk of Incident Ischemic Stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

BACKGROUND: Flavonoids may have beneficial cerebrovascular effects, but evidence from racially and geographically representative cohorts in comprehensive flavonoid databases is lacking. Given racial and geographic disparities in stroke incidence, representative cohort studies are needed. OBJECTIVES: We evaluated the association between flavonoid intake and incident ischemic stroke in a biracial, national cohort using updated flavonoid composition tables and assessed differences in flavonoid intake by sex, race, and region of residence. METHODS: We evaluated 20,024 participants in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a biracial prospective study. Participants with stroke history or missing dietary data were excluded. Flavonoid intake was estimated by using a Block98 food frequency questionnaire and the USDA's Provisional Flavonoid Addendum and Proanthocyanidin Database. Associations between quintiles of flavonoid intake and incident ischemic stroke were evaluated by using Cox proportional hazards models, adjusting for confounders. RESULTS: Over 6.5 y, 524 acute ischemic strokes occurred. Flavanone intake was lower in the Southeastern United States but higher in blacks than in whites. After multivariable adjustment, flavanone intake was inversely associated with incident ischemic stroke (HR: 0.72; 95% CI: 0.55, 0.95; P-trend = 0.03). Consumption of citrus fruits and juices was inversely associated with incident ischemic stroke (HR: 0.69; 95% CI: 0.53, 0.91; P-trend = 0.02). Total flavonoids and other flavonoid subclasses were not associated with incident ischemic stroke. There was no statistical interaction with sex, race, or region for any flavonoid measure. CONCLUSIONS: Greater consumption of flavanones, but not total or other flavonoid subclasses, was inversely associated with incident ischemic stroke. Associations did not differ by sex, race, or region for the association; however, regional differences in flavanone intake may contribute to regional disparities in ischemic stroke incidence. Higher flavanone intake in blacks suggests that flavanone intake is not implicated in racial disparities in ischemic stroke incidence.

Withdrawal of Antithrombotic Agents and the Risk of Stroke.

BACKGROUND AND PURPOSE: Antithrombotic medications are effective for ischemic stroke prevention, but stoppage of these medications is associated with an increased risk of thromboembolism. The frequency of antithrombotic withdrawal in the general population is unknown. METHODS: We conducted a random phone sample of 2036 households in the Greater Cincinnati metropolitan area, representative of the stroke population by age, sex, and race, to determine the frequency of antithrombotic medication use and stoppage by physicians for medically indicated procedures. RESULTS: Sixty-two percent of survey respondents reported that they were on an antithrombotic medication. Ten percent of participants reported that they had stopped taking their medication within the past 60 days for a medically indicated intervention. Of those who stopped taking the medication, it was more common for persons taking an anticoagulant to stop their medication (20%) than those taking an antiplatelet agent (9%). Colonoscopies and orthopedic surgeries were the most common reasons for withdrawal of antiplatelet agents, whereas orthopedic and vascular surgeries were the most common reason for withdrawal of anticoagulants. CONCLUSIONS: Recommended discontinuation of antithrombotic medication for surgical or diagnostic procedures is common practice for persons in the community representative of a stroke population. Because stoppage of these medications is associated with an increased risk of thromboembolic stroke, further clinical trials are needed to determine best management practices in this setting.

Endovascular Treatment for Acute Ischemic Stroke in the Setting of Anticoagulation.

BACKGROUND AND PURPOSE: Oral anticoagulation (OAC) plays a major role in atrial fibrillation stroke prevention but represents a contraindication to intravenous tissue-type plasminogen activator. Intra-arterial therapy remains a potential reperfusion strategy in these patients; however, supporting data are scarce. METHODS: Retrospective analysis of prospectively collected consecutive intra-arterial therapies from October 2010 to March 2015 comparing OAC (vitamin-K antagonists and novel oral anticoagulants) versus normal hemostasis versus intravenous tissue-type plasminogen activator patients. Primary safety end point is parenchymal hematoma. Secondary safety end point is 90-day mortality. Efficacy end points are successful reperfusion (modified Thrombolysis in Cerebral Infarction, 2b-3) and good outcome (90-day modified Rankin Scale score of 0-2). Logistic regression for predictors of parenchymal hematoma was performed. RESULTS: A total of 604 patients were qualified for the study. Baseline and outcomes variables were overall similar for vitamin-K antagonists (n=29) and novel oral anticoagulants (n=17) patients. When compared with normal hemostasis (n=265) and intravenous tissue-type plasminogen activator (n=297), OAC (n=46) patients were older and had more comorbidities. There were no statistically significant differences in the rates of parenchymal hematoma (8% versus 5%; P=0.42), 90-day modified Rankin Scale score of 0 to 2 (30% versus 40%; P=0.26), and 90-day mortality (32% versus 26%; P=0.46) among OAC and normal hemostasis patients. Similarly, there were no significant differences between OAC and intravenous tissue-type plasminogen activator patients in terms of parenchymal hematoma (8% versus 4%; P=0.16), 90-day modified Rankin Scale score of 0 to 2 (30% versus 43%; P=0.13), and 90-day mortality (32% versus 22%; P=0.18). The use of OAC was not associated with the occurrence of parenchymal hematoma on multivariate logistic regression analysis. CONCLUSIONS: Intra-arterial therapy seems to be safe in patients taking OACs; however, our study showed a nonsignificant increase in hemorrhage and mortality with a nonsignificant decrease in good outcomes in comparison with non-OAC patients. Although these nominal differences may have been related to older age and more comorbidities in the OAC group, larger studies are needed to confirm our findings given our limited sample size.