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Sport-related concussions (SRCs) affect millions of adolescents and young adults annually in the USA; however, current SRC consensus statements provide limited guidance on academic support for students within higher education.To generate consensus on appropriate academic recommendations for clinicians, students, and academic stakeholders to support university students during their recovery.Panelists participated in three stages of a modified Delphi procedure: the first stage included a series of open-ended questions after reviewing a literature review on post-SRC return-to-learn (RTL) in higher education; the second stage asked panelists to anonymously rate the recommendations developed through the first Delphi stage using a 9-point scale; and the final stage offered panelists the opportunity to change their responses and/or provide feedback based on the group's overall ratings.Twenty-two panelists including clinicians, concussion researchers, and academic stakeholders (54.5% female) from 15 institutions and/or healthcare systems participated in a modified Delphi procedure. A total of 42 statements were developed after round one. Following the next two rounds, 27 statements achieved consensus amongst the panel resulting in the four-stage Post-Concussion Collegiate RTL Protocol.There are several unique challenges when assisting university students back to the classroom after SRC. Explicit guidelines on when to seek additional medical care (e.g., if they are experiencing worsening or persistent symptoms) and how to approach their instructor(s) regarding academic support may help the student self-advocate. Findings from the present study address barriers and provide a framework for universities to facilitate a multidisciplinary approach amongst medical and academic stakeholders.

Supplementary Table S1. AML patients. Supplementary Table S2. RT-qPCR primers. Supplementary Table S3. IC50 concentrations (nM) of FLT3 inhibitors, PP2A activators and GSK-3beta inhibitors. Supplementary Figure S1. Concurrent PP2A-activating drug treatment increases cytotoxicity of FLT3 inhibitors in Ba/F3-ITD cells with FLT3-ITD and in an MV4-11 orthotopic mouse model. Supplementary Figure S2. Chou-Talalay analysis of FLT3-WT cell lines. Supplementary Figure S3. Images of all mice in the in vivo experiment. Supplementary Figure S4. Concurrent treatment with PP2A-activating drug and FLT3 inhibitor does not induce apoptosis in wild-type FLT3 AML, AML complete remission (CR) or AML complete remission with incomplete platelet recovery (CRp) marrows. Supplementary Figure S5. Concurrent treatment with PP2A-activating drug and FLT3 inhibitor downregulates c-Myc and Pim-1 protein expression in cells with FLT3-ITD. Supplementary Figure S6. p-c-Myc (T58) and p-c-Myc (S62) expression in Ba/F3-ITD and MV4-11 cells treated with gilteritinib and/or FTY720. Supplementary Figure S7. Concurrent treatment with PP2A-activating drug and FLT3 inhibitor produces variable changes in c-Myc and Pim-1 mRNA expression in cells with FLT3-ITD. Supplementary Figure S8. c-Myc and Pim-1 expression in FLT3-WT AML blasts treated with gilteritinib and/or FTY720. Supplementary Figure S9. Proteasome inhibition inhibits downregulation of c-Myc and Pim-1 expression by concurrent PP2A-activating drug and FLT3 inhibitor treatment. Supplementary Figure S10. Concurrent PP2A-activating drug and FLT3 inhibitor treatment increases c-Myc and Pim-1 protein turnover in cells with FLT3-ITD. Supplementary Figure S11. Concurrent PP2A activator and FLT3 inhibitor treatment downregulates p-ERK later than p-AKT in cells with FLT3-ITD. Supplementary Figure S12. The GSK-3beta inhibitor TWS119 prevents c-Myc and Pim-1 downregulation and apoptosis induction by PP2A-activating drug and FLT3 inhibitor combination in Ba/F3-ITD cells.

Fms-like tyrosine-like kinase 3 internal tandem duplication (FLT3-ITD) is present in acute myeloid leukemia (AML) in 30% of patients and is associated with short disease-free survival. FLT3 inhibitor efficacy is limited and transient but may be enhanced by multitargeting of FLT3-ITD signaling pathways. FLT3-ITD drives both STAT5-dependent transcription of oncogenic Pim-1 kinase and inactivation of the tumor-suppressor protein phosphatase 2A (PP2A), and FLT3-ITD, Pim-1, and PP2A all regulate the c-Myc oncogene. We studied mechanisms of action of cotreatment of FLT3-ITD–expressing cells with FLT3 inhibitors and PP2A-activating drugs (PADs), which are in development. PADs, including FTY720 and DT-061, enhanced FLT3 inhibitor growth suppression and apoptosis induction in FLT3-ITD–expressing cell lines and primary AML cells in vitro and MV4-11 growth suppression in vivo. PAD and FLT3 inhibitor cotreatment independently downregulated c-Myc and Pim-1 protein through enhanced proteasomal degradation. c-Myc and Pim-1 downregulation was preceded by AKT inactivation, did not occur in cells expressing myristoylated (constitutively active) AKT1, and could be induced by AKT inhibition. AKT inactivation resulted in activation of GSK-3β, and GSK-3β inhibition blocked downregulation of both c-Myc and Pim-1 by PAD and FLT3 inhibitor cotreatment. GSK-3β activation increased c-Myc proteasomal degradation through c-Myc phosphorylation on T58; infection with c-Myc with T58A substitution, preventing phosphorylation, blocked downregulation of c-Myc by PAD and FLT3 inhibitor cotreatment. GSK-3β also phosphorylated Pim-1L/Pim-1S on S95/S4. Thus, PADs enhance efficacy of FLT3 inhibitors in FLT3-ITD–expressing cells through a novel mechanism involving AKT inhibition–dependent GSK-3β–mediated increased c-Myc and Pim-1 proteasomal degradation.

The literature on fluid biomarkers for concussion has primarily focused on comparing athletes with and without a diagnosis of concussion and on examining the relationship between fluid biomarkers and exposure to head trauma. This systematic literature review aims to examine the strength of evidence for fluid biomarkers to be associated with clinically relevant outcomes in sports-related concussion.A systematic literature review was conducted using EmBASE, PubMed, and CINAHL. English-language articles that included athletes participating in organized sports and reported the relationship between at least one fluid biomarker and at least one clinical outcome measure, or provided data that could be used to analyze this relationship, were included.Studies of the relationship between fluid biomarkers and clinical outcomes of concussion have yielded small or variable effects. There were significant inconsistencies in methodology including duration of time post-injury of biomarker collection, use of control groups, the number of time points post-injury that biomarkers were collected, and what clinical outcomes were utilized.There is currently insufficient evidence to support a relationship between any of the included fluid biomarkers and clinical outcome measures of concussion. Future research including clinical outcome measures and using standardized study design and methodology is necessary.

Laser powder bed fusion (LPBF) was utilized to create a series of aluminum alloy (i.e., AlSi10Mg) 5 mm-diameter support pillars with a fixed height of 5 mm containing varying filet angles and build orientations (i.e., 0 deg, 10 deg, 20 deg, 30 deg, 40 deg, 50 deg, and 60 deg from the normal surface) to determine surface roughness and water wettability effects. From experiments, anisotropic wetting was observed due in part to the surface heterogeneity created by the LPBF process. The powder-sourced AlSi10Mg alloy, typically hydrophobic, exhibited primarily hydrophilic behavior for build angles of 0 deg and 60 deg, a mix of hydrophobic and hydrophilic behavior at build angles of 10 deg and 20 deg, and hydrophobic behavior at 30 deg, 40 deg, and 50 deg build angles. Measured surface roughness, Ra, ranged from 5 to 36 µm and varied based on location. 3D-topography maps were generated, and arithmetic mean heights, Sa, of 15.52–21.71 µm were observed; the anisotropy of roughness altered the wetting behavior, thereby prompting some hydrophilic behavior. Build angles of 30 deg and 40 deg provided for the smoothest surfaces. A significantly rougher surface was found for the 50 deg build angle. This abnormally high roughness is attributed to the melt pool contact angle having maximal capillarity with the surrounding powder bed. In this study, the critical melt pool contact angle was near equal to the build angle, suggesting that a critical build angle exists, which gives rise to pronounced melt pool wetting behavior and increased surface roughness due to enhanced wicking followed by solidification.

For the treatment of mesial temporal lobe epilepsy on the language-dominant side in patients at high risk of memory decline, we propose a minimally invasive diagnostic and treatment technique, adopting the principles of multiple hippocampal transections (MHT) using stereo-electroencephalography-guided radiofrequency (SEEG-guided-RF-MHT). This new technique allows targeting of the longitudinal fibers in the hippocampus critical for seizure spreading, while sparing the transverse circuits which are considered important for memory processing and avoiding discomfort and longer post-operatory recovery time associated with craniotomies. We report the efficacy and safety of this procedure in a preliminary observational study of cases. Five patients at high risk of memory decline, including three with non-lesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. A new strategy of SEEG electrode placement was used to mimic MHT. After confirming hippocampal seizure onset, all the patients had three linear ablations perpendicular to the amigdalohippocampal complex. The procedure was performed at the patient's bedside with the patient awake during the full length of the procedure. Four out of five patients were seizure-free (average follow up: 14-18 months). There were no associated complications. Visual inspection of brain MRI of patients at six months following SEEG-guided RF-MHT showed significant hippocampal volume preservation. Subjects who received the procedure in the dominant side reported no subjective memory complaints in the follow-up clinic assessments at six months. Our preliminary seizure outcome seems very promising since the majority of our patients (four out of five patients) were seizure-free. Since no lesions are made outside the amygdalo-hippocampal complex using this technique and the temporal stem remains intact, more favorable memory and language outcome is expected in patients at high risk of memory decline.

Additive manufacturing (AM) allows for the fabrication of complex metallic specimens which are otherwise very difficult or impossible to create using traditional manufacturing methods. For multi-phase heat spreaders such as vapor chambers, complex internal geometry lends itself well to AM as new design features can be realized. The internal geometries of vapor chambers frequently involve several thin pillars, which act as wicking structures and support a small internal cavity in which the phase change of a liquid, usually water, provides a means to effectively ‘spread’ a high heat flux throughout a larger area. In this case study, Laser Powder Bed Fusion (L-PBF) AM was utilized to create a series of aluminum alloy (AlSi10Mg) support pillars of fixed height with varying filet angles and build orientations (0°, 10°, 20°, 30°, 40°, 50° and 60° from the normal surface) to determine effects on surface roughness and resolution. Surface-to-water contact angles were measured on rinsed, un-polished surfaces, and microscopy was employed to obtain images demonstrating surface roughness profiles. This was done on both heated and unheated surfaces. Results clearly demonstrate that the surface roughness of upward and downward-facing surfaces during L-PBF depends on build orientation. The observational findings of this experiment showed that the surface roughness on surfaces representing horizontally oriented faces decreased as the printing orientation increased. This indicates that one must be cognizant of printing orientation for the L-PBF of capillary structures. A change in surface roughness as a result of printing orientation effects the heat transfer within an enclosed space due to a change in contact angles between the liquid and the heated surface. The results of this study will aid in future design considerations of heat pipes for their additive manufacture via current L-PBF technology.

A combination of anti-CTLA-4 plus anti-PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ-dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti-CTLA-4 therapy, with efficacy comparable to that of anti-CTLA-4 plus anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.

Sports neuropsychology is a rapidly emerging field that affords neuropsychologists, the opportunity to work with a diverse group of individuals in terms of age, gender, sports, ethnicity, and language and sports has a way of bringing diverse communities together. Although working with athletes can be associated with unique challenges, neuropsychological assessment with this population and being part of an interdisciplinary sports medicine team is both exciting and rewarding and can merge a passion for sports with professional interests. This paper is intended to highlight the contribution of neuropsychology to the evaluation and management of sport-related concussion as well as describe the neuropsychologist's role as an integral member of interdisciplinary sports medicine teams. Clinical model, special considerations, assessment strategy, and administrative aspects of practice are discussed.

The BrainScope Ahead 300 is designed for use by health care professionals to aid in the assessment of patients suspected of a mild traumatic brain injury. The purpose of the current study was to establish normative data for the cognitive test component of the Ahead 300 system and to evaluate the role of demographic factors on test performance. Healthy, community-dwelling adults between the ages of 18 and 80 recruited from five geographically distributed sites were administered Android versions of the ANAM Matching to Sample and Procedural Reaction Time tests that comprise the cognitive test component of the Ahead 300 system by trained personnel. Scores were correlated with age, education, and race. Age accounted for the majority of the variance in test scores with additional significant, but minor, contributions of education and race. Gender did not account for a significant proportion of the variance for either test. Based on these results, the normative data for 551 individuals are presented stratified by age. These are the first available normative data for these tests when administered using the Ahead 300 system and will assist health care professionals in determining the degree to which scores on the cognitive tests reflect impaired performance.

Objective This study provides normative data on the SCAT5 Cognitive Screening, establishes test-retest reliability, and creates clinically relevant cut points for low performance. Method The multisport baseline sample was composed of 727 uninjured college athletes (52% female) at a Division I university who were administered the SCAT5 before the 2017–2018 season. Descriptive statistics, including base rates of low performance, were calculated for SCAT5 indices. Repeat baseline testing was completed by 325 athletes (48% female) at 1 year (days M = 352.56;SD = 56.03) who were included in the test-retest reliability and practice effect analyses. Reliable change indices were calculated. Results Descriptive statistics for SCAT5 were computed for both baselines (Baseline 1: SAC total M = 35.15,SD = 4.93; immediate recall total M = 20.01,SD = 3.46; delayed recall total M = 6.43,SD = 1.75). A difference in descriptive statistics and practice effects by sex on the SCAT5 Cognitive Screening has been demonstrated (Bailey, Meyer, Tangen et al., under review). For female athletes, the 1st administration cutoff scores for abnormal performance ( Conclusions The present study provides clinically relevant normative data for the SCAT5 Cognitive Screening. Cut points for low performance on both reliable chance indices (RCIs) and normative performance reflected meaningful sex differences that could influence clinical interpretation.

This article explores the potential advantages of using a clustering approach to distill information contained within a large ensemble of forecasts in the medium-range time frame. A divisive clustering algorithm based on the one-dimensional discrete Fourier transformation is described and applied to the 70-member combination of the 20-member National Centers for Environmental Prediction (NCEP) Global Ensemble Forecast System (GEFS) and the 50-member European Centre for Medium-Range Weather Forecasts (ECMWF) ensemble. Cumulative statistical verification indicates that clusters selected objectively based on having the largest number of members do not perform better than the ECMWF ensemble mean. However, including a cluster in a blended forecast to maintain continuity or to nudge toward a preferred solution may be a reasonable strategy in some cases. In such cases, a cluster may be used to sharpen a forecast weakly depicted by the ensemble mean but favored in consideration of continuity, consistency, collaborative thinking, and/or the trend in the guidance. Clusters are often useful for depicting forecast solutions not apparent via the ensemble mean but supported by a subset of ensemble members. A specific case is presented to demonstrate the possible utility of a clustering approach in the forecasting process.

Memory loss after brain injury can be a source of considerable morbidity, but there are presently few therapeutic options for restoring memory function. We have previously demonstrated that burst stimulation of the fornix is able to significantly improve memory in a rodent model of traumatic brain injury. The present study is a preliminary investigation with a small group of cases to explore whether theta burst stimulation of the fornix might improve memory in humans. Four individuals undergoing stereo-electroencephalography evaluation for drug-resistant epilepsy were enrolled. All participants were implanted with an electrode into the proximal fornix and dorsal hippocampal commissure on the language dominant (n = 3) or language non-dominant (n = 1) side, and stimulation of this electrode reliably produced a diffuse evoked potential in the head and body of the ipsilateral hippocampus. Each participant underwent testing of verbal memory (Rey Auditory-Verbal Learning Test), visual-spatial memory (Medical College of Georgia Complex Figure Test), and visual confrontational naming (Boston Naming Test Short Form) once per day over at least two consecutive days using novel test forms each day. For 50% of the trials, the fornix electrode was continuously stimulated using a burst pattern (200 Hz in 100 ms trains, five trains per second, 100 µs, 7 mA) and was compared with sham stimulation. Participants and examiners were blinded to whether stimulation was active or not, and the order of stimulation was randomized. The small sample size precluded use of inferential statistics; therefore, data were analysed using descriptive statistics and graphic analysis. Burst stimulation of the fornix was not perceived by any of the participants but was associated with a robust reversible improvement in immediate and delayed performance on the Medical College of Georgia Complex Figure Test. There were no apparent differences on either Rey Auditory-Verbal Learning Test or Boston Naming Test. There was no apparent relationship between performance and side of stimulation (language dominant or non-dominant). There were no complications. Preliminary evidence in this small sample of patients with drug-resistant epilepsy suggests that theta burst stimulation of the fornix may be associated with improvement in visual-spatial memory.