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BACKGROUND Migraine is a common major cause of disability, poor quality of life, and high health care utilization. Access to evidence-based migraine care is limited and projected to worsen. Novel health care delivery models including mHealth app-based tools may mitigate these challenges. OBJECTIVE We developed an electronic health record (EHR) integrated mobile app-based migraine interactive care plan (MICP) to remotely monitor, deliver education and facilitate care team communication for patients with migraine. This multi-method study describes the MICP and pilot evaluation of its feasibility, usability, and impact on care teams in a community neurology practice. METHODS Consecutive enrollees between 9/1/2020 and 2/16/2022 were assessed in a single arm observational study. Usability was defined by ≥ 75% of patients completing ≥ 1 assigned task. Task response rates, rate and type of care team escalations, and patient reported clinical outcomes were summarized. Feasibility was defined by equal-to or fewer downstream face-to-face visits, telephone contacts, and electronic messages. From 9/1/2020 to 9/1/21 eligible patients were prospectively recruited and randomly assigned to routine care with or without the MICP. Demographic data and occurrence of face-to-face visits, telephone contacts, electronic messages were extracted from the EHR. The Wilcoxon ranked summed test was used to compare continuous variables and the Chi-square test for categorical variables for those with at least 3 months of follow-up. RESULTS A total of 171 patients enrolled and 127 (74.3%) completed ≥ 1 MICP assigned task. Mean escalations per patient per month was 0.9 (SD 0.37; range 0-1.7). Patient confirmed understanding of educational materials ranged from 26.7% to 56.3%. Initial mean headache days per week was 4.54 days (SD 2.06) and trended down to 2.86 days (SD 1.87) at week 26. Baseline mean total MIDAS score was 110 (SD 107; range 3-452) with a response rate of 59% (n=100/170). The percentage of patients reporting favorable satisfaction increased from a baseline of 35% to 59% (response rate of 30-41%) over the first 6 months. A total of 121 with MICP were compared to 62 patients in the control group. No differences were observed in the rate of telephone contacts or electronic messages. Fewer face-to-face visits were observed in the MICP cohort (n=13/121, 10.7%) compared to controls (n=26/62, 42%; P < .001). CONCLUSIONS We describe successful implementation of an EHR integrated mobile app-based interactive care plan for migraine in a community neurology practice. Our findings suggest that the MICP holds potential for improving patient access and reducing healthcare utilization without increasing care team work. Additional studies are needed to assess the impact on utilization and outcomes in other settings such as primary care. Our findings also suggest the need for direct patient input from diverse populations to improve the MICP and sustain patient-engagement.

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

Tables S1-S3, Figures S1-S5

Supplementary Figure 2 from Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis

Supplementary Figure 1 from Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis

Supplementary Methods from Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis

Cardiac tissue engineering has been working to alleviate the immense burden of cardiovascular disease for several decades. To improve cardiac tissue homogeneity and cardiomyocyte (CM) maturation, in this study, we investigated altering initial encapsulation geometry in a three-dimensional (3D) direct cardiac differentiation platform. Traditional engineered cardiac tissue production utilizes predifferentiated CMs to produce 3D cardiac tissue and often involves various cell selection and exogenous stimulation methods to promote CM maturation. Starting tissue formation directly with human induced pluripotent stem cells (hiPSCs), rather than predifferentiated CMs, simplifies the engineered cardiac tissue formation process, making it more applicable for widespread implementation and scale-up. In this study, hiPSCs were encapsulated in poly (ethylene glycol)-fibrinogen in three tissue geometries (disc-shaped microislands, squares, and rectangles) and subjected to established cardiac differentiation protocols. Resulting 3D engineered cardiac tissues (3D-ECTs) from each geometry displayed similar CM populations (∼65%) and gene expression over time. Notably, rectangular tissues displayed less tissue heterogeneity and suggested more advanced features of maturing CMs, including myofibrillar alignment and Z-line formation. In addition, rectangular tissue showed significantly higher anisotropic contractile properties compared to square and microisland tissues (MI 0.28 ± 0.03, SQ 0.35 ± 0.05, RT 0.79 ± 0.04). This study demonstrates a straightforward method for simplifying and improving 3D-ECT production without the use of exogenous mechanical or electrical pacing and has the potential to be utilized in bioprinting and drug testing applications. Impact statement Current methods for improving cardiac maturation postdifferentiation remain tedious and complex. In this study, we examined the impact of initial encapsulation geometry on improvement of three-dimensional engineered cardiac tissue (3D-ECT) production and postdifferentiation maturation for three tissue geometries, including disc-shaped microislands, squares, and rectangles. Notably, rectangular 3D-ECTs displayed less tissue heterogeneity and more advanced features of maturing cardiomyocytes, including myofibrillar alignment, Z-line formation, and anisotropic contractile properties, compared to microisland and square tissues. This study demonstrates an initial human induced pluripotent stem cell-encapsulated rectangular tissue geometry can improve cardiac maturation, rather than implementing cell selection or tedious postdifferentiation manipulation, including exogenous mechanical and/or electrical pacing.

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

Background Vertebral arteriovenous fistulas (VAVFs) are uncommon high-flow communications between a vertebral artery and surrounding venous plexus that occur spontaneously or secondary to trauma. Case Description A woman aged 57 years presented with a multiday history of rapidly progressive numbness and weakness in the left C5-C6 dermomyotomes. Her physical examination findings and subsequent electrophysiological testing were suggestive of a brachial radiculoplexopathy. Noninvasive imaging demonstrated venous congestion with multilevel compromise of the left-sided cervical foramina, and subsequent vertebral angiography confirmed a VAVF, which was treated with trapping of the involved vertebral artery segment. Her numbness and weakness progressively improved with concurrent involution of the dilated veins. Conclusions This is a rare case of VAVF manifesting as a brachial radiculoplexopathy. Although rare, VAVF may be considered as a potential cause in patients presenting with similar symptoms.

Background and ObjectivesDeveloping high-value care models with limited resources for large populations of individuals with migraine requires advanced understanding of patient preferences for care delivery methods. In this study, we aimed to inform the development of migraine care models by assessing patient preferences for types of care delivery and determining differences based on migraine frequency and disability.MethodsWe analyzed unpublished data from a cross-sectional survey of 516 randomly selected individuals with migraine within a community practice associated with Mayo Clinic, Rochester, MN.ResultsIndividuals with chronic migraine, compared with those with episodic migraine, were more likely to prefer a visit with a neurologist (p= 0.0005), synchronous telephone conference with primary care provider (PCP) and neurologist (p= 0.0102), and a written migraine action plan in the medical record (p= 0.0343). Compared with those with mild/no disability, individuals with moderate-to-severe disability were more likely to prefer a visit with a neurologist (p< 0.0001), synchronous video or telephone conference with PCP and neurologist (p< 0.0001), PCP communication with neurologist (p= 0.0099), electronic message to primary care team with access to neurologist (p= 0.0216), and written action plan in the medical record (p= 0.0011). Collectively, individuals most preferred telephone follow-up and least preferred communications with a nurse or pharmacist or generalized education (allp< 0.001).DiscussionWe observed differences in migraine care delivery preferences between migraine frequency and level of migraine disability. Observations support development of care pathways that include a written migraine action plan, primary care–neurology collaboration including nontraditional interactions, and prioritization of traditional neurology consultation for the most disabled patients.

BackgroundSynchronous collaboration as defined by a simultaneous encounter between primary care providers (PCPs), patients, and neurologists may improve access to neurologic expertise, care value, and satisfaction of PCPs and patients. We examined a series of synchronous collaborations and report outcomes, PCP satisfaction, downstream utilization, and illustrative case examples.MethodsWithin an outpatient collaborative primary care–neurology care model, we implemented synchronous video consultations from a central hub to satellite clinics while increasing availability of synchronous telephone and face-to-face collaboration. PCP experience was assessed by a postcollaboration survey. Individual cases were summarized. Clinical and utilization outcomes were assessed by a neurologist immediately after and by follow-up chart review.ResultsA total of 58 total synchronous collaborations were performed: 30 by telephone (52%), 18 face to face (31%), and 10 by video (17%) over 27 clinic half-days. The most frequent outcomes as assessed by the neurologist were reassurance of the PCP (23/58; 40%) and patient (22/59; 38%), and the neurologist changed the treatment plan (23/58; 40%). A subsequent face-to-face consultation was completed in 15% (6/58) of patients initially assessed by telephone or video. Test utilization was avoided in 40% (23/58). Unintended utilization occurred 9% (5/58). Most PCPs were very satisfied with the ease of access, quality of care, and reported high likelihood of subsequent use. PCPs perceived similar or less time spent during synchronous vs asynchronous collaboration and neurologist usually altered the testing (87.8%) and treatment plan (95.2%).ConclusionsSynchronous collaboration between neurologists and PCPs may improve timely access to neurologic expertise, downstream utilization, and PCP satisfaction.

OBJECTIVE: Inform migraine care model development by assessing differences between patients with chronic migraine and episodic migraine in current state of treatment, disability, patient satisfaction, and quality improvement opportunities. BACKGROUND: Efficient and focused use of scarce resources will be needed to address challenges within large populations of migraine patients. METHODS: We deployed a cross-sectional survey study of randomly selected migraine patients within a community primary care practice. RESULTS: There were 516 survey respondents (516/1804 (30%) response rate). Chronic migraine patients were more likely than episodic migraine patients to report care from a neurologist (76/110 (69%) vs. 229/406 (56%); p=0.0026), and higher disability according to the MIDAS and HIT-6 questionnaires (p

ObjectivesTo develop neurology scenarios for use with the Quality Improvement Knowledge Application Tool Revised (QIKAT-R), gather and evaluate validity evidence, and project the impact of scenario number, rater number and rater type on score reliability.MethodsSix neurological case scenarios were developed. Residents were randomly assigned three scenarios before and after a quality improvement (QI) course in 2015 and 2016. For each scenario, residents crafted an aim statement, selected a measure and proposed a change to address a quality gap. Responses were scored by six faculty raters (two with and four without QI expertise) using the QIKAT-R. Validity evidence from content, response process, internal structure, relations to other variables and consequences was collected. A generalisability (G) study examined sources of score variability, and decision analyses estimated projected reliability for different numbers of raters and scenarios and raters with and without QI expertise.ResultsRaters scored 163 responses from 28 residents. The mean QIKAT-R score was 5.69 (SD 1.06). G-coefficient and Phi-coefficient were 0.65 and 0.60, respectively. Interrater reliability was fair for raters without QI expertise (intraclass correlation = 0.53, 95% CI 0.30 to 0.72) and acceptable for raters with QI expertise (intraclass correlation = 0.66, 95% CI 0.02 to 0.88). Postcourse scores were significantly higher than precourse scores (6.05, SD 1.48 vs 5.22, SD 1.5; p < 0.001). Sufficient reliability for formative assessment (G-coefficient > 0.60) could be achieved by three raters scoring six scenarios or two raters scoring eight scenarios, regardless of rater QI expertise.ConclusionsValidity evidence was sufficient to support the use of the QIKAT-R with multiple scenarios and raters to assess resident QI knowledge application for formative or low-stakes summative purposes. The results provide practical information for educators to guide implementation decisions.

IMPORTANCE: Transient global amnesia (TGA) is usually considered a benign event with a low recurrence rate. However, recurrence rates vary considerably among studies and there are no known risk factors for TGA. OBJECTIVE: To examine risk factors for the recurrence of TGA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study involved medical record review of patients with isolated or recurrent TGA presenting to the Mayo Clinic in Rochester, Minnesota, between August 1, 1992, and February 28, 2018. A total of 1491 cases were reviewed and 1044 met diagnostic inclusion criteria for TGA, with the remainder excluded owing to indeterminate or alternate diagnoses or limited information available in the medical record. EXPOSURES: Single vs recurrent episodes of TGA. MAIN OUTCOMES AND MEASURES: Demographics, precipitating factors, migraine history, imaging and electrodiagnostic findings, and family history of TGA were collected. The main outcome measure was TGA recurrence. RESULTS: Of 1044 included patients, 575 (55.1%) were male, and the mean (SD) age at inclusion was 75.0 (11.5) years. A total of 901 patients (86.3%) had a single episode of TGA and 143 (13.7%) had recurrent episodes of TGA. The 2 groups were similar in age at inclusion, sex, identifiable triggers, and duration of anterograde amnesia. The number of recurrences ranged from 1 to 9, with 137 individuals (95.8%) having 3 or fewer recurrences. The mean (SD) age at first episode of TGA was 65.2 (10.0) years for individuals with a single episode vs 58.8 (10.3) years for those with recurrent episodes (P

Vertebral arteriovenous fistulas (VAVF) are uncommon, high-flow communications between a vertebral artery and surrounding venous plexus that occur spontaneously or secondary to trauma. A 57-year-old female presented with a multi-day history of rapidly progressive numbness and weakness in the left C5-C6 dermomyotomes. Her physical exam findings and subsequent electrophysiological testing were suggestive of a brachial radiculo-plexopathy. Noninvasive imaging demonstrated venous congestion with multilevel compromise of the left-sided cervical foramina, and subsequent vertebral angiography confirmed a VAVF, which was treated with trapping of the involved VA segment. Her numbness and weakness progressively improved with concurrent involution of the dilated veins. An exceptional case of VAVF manifesting as a brachial radiculo-plexopathy is presented. VAVF are rare, though they may be considered as a potential underlying cause in patients with comparable symptoms. Endovascular embolization has been demonstrated as a safe and efficacious method in treating VAVFs, though multiple patient-specific factors must be contemplated. Disclosures A. Larson: None. L. Rinaldo: None. C. Arnold Fiebelkorn: None. N. Young: None. G. Lanzino: None.

Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

Background We examined predictors of recurrent hospitalizations and the importance of these hospitalizations for subsequent mortality after incident transient ischemic attacks (TIA) that have not yet been investigated. Methods Adults hospitalized for TIA from 2000 through 2017 were examined for recurrent hospitalizations, days, and percentage of time spent hospitalized and long-term mortality. Results Of 266 patients hospitalized for TIA, 122 died, 212 had 826 anycondition hospitalization (59 from TIA-related conditions) corresponding to 3384 inpatient days during 1693 person-years of follow-up. Of 42 patient-level characteristics, age greater than or equal to 65 years (Incidence rate ratio [IRR] 1.75, 95% confidence interval [CI] 1.19-2.55), current smoking (IRR 2.15, 95% CI 1.39-3.33), concurrent heart failure (IRR 1.81, 95% CI 1.17-2.80) or anemia (IRR 1.90, 95% CI 1.40-2.48), and no prescription statin (IRR 1.45, 95% CI 1.04-2.03, P = .0289) emerged as significant predictors of anycondition rehospitalization. All these variables except heart failure remained significant predictors of TIA-related rehospitalizations. All-cause mortality was significantly increased after each hospitalization from anycondition (hazard ratio [HR] 1.32, 95% CI 1.26-1.39), TIA-related condition (HR 1.72; 95% CI 1.28-2.30), and per each day (HR 1.05, 95% CI 1.04-1.05) and per 1% of follow-up time spent hospitalized from anycondition (HR 1.45, 95% CI 1.34-1.58). Conclusions Older age, current tobacco smoking, concurrent heart failure or anemia, and no prescription statin, easily measured patient-level characteristics, identifies patients with TIA at high risk for recurrent hospitalizations and the burden of these hospitalizations predicts subsequent mortality.

eFT226: A Selective and Highly Potent Inhibitor of Eukaryotic Initiation Factor 4A (eIF4A), a Novel Approach for the Treatment of Cancer Siegfried H Reich, Peggy A Thompson, Justin T Ernst, Boreth Eam, Nathan P Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Ana Parra, Eric Sung, Jocelyn Staunton, Ivy NJ Hung, Gregory S Parker, Gary G Chiang, Christopher J Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K Packard, Theodore Michels, Paul A Sprengeler, and Kevin R Webster Effector Therapeutics, San Diego, CA Oncoprotein expression is tightly controlled at the level of RNA translation which is largely regulated by the eukaryotic translation initiation factor 4F (eIF4F). eIF4A1, a component of the eIF4F complex, catalyzes the ATP dependent unwinding of RNA duplexes and facilitates 43S ribosome complex scanning within the 5'-untranslated region (UTR). eIF4A1 is required for efficient translation of key oncogenes that contain complex secondary structures within the 5'-UTR. eFT226 is a novel, potent and selective eIF4A small molecule inhibitor with excellent physicochemical and pharmaceutical properties. The design of eFT226 involved ab initio ligand-based methods coupled with small molecule crystal structure analysis. eFT226 inhibits eIF4A1 through a reversible sequence-selective enhancement of eIF4A1 binding to mRNA with specific polypurine motifs within the 5'-UTR. The formation of a stable ternary complex [eIF4A1/eFT226/mRNA] with specific sequence recognition motifs leads to a block in ribosome scanning of select mRNAs. Treatment of lymphoma, AML, breast, colorectal, lung and hepatocellular tumor cell lines with eFT226 led to a dose dependent translational down regulation (IC50 of ~5-20 nM) of key oncogenes that drive tumor cell survival and proliferation (i.e., c-MYC, CCND1, BCL2 and MCL-1). Oncogene down regulation results in potent inhibition of cellular proliferation (GI50 of ~2-30 nM) across a panel of tumor cell lines. Enhanced anti-tumor sensitivity and a rapid induction of apoptosis was observed in hematological cell lines including lymphoma and AML. Inhibition of tumor cell proliferation and survival with eFT226 treatment results in significant antitumor activity in vivo in multiple human tumor models of DLBCL, Burkitt's lymphoma, acute myeloid leukemia (AML), and solid tumors following ≤ 1 mg/kg/week IV administration. eFT226 regulates the protein expression of multiple metabolic markers (i.e. c-MYC, HK2, TXNIP and GLUT1) that result in inhibition of tumor glucose uptake supporting the use of 18F-FDG-PET imaging as a measure of eFT226 target engagement in the clinic. These data demonstrate that eFT226 is a sequence-selective translational repressor of key oncogenic drivers that are essential for tumor cell proliferation and survival and support the clinical development of eFT226 in cancer patients. Citation Format: Siegfried H. Reich, Peggy A. Thompson, Justin T. Ernst, Boreth Eam, Nathan P. Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Ana Parra, Eric Sung, Jocelyn Staunton, Ivy Nj Hung, Gregory S. Parker, Gary G. Chiang, Christopher J. Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K. Packard, Theodore Michels, Paul A. Sprengeler, Kevin R. Webster. eFT226: A selective and highly potent inhibitor of eukaryotic initiation factor 4A (eIF4A), a novel approach for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT02-05.

Background and Purpose— We aimed at providing estimates of mortality associated with cardiometabolic comorbidity and incident readmission from cardiometabolic as compared with noncardiometabolic conditions after a first transient ischemic attack. Methods— Between 2000 and 2015, patients hospitalized for a first transient ischemic attack were examined for cardiometabolic comorbidities (diabetes mellitus, coronary artery disease, heart failure, and atrial fibrillation), 5-year incident hospitalization, and time to death. Results— Of 251 patients with transient ischemic attack, 134 (53%) had at least 1 and 55 (22%) had at least 2 cardiometabolic conditions. By 5 years, 491 readmissions (134 [27%] cardiometabolic and 357 [73%] noncardiometabolic) and 75 deaths (27 [36%] cardiometabolic and 47 [64%] noncardiometabolic) were observed. Mortality was increased with any concurrent cardiometabolic comorbidity (hazard ratio, 1.89; 95% confidence interval, 1.17–3.03; P =0.0089) with multiplicative mortality risk from a combination of coronary artery disease and heart failure. Each hospitalization was associated with a 1.5-fold risk of death (95% confidence interval, 1.37–1.64; P Conclusions— Among patients hospitalized for first transient ischemic attack, 5-year mortality is associated with concurrent cardiometabolic comorbidity and rates of subsequent hospitalization.

Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18–91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a “red flag” justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented.

Background The prevalence and clinical impact of chronic conditions (CCs) have increasingly been recognized as an important public health concern. We evaluated the prevalence of coexisting CCs and their association with 30-day mortality and readmission in hospitalized patients with stroke and transient ischemic attack (TIA). Methods In a retrospective study of patients aged ≥18 years hospitalized for first-ever stroke and TIA, we assessed the prevalence of coexisting CCs and their predictive value for subsequent 30-day mortality and readmission. Results Study cohort comprised 6771 patients, hospitalized for stroke (n = 4068) and TIA (n = 2703), 51.4% men, with mean age of 68.2 years (standard deviation: ±15.6), mean number of CCs of 2.9 (±1.7), 30-day mortality rate of 8.6% (entire cohort), and 30-day readmission rate of 9.7% (in 2498 patients limited to Olmsted and surrounding counties). In multivariable models, significant predictors of (1) 30-day mortality were coexisting heart failure (HF) (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.09-1.92), cardiac arrhythmia (OR: 1.74, 95% CI: 1.40-2.17), coronary artery disease (CAD) (OR: 1.64, 95% CI: 1.29-2.08), cancer (OR: 1.67, 95% CI: 1.31-2.14), and diabetes (HR: 1.28, 95% CI: 1.01-1.62); and (2) 30-day readmission (n = 2498) were CAD (OR: 1.50, 95% CI: 1.09-2.07), cancer (OR: 1.46, 95% CI: 1.01-2.10), and arthritis (OR: 1.62, 95% CI: 1.09-2.40). Conclusions In patients hospitalized with stroke and TIA, CCs are highly prevalent and influence 30-day mortality and readmission. Optimal therapeutic and lifestyle interventions for CAD, HF, cardiac arrhythmia, cancer, diabetes, and arthritis may improve early clinical outcome.

RATIONALE, AIMS, AND OBJECTIVES Novel health care delivery models are needed to reduce health care use while delivering effective and safe care. We developed a model of a neurologist integrated and colocated in primary care leveraging "curbside," electronic, and traditional consultations. Our objective was to examine the impact on health care resource use of diagnostic testing and referrals for face-to-face neurological consultation and adverse outcomes associated with electronic and curbside consultations. METHODS Consecutive patients from December 1, 2014, to March 13, 2015, were included in the analysis about whom contact was made between a primary care clinician and a colocated neurologist. RESULTS Over 3.5 months of the pilot, 359 unique patients generated 429 consultations (179 curbsides, 68 electronic consultations, and 182 face-to-face visits). The integrated model resulted in avoidance of 78 face-to-face tertiary neurology consultations, 39 brain magnetic resonance imaging, 50 electromyograms, and 53 other advanced imaging studies. Earlier curbside consultation may have prevented unnecessary testing or face-to-face tertiary neurology consultations in 40 (22%) patients. Earlier face-to-face consultation may have avoided expensive testing in 31 (17%) patients. No cases met criteria for an adverse outcome. The number of referrals to tertiary neurology declined by 64%, and the total number of face-to-face visits per month declined by 25%. CONCLUSION Colocated neurology in a primary care medical home offers a promising intervention to deliver high-value care.

Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK−/− EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation.

Mutations or amplifications affecting receptor tyrosine kinases (RTKs) activate the RAS/MAPK and PI3K/AKT signaling pathways thereby promoting cancer cell proliferation and survival. Oncoprotein expression is tightly controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex consisting of eIF4A, eIF4E, and eIF4G. eIF4A functions to catalyze the unwinding of secondary structure in the 5'-untranslated region (5'-UTR) of mRNA facilitating ribosome scanning and translation initiation. The activation of oncogenic signaling pathways, including RAS and PI3K, facilitate formation of eIF4F and enhance eIF4A activity promoting the translation of oncogenes with highly structured 5'-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a selective eIF4A inhibitor that converts eIF4A into a sequence specific translational repressor by increasing the affinity between eIF4A and 5'-UTR polypurine motifs leading to selective downregulation of mRNA translation. The polypurine element is highly enriched in the 5'-UTR of eFT226 target genes, many of which are known oncogenic drivers, including FGFR1,2 and HER2, enabling eFT226 to selectively inhibit dysregulated oncogene expression. Formation of a ternary complex [eIF4A-eFT226-mRNA] blocks ribosome scanning along the 5'-UTR leading to dose dependent inhibition of RTK protein expression. The 5'-UTR sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating 10-45-fold greater sensitivity for reporter constructs containing an RTK 5'-UTR compared to a control. In solid tumor cell lines driven by alterations in FGFR1, FGFR2 or HER2, downregulation of RTK expression by eFT226 resulted in decreased MAPK and AKT signaling, potent inhibition of cell proliferation and an induction of apoptosis suggesting that eFT226 could be effective in treating tumor types dependent on these oncogenic drivers. Solid tumor xenograft models harboring FGFR1,2 or HER2 amplifications treated with eFT226 resulted in significant in vivo tumor growth inhibition and regression at well tolerated doses in breast, non-small cell lung and colorectal cancer models. Treatment with eFT226 also decreased RTK protein levels supporting the potential to use these eFT226 target genes as pharmacodynamic markers of target engagement. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to eFT226. The association of eFT226 activity in RTK tumor models with mTOR pathway activation provides a means to further enrich for sensitive patient subsets during clinical development. Clinical trials with eFT226 in patients with solid tumor malignancies have initiated. Citation Format: Peggy A. Thompson, Nathan P. Young, Adina Gerson-Gurwitz, Boreth Eam, Vikas Goel, Craig R. Stumpf, Joan Chen, Gregory S. Parker, Sarah Fish, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G. Chiang, Kevin R. Webster. Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1,2 and HER2 driven cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3399.

AMPK, a conserved sensor of low cellular energy. can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine Kras(G12D) mediated non-small cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor - the predominant upstream activating kinase of AMPK and twelve related kinases. Unlike LKB1 deletion, AMPK deletion in Kras(G12D) lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in Kras(G12D) p53(f/f) tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of Kras(G12D) dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC.

Background The implications of early readmission on long‐term mortality after transient ischemic attack (TIA) are not known. We aimed at examining the effect of 180‐day readmission on subsequent long‐term mortality after index hospitalization for TIA. Methods A retrospective study of patients hospitalized for first‐ever TIA at Mayo Clinic from 2000 through 2017. Patients readmitted within 180 days postdischarge were compared with those not readmitted in long‐term risk of death. Results Of 251 TIA patients aged 73 ± 15 years with 1509 person‐years of follow‐up, 65 (26%) were readmitted within 180 days of discharge and 125 died during a median follow‐up of 5.7 years. The mortality was 10 vs. 7 deaths per 100 person‐years in patients who were readmitted compared to those who were not readmitted with hazard ratio (HR) 1.73 (95% confidence interval [CI] 1.13–2.66). Other competing predictors of mortality were age ≥65 years (HR 5.70, 95% CI 2.72–11.96), cancer (HR 1.65, 95% CI 1.03–3.38), chronic obstructive pulmonary disease (HR 1.90, 95% CI 1.07–3.38), heart failure (HR 3.03, 95% CI 1.82–5.06), dementia (HR 5.87, 95% CI 3.27–10.52), creatinine ≥1.4 mg/dl (HR 1.89, 95% CI 1.17–3.06), and hemoglobin level

Background:The primary care medical home (PCMH) aims to promote delivery of high-value health care. However, growing demand for specialists due to increasingly older adults with complicated and chronic disease necessitates development of novel care models that efficiently incorporate specialty expertise while maintaining coordination and continuity with the PCMH. We describe the effect of a model of integrated community neurology (ICN) on health care utilization, diagnostic testing, and access.Methods:This is a retrospective, matched case-control comparison of patients referred to ICN for a face-to-face consultation over a 12-month period. The control group consisted of propensity score–matched patients referred to a non-colocated neurology practice during the study period. Administrative data were used to assess for diagnostic testing, visit utilization, and patient time to appointment.Results:From October 1, 2014, to September 30, 2015, we identified 459 patients evaluated by ICN for a face-to-face visit and 459 matched controls evaluated by the non-colocated neurology practice. The majority of patients were Caucasian and female. ICN patients had lower odds of EMGs ordered (adjusted odds ratio [OR] 0.64; 95% confidence interval [CI] 0.46–0.89; p = 0.009), MRI brain (adjusted OR 0.60; 95% CI 0.45–0.79; p = 0.0004), or subsequent referral to outpatient neurology (adjusted OR 0.62; 95% CI 0.47–0.83; p = 0.001). ICN was not associated with an increase in emergency department visits, hospitalizations, or appointment wait time.Conclusions:The ICN model in a PCMH has the potential to reduce diagnostic testing and utilization.

Background: Chronic illness is often comorbid with the psychological state of loneliness. Models of care for patients who experience chronic migraines may often lack an understanding of psychosocial influences of the illness. Addressing the effects of loneliness on the health behaviors of chronic migraine patients may further elucidate gaps in care that exist beyond the biomedical approach to migraine treatment. The primary aim of this study was to assess the relationship between loneliness and behavioral health decisions in chronic migraine patients, specifically patient ability to self-manage, and effectiveness of treatments. Methods: We conducted a cross-sectional survey among patients (n = 500) with migraine and assessed for the experience of loneliness by using the University of California, Los Angeles–Revised (UCLA-R) Three-item Loneliness Scale and the extent of migraine-related disability via the Migraine Disability Assessment (MIDAS). Furthermore, we evaluated patients for their ability to self-manage their migraines, and perceived effectiveness of treatment. Results: Nearly half of our population reported at least one measure of loneliness (230/500, 46.0%). Patients experiencing chronic migraine were statistically more likely to report feeling lonely when compared to patients with episodic migraines ( P < .001). Patients who report loneliness had lower odds of feeling ’very satisfied” with their ability to self-manage their migraine symptoms (aOR = 0.34, 95% CI 0.14-0.81) and had lower odds of feeling “very satisfied” with their ability to avoid conditions that cause their headache (aOR = 0.39, 95% CI 0.16-0.91). Conclusions: Loneliness has significant effects on the illness experience of patients with chronic migraines, including their ability to self-manage or be satisfied with their current state of care. Psychosocial models of care that address loneliness among patients with chronic migraine may help improve health outcomes and management.

Background: Mutations or amplifications affecting receptor tyrosine kinases (RTKs) activate the RAS/MAPK and PI3K/AKT signaling pathways thereby promoting cancer cell proliferation and survival. Oncoprotein expression is tightly controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex consisting of eIF4A, eIF4E, and eIF4G. eIF4A functions to catalyze the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA facilitating ribosome scanning and translation initiation. eFT226 is a first in class inhibitor that converts eIF4A1 into a sequence specific translational repressor. eFT226 increases the affinity between eIF4A1 and polypurine recognition elements in the 5’-UTR leading to selective downregulation of mRNA translation. The polypurine element is highly enriched in the 5’-UTR of eFT226 target genes, many of which are known oncogenic drivers, including FGFR1/2 and HER2, enabling eFT226 to selectively inhibit dysregulated oncogene expression. Methods: 5’-UTR dependency was evaluated using cell-based luciferase reporter assays. Regulation of protein expression was analyzed by western blot analysis. Antitumor activity was assessed in vitro by proliferation and apoptosis assays. For in vivo experiments, athymic nude or NOD/SCID mice were implanted with subcutaneous xenograft models of FGFR1, FGFR2 or HER2 driven tumors and treated with eFT226 administered Q4D IV. Results: eFT226 inhibits the translation of FGFR1, FGFR2 and HER2 through formation of a sequence dependent ternary complex with eIF4A1 and polypurine elements within the 5’-UTR of mRNA [eFT226-eIF4A1-mRNA]. Formation of this ternary complex blocks ribosome scanning along the 5’-UTR leading to dose dependent inhibition of RTK protein expression. Cells transiently transfected with luciferase reporter constructs containing the 5’-UTR of each RTK resulted in 10-45-fold greater sensitivity to inhibition by eFT226 compared to a control 5’-UTR confirming the 5’-UTR dependency. In solid tumor cell lines driven by alterations in FGFR1, FGFR2 or HER2, downregulation of RTK expression by eFT226 resulted in decreased MAPK and AKT signaling, potent inhibition of cell proliferation and an induction of apoptosis suggesting that eFT226 could be effective in treating tumor types dependent on these oncogenic drivers. Solid tumor xenograft models harboring FGFR1/2 or HER2 amplifications treated with eFT226 resulted in significant in vivo tumor growth inhibition and regression at well tolerated doses in breast, non-small cell lung and colorectal cancer models. Treatment with eFT226 also decreased RTK protein levels supporting the potential to use these eFT226 target genes as pharmacodynamic markers of target engagement. Conclusions: eFT226 is efficacious against tumor models with alterations in FGFR1, FGFR2 and HER2 RTKs. The antitumor response observed in preclinical in vivo models driven by RTK amplifications demonstrates the potential for eFT226 in the treatment of solid tumors with FGFR1/2 or HER2 alterations. Furthermore, this data provides a means to select sensitive patient subsets during clinical development. Clinical trials in patients with solid tumor malignancies are planned. Citation Format: Peggy A Thompson, Nathan P Young, Craig R Stumpf, Boreth Eam, Vikas K Goel, Joan Chen, Sarah Fish, Gregory S Parker, Adina Gerson-Gurwitz, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G Chiang, Christopher J Wegerski, Samuel Sperry, Kevin R Webster, Siegfried H Reich. eFT226, a first in class inhibitor of eIF4A1, targets FGFR1/2 and HER2 driven cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B133. doi:10.1158/1535-7163.TARG-19-B133

Tumor development is often characterized by dysregulated messenger RNA (mRNA) translation of key oncogenic factors that promote increased proliferation, resistance to apoptosis and enhanced metastatic potential. The eukaryotic translation initiation factor 4F (eIF4F) complex, a master regulator of protein synthesis, is comprised of eIF4E (mRNA-cap-binding protein), eIF4A (RNA-helicase), and eIF4G (scaffolding protein), that together orchestrate mRNA recruitment to ribosomal subunits as well as efficient scanning of the mRNA 5’-untranslated region. As a downstream target of growth-promoting signaling cascades, eIF4F also serves as a central node in several important oncogenic pathways including KRAS and PI3K/mTOR. eIF4F subunits are frequently over-expressed in various malignancies; therefore, repressing eIF4F activity has emerged as a promising anti-cancer therapeutic strategy. eFT226 is a potent and selective translational regulator that targets eIF4A1. eFT226 down-regulates the translation of a unique gene set and displays robust anti-tumor activity across multiple models in vitro and in vivo. A functional genomic screen using CRISPR/Cas9 was performed to discover synthetic lethal genetic interactions with eFT226 to enable development of novel drug combination and/or patient selection strategies. The screen was conducted in a panel of non-small cell lung cancer (NSCLC) cell lines driven by oncogenic KRAS and p53 pathway mutations, a tumor subtype with limited therapeutic options. Utilizing a focused guide RNA (gRNA) lentiviral library of ~700 cancer-related targets with diverse roles in growth-factor signaling, metabolism, epigenetics, translation and stress-responses, several genetic perturbations that sensitized tumor cells to eFT226 were uncovered. Interestingly, many of the genes whose loss-of-function enhanced eFT226’s activity fall into distinct classes including an oncogenic signaling pathway commonly activated in many cancers as well as redox homeostasis. Moreover, a number of these targets include tumor suppressor genes that are frequently mutated or inactivated through loss of function in certain cancer types suggesting that specific genetic contexts may dictate eFT226 efficacy. Ongoing studies are aimed at confirming these hits from the primary screen. Collectively, these validated targets will represent genomic vulnerabilities to eFT226 that can aid in the design of drug combination and patient selection strategies for NSCLC. Citation Format: Nathan P. Young, Craig R. Stumpf, Joan Chen, Gary G. Chiang, Peggy A. Thompson, Kevin R. Webster. A focused CRISPR screen to identify synthetic lethal interactions with the novel eIF4A inhibitor eFT226 in KRAS driven NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4343.

Chimeric antigen receptor (CAR) T cells have shown great promise in treating hematopoietic malignancies, such as leukemia and non-Hodgkin’s lymphoma. The efficacy and durability of CAR T cell therapy have been correlated with higher levels of T stem cell memory (TSCM) and T central memory (TCM) populations. Accordingly, various strategies to enrich these CAR T cell populations are of intense interest. It is well-established that the PI3K/mTOR pathway plays an important role in T cell activation and differentiation, and perturbations in this pathway can enhance T cell memory populations. Work from our group has demonstrated that MNK modifies mTOR signaling and T cell differentiation. Here, we demonstrate that the MNK1/2 inhibitor tomivosertib can substantially increase TCM and TSCM populations in both primary murine and human T cells. Tomivosertib treatment of murine OT-I T cells biases T cell differentiation towards a TCM (CD8+ CD44+ CD62L+) population upon SIINFEKL peptide stimulation in vitro without adverse effects on T cell proliferation, interferon-γ production or cytotoxic function. Similar effects are seen in vivo, where tomivosertib treatment also enriches the TCM cell pool in a SIINFEKL vaccine-induced OT-I adoptive T cell transfer model, which results in increased persistence as demonstrated by a higher memory-recall T cell response upon re-challenge. Furthermore, addition of tomivosertib during production of human CAR (anti-CD19 scFv-4-1BB-CD3ζ) T cells leads to a significantly increased population of TSCM (CD8+ CD45RO CD45RA+ CD27+ CD95+) cells. Based on these data, the combination of tomivosertib with CD19-directed CAR T cells was assessed in the CD19+ Pfeiffer DLBCL model in vivo. Daily oral administration of tomivosertib in combination with CD19-directed CAR T cells results in improved efficacy in comparison to either monotherapy alone, consistent with tomivosertib promoting and maintaining TSCM populations in vivo. Tomivosertib is currently in multiple Phase II clinical trials as a monotherapy or in combination with checkpoint inhibitors. Citation Format: Vikas K. Goel, Rajesh K. Sharma, Jocelyn Staunton, Craig R. Stumpf, Nathan P. Young, Peggy A. Thompson, Gary G. Chiang, Kevin R. Webster. Tomivosertib (eFT508), a potent and highly selective inhibitor of MNK1 and MNK2, enhances CAR T cell activity through modulating T cell differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-068.

Dysregulated messenger RNA (mRNA) translation drives the pathogenesis of multiple hematological malignancies. In lymphoma this includes the upregulation of key driver oncogenes and anti-apoptotic proteins (e.g., MYC, CCND1/3, BCL2 and MCL1) that contain a highly structured 5’-untranslated region (UTR) in their mRNA requiring enhanced eIF4A helicase activity for translation. eIF4A is a component of the eIF4F translation initiation complex and catalyzes the ATP-dependent unwinding of RNA duplexes and facilitates 43S ribosome scanning within the 5’-UTR. The activation of oncogenic signaling pathways, including RAS and PI3K, enhance eIF4A activity through phosphorylation of eIF4B, eIF4G and PDCD4 which facilitates formation of eIF4F and full activation of eIF4A. The PI3K/AKT/mTOR pathway is frequently activated in lymphoma, promoting the translation of oncogenes with complex 5’-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a potent and sequence selective eIF4A1 inhibitor that promotes eIF4A1 binding to specific 5’-UTR polypurine and/or G-quadraplex recognition motifs leading to a selective block in ribosome mRNA scanning. The sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating >100-fold greater sensitivity for reporter constructs containing a polypurine motif in the 5’-UTR (IC50 ~2 nM). Direct binding studies also confirmed the formation of a stable ternary complex with increased drug residence time between eFT226, eIF4A1 and RNA oligonucleotides containing polypurine motifs. The ability of eFT226 to inhibit MYC or MCL1 expression was found to be dependent on the presence of their respective 5’-UTR supporting a translational regulation mechanism dependent on recognition elements within the 5’-UTR. eFT226 shows potent anti-proliferative activity (GI50 < 15 nM) against a panel of B-cell lymphoma cell lines. Treatment with eFT226 leads to coordinated inhibition of MYC, CCND1/3, BCL2 or MCL1 protein expression resulting in significant anti-tumor activity. eFT226 has good pharmacokinetic properties and exhibits significant in vivo activity across a panel of diffuse large B cell lymphoma (DLBCL), and Burkitt lymphoma tumor models with ≤1 mg/kg/week IV administration. Further evaluation of predictive markers of sensitivity or resistance has shown that tumors with mTOR mediated activation of eIF4A are most sensitive to eFT226. In addition, tumors with PTEN mutations do not exhibit activated eIF4A and are generally resistant to induction of apoptosis by eFT226, resulting in reduced in vivo efficacy. The association of eFT226 activity with PI3K/mTOR pathway activation and mutational status provides a means to identify patient subsets during clinical development. Clinical trials in patients with lymphoma and other malignancies are planned. Citation Format: Peggy A. Thompson, Boreth Eam, Nathan P. Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Eric Sung, Ana Parra, Jocelyn Staunton, Gary G. Chiang, Christopher J. Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Chinh Tran, Christian Nilewski, Garrick K. Packard, Theodore Michels, Paul A. Sprengeler, Justin T. Ernst, Siegfried H. Reich, Kevin R. Webster. eFT226, a potent and selective inhibitor of eIF4A, is efficacious in preclinical models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2698.

A 73-year-old, right-handed man presented with new-onset right visual field diminution and visual hallucinations. Examination showed a right homonymous hemianopia without cognitive impairment. Brain imaging showed left occipital cortex abnormalities (figure, A and B). EEG showed sleep-predominant, periodic left occipital spikes and an occipital photoparoxysmal response (figure, C and D). A second-generation RT-QulC (real-time quaking-induced conversion) test detected pathogenic prion proteins in the CSF, confirming Creutzfeldt-Jakob disease (CJD).

Novel health care delivery models are needed to reduce health care use while delivering effective and safe care. We developed a model of a neurologist integrated and colocated in primary care leveraging "curbside," electronic, and traditional consultations. Our objective was to examine the impact on health care resource use of diagnostic testing and referrals for face-to-face neurological consultation and adverse outcomes associated with electronic and curbside consultations.Consecutive patients from December 1, 2014, to March 13, 2015, were included in the analysis about whom contact was made between a primary care clinician and a colocated neurologist.Over 3.5 months of the pilot, 359 unique patients generated 429 consultations (179 curbsides, 68 electronic consultations, and 182 face-to-face visits). The integrated model resulted in avoidance of 78 face-to-face tertiary neurology consultations, 39 brain magnetic resonance imaging, 50 electromyograms, and 53 other advanced imaging studies. Earlier curbside consultation may have prevented unnecessary testing or face-to-face tertiary neurology consultations in 40 (22%) patients. Earlier face-to-face consultation may have avoided expensive testing in 31 (17%) patients. No cases met criteria for an adverse outcome. The number of referrals to tertiary neurology declined by 64%, and the total number of face-to-face visits per month declined by 25%.Colocated neurology in a primary care medical home offers a promising intervention to deliver high-value care.

The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras G12D in vivo has not been examined. Using compound mutant mice containing the Arf GFP reporter and the spontaneously activating K-ras LA2 allele, we have uncovered dramatic tissue specificity of K-ras G12D -dependent p19 Arf up-regulation. Lung tumors, which can arise in the presence of functional p19 Arf , rarely display p19 Arf induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19 Arf -p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19 Arf induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.

Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic idiopathic inflammatory demyelinating disease. Available diagnostic criteria do not reliably distinguish it from first presentations of relapsing diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this article, we review current concepts about ADEM and what distinguishes it from other idiopathic inflammatory demyelinating disease, and we highlight controversial aspects and diagnostic problems. We review pathological differences between ADEM and MS in terms of their utility in the diagnosis of ADEM. Finally, we present a practical approach for management of patients suspected of having ADEM when the diagnosis is uncertain.

How to shape mitochondrial networks Mitochondria undergo fragmentation or fusion in response to changes in cellular metabolism. Toyama et al. report that adenosine monophosphate-activated protein kinase (AMPK) is both necessary and sufficient to control mitochondrial fragmentation. AMPK functions as a sensor to monitor the energy status of the cell by phosphorylating mitochondrial fission factor (MFF), a protein of the mitochondrial outer membrane. MFF then acts to recruit a cytoplasmic guanosine triphosphatase that promotes mitochondrial fission. Science , this issue p. 275

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

We review the spectrum of mononeuropathies caused by extraneural (EG) and intraneural (IG) ganglia and their pathogenesis according to the unifying articular (synovial) theory. Peroneal neuropathy at the knee is highlighted as the most common mononeuropathy due to IG. These cysts are an underrecognized cause of common peroneal neuropathy and a prototype for understanding the diagnosis and treatment of neuropathy due to ganglia in all locations. The clinical, electrophysiologic, and imaging presentations are discussed to facilitate the diagnosis of peroneal IG as well as other mononeuropathies due to ganglia at other sites for physicians in clinical practice.

We describe a case of painful radial mononeuropathy due to focal heterotopic ossification with diagnostic imaging, intraoperative illustration, and literature review.

Background: The locked-in syndrome is typically caused by basilar artery thrombosis, resulting in ventral pontine infarction. Infectious basilar arteritis is a rare alternative etiology. Case Summary: We present a 24-year-old female with a prodrome of facial pain without fever or meningismus, who developed a locked-in syndrome due to an invasive fungal infection after bone marrow transplantation. The clinical course and neuroimaging demonstrating sinusitis with adjacent pontine infarction but without basilar artery thrombosis are presented. The infectious differential diagnosis and management of invasive fungal infection are discussed. Conclusion: Facial pain without fever or meningismus may be an early symptom of invasive fungal rhinosinusitis, which may involve small basilar pontine perforating arteries, leading to a locked-in syndrome in immunosuppressed patients. Early recognition and treatment may prevent life-threatening neurologic complications.

It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-ras[superscript G12D] with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-ras[superscript G12D] activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell-cycle arrest as an extremely potent tumor suppressor mechanism., National Institutes of Health (U.S.) (grant 5-U01-CA84306), National Cancer Institute (U.S.) (Cancer Center Support (core) Grant P30-CA14051), Howard Hughes Medical Institute (Investigator), Virginia and D.K. Ludwig Fund for Cancer Research (Scholar)