Structural network heterogeneities and network dynamics: a possible dynamical mechanism for hippocampal memory reactivation

The hippocampus has the capacity for reactivating recently acquired memories [1-3] and it is hypothesized that one of the functions of sleep reactivation is the facilitation of consolidation of novel memory traces [4-11]. The dynamic and network processes underlying such a reactivation remain, however, unknown. We show that such a reactivation characterized by local, self-sustained activity of a network region may be an inherent property of the recurrent excitatory-inhibitory network with a heterogeneous structure. The entry into the reactivation phase is mediated through a physiologically feasible regulation of global excitability and external input sources, while the reactivated component of the network is formed through induced network heterogeneities during learning. We show that structural changes needed for robust reactivation of a given network region are well within known physiological parameters [12,13].Comment: 16 pages, 5 figure

“\u3cb\u3ePICO\u3c/b\u3e”: \u3cb\u3eP\u3c/b\u3eractice EBM skills, \u3cb\u3eI\u3c/b\u3encrease student interests with \u3cb\u3eC\u3c/b\u3eollaboration of librarians and improve \u3cb\u3eO\u3c/b\u3eutcomes

Available literature on teaching evidence-based medicine (EBM) to medical students focuses on teaching critical appraisal skills, often in the context of a journal club, workshops or lectures. Being able to utilize EBM effectively means that a learner is able to take a clinical scenario, develop a clinically relevant question, search for the evidence, appraise that evidence, and apply the results of this appraisal back to the individual patient. Hence EBM activity is more likely to become a part of clinical decision-making if medical students practice the skills in the context of direct patient care

Evidence-Based Practice for Medical Students in a Family Medicine Clerkship: Collaborative, Active Learning for Clinical Decision Skills

Objectives: This active learning experience was designed to enhance the information literacy knowledge and skills of medical students for patient-centered, evidence-based decisions at the point of care. It includes formulating clinical questions using patient/problem, intervention, comparison, outcome (PICO), accessing the highest level of evidence-based medicine (EBM) information available in an effective manner, and evaluating the information in relation to a specific patient in an outpatient setting. Methods: Third-year medical students participate in a small-group collaborative, patient-centered learning experience during the family medicine clerkship, coordinated by the clerkship directors with participation by two medical librarians. At orientation, the clerkship directors provide the students with an overview of the evidence-based process and creating PICO questions. Librarians then direct a hands-on instruction session covering evidence-based resources and search strategies for finding point-of-care EBM information. Students select a clinical question from a patient encounter in their outpatient clinics. Each student submits a worksheet providing the PICO question, resources consulted, search strategy, selected bibliographic references, and clinical recommendations for their patient. Librarians provide a written assessment and suggestions for improvement relative to the students\u27 search strategies and resource selections. Students then present their patient clinical question, research, and recommendations to the clinical faculty and student group. Results: In the most recent 6 months of this course, 85% of the 55 students participating were rated as “competent” in the areas of resource selection and literature searching on their EBM assignment. Pre- and post-tests results indicate that a majority of the students had an increased familiarity with and appreciation of key evidence-based medicine resources such as Cochrane Reviews, ACP PIER, and FPIN after completing the EBM assignment. Student evaluations reflect increased interest and value in EBM through this experience. Conclusion: Providing an active learning, patient-centered experience with collaboration between clinical faculty and medical librarians has been successful in improving third-year medical student knowledge and skills in medical information literacy for clinical decision making. The project has also provided useful data for ongoing discussions with the college of medicine regarding increasing the longitudinal role of the library throughout the curriculum

Aminorex Identified in Horse Urine Following Consumption of \u3cem\u3eBarbarea vulgaris\u3c/em\u3e; a Preliminary Report

Background: Aminorex, (RS)-5- Phenyl-4,5-dihydro-1,3-oxazol-2-amine, is an amphetamine-like anorectic and in the United States a Drug Enforcement Administration [DEA] Schedule 1 controlled substance. Aminorex in horse urine is usually present as a metabolite of Levamisole, an equine anthelmintic and immune stimulant. Recently, Aminorex identifications have been reported in horse urine with no history or evidence of Levamisole administration. Analysis of the urine samples suggested a botanical source, directing attention to the Brassicaceae plant family, with their contained GlucoBarbarin and Barbarin as possible sources of Aminorex. Since horsepersons face up to a 1 year suspension and a $10,000.00 fine for an Aminorex identification, the existence of natural sources of Aminorex precursors in equine feedstuffs is of importance to both individual horsepersons and the industry worldwide. Results: Testing the hypothesis that Brassicaceae plants could give rise to Aminorex identifications in equine urine we botanically identified and harvested flowering Kentucky Barbarea vulgaris, (“Yellow Rocket”) in May 2018 in Kentucky and administered the plant orally to two horses. Analysis of post-administration urine samples yielded Aminorex, showing that consumption of Kentucky Barbarea vulgaris can give rise to Aminorex identifications in equine urine. Conclusions: Aminorex has been identified in post administration urine samples from horses fed freshly harvested flowering Kentucky Barbarea vulgaris, colloquially “Yellow Rocket”. These identifications are consistent with occasional low concentration identifications of Aminorex in equine samples submitted for drug testing. The source of these Aminorex identifications is believed to be the chemically related Barbarin, found as its precursor GlucoBarbarin in Kentucky Barbarea vulgaris and related Brassicaceae plants worldwide

Feasibility of Using Ring-Mounted Halcyon Linac for Single-Isocenter/Two-Lesion Lung Stereotactic Body Radiation Therapy

PURPOSE: To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of single-isocenter/two-lesion lung stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Sixteen previously treated non-coplanar VMAT single-isocenter/two-lesion lung SBRT plans delivered with SBRT-dedicated C-arm TrueBeam Linac were selected. Prescribed dose was 50 Gy to each lesion over five fractions with treatment delivery every other day and AcurosXB algorithm as the final dose calculation algorithm. TrueBeam single-isocenter plans were reoptimized for Halcyon Linac with coplanar geometry. Both TrueBeam and Halcyon plans were normalized for identical combined target coverage and evaluated. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were compared. The normal lung V5Gy, V10Gy, V20Gy, mean lung dose (MLD), and dose to organs at risk (OAR) were evaluated. Treatment delivery parameters, including beam-on time, were recorded. RESULTS: Halcyon plans were statistically similar to clinically delivered TrueBeam plans. No statistical differences in target conformity, dose heterogeneity, or intermediate-dose spillage were observed (all, p \u3e 0.05). Halcyon plans, on average, demonstrated statistically insignificant reduced maximum dose to most adjacent OAR and normal lung. However, Halcyon yielded statistically significant lower maximal dose to the ribs (p = 0.041) and heart (p = 0.026), dose to 1 cc of ribs (p = 0.035) and dose to 5 cc of esophagus (p = 0.043). Plan complexity slightly increased as seen in the average increase of total monitor units, modulation factor, and beam-on time by 480, 0.48, and 2.78 min, respectively. However, the estimated overall treatment time was reduced by 2.22 min, on average. Mean dose delivery accuracy of clinical TrueBeam plans and the corresponding Halcyon plans was 98.9 ± 0.85% (range: 98.1%–100%) and 98.45 ± 0.99% (range: 97.9%–100%), respectively, demonstrating similar treatment delivery accuracy. CONCLUSION: SBRT treatment of synchronous lung lesions via single-isocenter VMAT on Halcyon RDS is feasible and dosimetrically equivalent to clinically delivered TrueBeam plans. Halcyon provides excellent plan quality and shorter overall treatment time that may improve patient compliance, reduce intrafraction movement, improve clinic efficiency, and potentially offering lung SBRT treatments for underserved patients on a Halcyon only clinic

Fast Generation of Lung SBRT Plans with a Knowledge-Based Planning Model on Ring-Mounted Halcyon Linac

PURPOSE: To demonstrate fast treatment planning feasibility of stereotactic body radiation therapy (SBRT) for centrally located lung tumors on Halcyon Linac via a previously validated knowledge-based planning (KBP) model to support offline adaptive radiotherapy. MATERIALS/METHODS: Twenty previously treated non-coplanar volumetric-modulated arc therapy (VMAT) lung SBRT plans (c-Truebeam) on SBRT-dedicated C-arm Truebeam Linac were selected. Patients received 50 Gy in five fractions. c-Truebeam plans were re-optimized for Halcyon manually (m-Halcyon) and with KBP model (k-Halcyon). Both m-Halcyon and k-Halcyon plans were normalized for identical or better target coverage than clinical c-Truebeam plans and compared for target conformity, dose heterogeneity, dose fall-off, and dose tolerances to the organs-at-risk (OAR). Treatment delivery parameters and planning times were evaluated. RESULTS: k-Halcyon plans were dosimetrically similar or better than m-Halcyon and c-Truebeam plans. k-Halcyon and m-Halcyon plan comparisons are presented with respect to c-Truebeam. Differences in conformity index were statistically insignificant in k-Halcyon and on average 0.02 higher (p = 0.04) in m-Halcyon plans. Gradient index was on average 0.43 (p = 0.006) lower and 0.27 (p = 0.02) higher for k-Halcyon and m-Halcyon, respectively. Maximal dose 2 cm away in any direction from target was statistically insignificant. k-Halcyon increased maximal target dose on average by 2.9 Gy (p \u3c 0.001). Mean lung dose was on average reduced by 0.10 Gy (p = 0.004) in k-Halcyon and increased by 0.14 Gy (p \u3c 0.001) in m-Halcyon plans. k-Halcyon plans lowered bronchial tree dose on average by 1.2 Gy. Beam-on-time (BOT) was increased by 2.85 and 1.67 min, on average for k-Halcyon and m-Halcyon, respectively. k-Halcyon plans were generated in under 30 min compared to estimated dedicated 180 ± 30 min for m-Halcyon or c-Truebeam plan. CONCLUSION: k-Halcyon plans were generated in under 30 min with excellent plan quality. This adaptable KBP model supports high-volume clinics in the expansion or transfer of lung SBRT patients to Halcyon

Using Low-Dose Radiation to Potentiate the Effect of Induction Chemotherapy in Head and Neck Cancer: Results of a Prospective Phase 2 Trial

Purpose: Low-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN). Experimental Design: Two cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity. Results: A total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4). Conclusion: Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy

Radiobiological Evaluation of Intensity Modulated Radiation Therapy Treatments of Patients with Head and Neck Cancer: A Dual-Institutional Study

In clinical practice, evaluation of clinical efficacy of treatment planning stems from the radiation oncologist\u27s experience in accurately targeting tumors, while keeping minimal toxicity to various organs at risk (OAR) involved. A more objective, quantitative method may be raised by using radiobiological models. The purpose of this work is to evaluate the potential correlation of OAR-related toxicities to its radiobiologically estimated parameters in simultaneously integrated boost (SIB) intensity modulated radiation therapy (IMRT) plans of patients with head and neck tumors at two institutions. Lyman model for normal tissue complication probability (NTCP) and the Poisson model for tumor control probability (TCP) models were used in the Histogram Analysis in Radiation Therapy (HART) analysis. In this study, 33 patients with oropharyngeal primaries in the head and neck region were used to establish the correlation between NTCP values of (a) bilateral parotids with clinically observed rates of xerostomia, (b) esophagus with dysphagia, and (c) larynx with dysphagia. The results of the study indicated a strong correlation between the severity of xerostomia and dysphagia with Lyman NTCP of bilateral parotids and esophagus, respectively, but not with the larynx. In patients without complications, NTCP values of these organs were negligible. Using appropriate radiobiological models, the presence of a moderate to strong correlation between the severities of complications with NTCP of selected OARs suggested that the clinical outcome could be estimated prior to treatment

Synthesis and Characterization of \u3cem\u3ed\u3c/em\u3e\u3csub\u3e5\u3c/sub\u3e-Barbarin for Use in Barbarin-Related Research

Based on structural similarities and equine administration experiments, Barbarin, 5-phenyl-2-oxazolidinethione from Brassicaceae plants, is a possible source of equine urinary identifications of aminorex, (R,S)-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, an amphetamine-related US Drug Enforcement Administration (DEA) controlled substance considered illegal in sport horses. We now report the synthesis and certification of d5-barbarin to facilitate research on the relationship between plant barbarin and such aminorex identifications. D5-barbarin synthesis commenced with production of d5-2-oxo-2-phenylacetaldehyde oxime (d5-oxime) from d5-acetophenone via butylnitrite in an ethoxide/ethanol solution. This d5-oxime was then reduced with lithium aluminum hydride (LiAlH4) to produce the corresponding d5-2-amino-1-phenylethan-1-ol (d5-phenylethanolamine). Final ring closure of the d5-phenylethanolamine was performed by the addition of carbon disulfide (CS2) with pyridine. The reaction product was purified by recrystallization and presented as a stable white crystalline powder. Proton NMR spectroscopy revealed a triplet at 5.88 ppm for one proton, a double doublet at 3.71 ppm for one proton, and double doublet at 4.11 ppm for one proton, confirming d5-barbarin as the product. Further characterization by high resolution mass spectrometry supports the successful synthesis of d5-barbarin. Purity of the recrystallized product was ascertained by High Performance Liquid Chromatography (HPLC) to be greater than 98%. Together, we have developed the synthesis and full characterization of d5-barbarin for use as an internal standard in barbarin-related and equine forensic research

A Cluster of Trace-Concentration Methamphetamine Identifications in Racehorses Associated with a Methamphetamine-Contaminated Horse Trailer: A Report and Analysis

Three low concentration methamphetamine “positive” tests were linked to use of a methamphetamine-contaminated trailer to transport the affected horses. This incident establishes methamphetamine as a human-use substance that can inadvertently enter the environment of racing horses, resulting in urinary methamphetamine “positives;” an interim regulatory cut-off of 15 ng/mL for methamphetamine in post-race urine is proposed