Citations

AbstractObjectivesNeurovascular and neurocritical care emergencies constitute a leading cause of morbidity/mortality. There has been great evolution in this field, including but not limited to extended time‐window therapeutic interventions for acute ischemic stroke. The intent of this article is to evaluate the goals and future direction of clinical rotations in neurovascular and neurocritical care for emergency medicine (EM) residents.MethodsA panel of 13 board‐certified emergency physicians from the Society for Academic Emergency Medicine (SAEM) neurologic emergencies interest group (IG) convened in response to a call for publications—three with fellowship training/board certification in stroke and/or neurocritical care; five with advanced research degrees; three who have been authors on national practice guidelines; and six who have held clinical duties within neurology, neurosurgery, or neurocritical care. A mixed‐methods analysis was performed including a review of the literature, a survey of Council of Emergency Medicine Residency Directors (CORD) residency leaders/faculty and SAEM neuro‐IG members, and a consensus review by this panel of select neurology rotations provided by IG faculty.ResultsThirteen articles for residency neurovascular education were identified: three studies on curriculum, three studies evaluating knowledge, and seven studies evaluating knowledge after an educational intervention. Intervention outcomes included the ability to recognize and manage acute strokes, manage intracerebral hemorrhage, calculate National Institutes of Health Stroke Scale (NIHSS), and interpret images. In the survey sent to CORD residency leaders and neuro‐IG faculty, response was obtained from 48 programs. A total of 52.1% indicated having a required rotation (6.2% general neurology, 2% stroke service, 18.8% neurologic intensive care unit, 2% neurosurgery, 22.9% on a combination of services). The majority of programs with required rotations have a combination rotation (residents rotate through multiple services) and evaluations were positive.ConclusionsVariability exists in the availability of neurovascular/neurocritical care rotations for EM trainees. Dedicated clinical time in neurologic education was beneficial to participants. Given recent advancements in the field, augmentation of EM residency training in this area merits strong consideration.

Study Design: This is a prospective cohort study. Objective: To characterize the accuracy of patient recollection of preoperative symptoms after cervical spine surgery. Summary of Background Data: Recall bias is a well-known source of systematic error. The accuracy of patient recall after cervical spine surgery remains unknown. Methods: Consecutive patients undergoing cervical spine surgery for myelopathy or radiculopathy were enrolled. Neck and arm numeric pain scores and Neck Disability Indices were recorded preoperatively. Patients were asked to recall their preoperative status at either short (<1 y) or long-term (≥1 y) follow-up. Actual and recalled scores were compared using paired t tests and relations were quantified using the Pearson correlation coefficients. Multivariable linear regression was used to identify factors impacting recollection. Results: In total, 73 patients with a mean age of 58.2 years were included. Compared with their preoperative scores, patients showed significant improvement in neck pain [mean difference (MD)=−2.9; 95% confidence intervals (CIs), −3.5 to −2.3], arm pain (MD, −3.4; 95% CI, −4.0 to −2.8), and disability (MD, −12.4%; 95% CI, −16.9 to −7.9). Patient recollection of preoperative status was significantly more severe than actual for neck pain (MD, +1.5; 95% CI, 0.8–2.2), arm pain (MD, +2.3; 95% CI, 1.6–3.0), and disability (MD, +5.8%; 95% CI, 2.4–9.2). Moderate correlation between actual and recalled scores with regard to neck (r=0.41), arm (r=0.50) pain, and disability (r=0.67) was seen. This was maintained across age, sex, and time between date of surgery and recollection. Over 30% of patients switched their predominant symptom from neck-to-arm pain or vice versa on recall of their preoperative symptoms. Conclusions: Relying on patient recollection does not provide an accurate measure of preoperative status after cervical spine surgery. Prospective and not retrospective collection of patient-reported outcomes remain the gold standard to measure and interpret outcomes after cervical spine surgery. Recall bias has the potential to affect patient satisfaction and requires further study.

Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.

Significance Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and patients exhibit high rates of recurrence and mortality in part due to lack of treatment options beyond standard-of-care chemotherapy regimens. In the subset of TNBCs that express estrogen receptor beta (ERβ), ligand-mediated activation of ERβ elicits potent anticancer effects. We report here the elucidation of the ERβ cistrome and transcriptome in TNBC and identify a mechanism whereby ERβ induces cystatin gene expression resulting in inhibition of canonical TGFβ signaling and a blockade of metastatic phenotypes. These findings suggest that ERβ-targeted therapies represent a treatment option for the subset of women with ERβ-expressing TNBC.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long‐term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event‐free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver‐related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5‐year event‐free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5‐year event‐free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5‐year event‐free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5‐year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

Metabolic alterations are increasingly recognized as important novel anti‐cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158‐induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co‐immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158‐mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX‐resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.