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Background: The prognosis for advanced/metastatic triple negative breast cancer (TNBC) remains poor and novel therapeutic strategies are urgently needed to improve outcomes. Insulin resistance and obesity contribute to cancer progression and are independent predictors of worse survival after TNBC diagnosis. Chemotherapy worsens insulin resistance, body mass index, and multiple other metabolic parameters which can paradoxically limit treatment efficacy and survival. Methionine aminopeptidase 2 (MetAP2/p67) is overexpressed in many tumor types and MetAP2 inhibitors exhibit broad anti-tumor activity. Additionally, MetAP2 inhibitors improve insulin resistance, reduce adiposity, and normalize levels of adipokines, attenuating the effects of metabolic dysfunction on tumor growth. Evexomostat (SDX-7320) is a second-generation MetAP2 inhibitor designed to improve drug-like properties and minimize central nervous system toxicities. Evexomostat improved insulin sensitivity, reduced fat mass and normalized adipokine levels in preclinical models of obesity, and reduced tumor growth in preclinical models of TNBC. In phase 1 trials, MetAP2 inhibition combined with chemotherapy was safe and well tolerated, while evexomostat monotherapy partially restored insulin sensitivity, reduced angiogenic factors as well as adipokines and showed anti-metastatic effects in patients with advanced solid tumors. The goal of this phase 2 study is to test whether evexomostat in combination with eribulin chemotherapy prevents worsening of insulin resistance and augments tumor response in patients with metastatic TNBC and concomitant metabolic dysfunction. Methods: This is a single-center, placebo-controlled phase 2 randomized control trial of evexomostat, a MetAP2 inhibitor, in combination with eribulin chemotherapy. Eligible patients must have histologically confirmed metastatic TNBC, measurable disease or ≥1 predominantly lytic bone lesion, baseline metabolic dysfunction defined as hemoglobin A1c >5.5% and/or BMI ≥30 kg/m2, have received ≤2 prior lines of therapy in the advanced/metastatic setting, have ECOG performance status ≤1, and adequate organ function. Patients with uncontrolled or insulin-dependent type II diabetes, or who require combination antihyperglycemic therapy are excluded. During the safety run-in period, 15 patients will be assigned to receive evexomostat 49 mg/m2 every 2 weeks in combination with eribulin 1.4 mg/m2 administered on days 1 and 8 of a 21-day cycle. Upon safety confirmation, an additional 40 patients will be randomized 2:1 to receive evexomostat or placebo in combination with eribulin. The primary endpoint is metabolic efficacy assessed by change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Secondary endpoints include objective response rate, progression-free survival, duration of response, safety and tolerability, patient-reported outcomes, changes in metabolic markers, and changes in body composition parameters. Historically, HOMA-IR scores double during chemotherapy, and this trial will test whether evexomostat will attenuate the expected rise in HOMA-IR. Specifically, the trial will have >90% power to detect a difference between a 1.5-fold change in HOMA-IR in the control arm versus no change in the investigational arm while controlling the Type I error at 5%. This trial opened to accrual in July 2022. A total accrual of 61 patients is planned with a goal of 55 evaluable patients. For any inquiries/questions, please contact Sherry Shen at shens1@mskcc.org. Clinical trial registry number: pending Funding, study drug evexomostat and other support provided by: SynDevRx, Inc. Citation Format: Sherry Shen, Anna Whalen, Mark E. Robson, Larry Norton, Tiffany A. Traina, Neil M. Iyengar. The ARETHA Study: A phase 2 randomized control trial of Eribulin with Evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer and metabolic dysfunction [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-17-02.

Headaches in the post-partum period are common, while new seizures are not. While many causes of post-partum headache are benign, it can be difficult to determine which patients warrant a more comprehensive workup to investigate for serious causes, which may only present later with neurologic sequelae such as new seizures. We suggest that persistent post-dural puncture headaches in the context of intrapartum epidural anesthesia can be suggestive of a serious cause such as intracranial hypotension or subdural hematoma. We describe a case of a 28-year-old G1P1 female presenting with a first-time seizure at 19 days post-partum caused by subdural hematoma from a persistent cerebrospinal fluid leak. This was in the context of a history of typical post-dural puncture headache following delivery. RÉSUMÉLes maux de tête dans la période post-partum sont fréquents, alors que les nouvelles crises ne le sont pas. Bien que de nombreuses causes de céphalées post-partum soient bénignes, il peut être difficile de déterminer quels patients justifient un bilan plus complet pour rechercher les causes graves, qui peuvent ne se présenter que plus tard avec des séquelles neurologiques comme de nouvelles crises. Nous suggérons que les maux de tête persistants post-ponctionnels dans le contexte de l’anesthésie épidurale intra-partum peuvent suggérer une cause grave comme l’hypotension intracrânienne ou un hématome sous-dural. Nous décrivons le cas d’une femme G1P1 de 28 ans qui présente une première crise d’épilepsie 19 jours après l’accouchement causée par un hématome sous-dural causé par une fuite persistante de liquide céphalorachidien. C’était dans le contexte d’une histoire de céphalées typiques après une ponction post-durale après l’accouchement.

Background Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations. Objectives We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool. Methods As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability. Results Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95). Conclusions We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Balínt Syndrome is an acquired disorder manifesting in the inability to recognize several objects at once (simultagnosia), inaccurate visually guided limb movements despite intact motor function (optic ataxia) and the inability to make accurate voluntary saccades to visual targets despite demonstrating unrestricted range of eye movements (ocular motor apraxia). Here we report the first case of a patient presenting with Balínt Syndrome caused by a platelet-derived growth factor receptor A mutation (PDGFRA)-induced Hypereosinophilic Syndrome (HES).

Importance The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear. Objective To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma. Data sources MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction. Study selection Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma. Data extraction and synthesis Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence. Main outcomes and measures Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events. Results Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], -0.06 [95% CI, -0.10 to -0.02]; mean difference in ACQ-7 scale, -0.04 [95% CI, -0.07 to -0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, -0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, -0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence). Conclusions and relevance Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality.