A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Simulation of interlayer coupling for electroactive covalent organic framework design.

Porous, stacked two-dimensional covalent organic frameworks (2D COFs) bearing semiconducting linkers can support directional charge transfer across adjacent layers of the COF. To better inform the current and possible future design rules for enhancing electron and hole transport in such materials, an understanding of how linker selection and functionalization affects interlayer electronic couplings is essential. We report electronic structure simulation and analysis of electronic couplings across adjacent linker units and to encapsulated species in functionalized electroactive 2D COFs. The detailed dependence of these electronic couplings on interlayer interactions is examined through scans along key interlayer degrees of freedom and through configurational sampling from equilibrium molecular dynamics on semiempirical potential energy surfaces. Beyond affirming the sensitivity of the electronic coupling to interlayer distance and orientation, these studies offer guidance toward linker functionalization strategies for enhancing charge carrier transport in electroactive 2D COFs.

Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.

Expanding the adenovirus toolbox: reporter viruses for studying the dynamics of human adenovirus replication.

To streamline standard virological assays, we developed a suite of nine fluorescent or bioluminescent replication competent human species C5 adenovirus reporter viruses that mimic their parental wild-type counterpart. These reporter viruses provide a rapid and quantitative readout of various aspects of viral infection and replication based on EGFP, mCherry, or NanoLuc measurement. Moreover, they permit real-time non-invasive measures of viral load, replication dynamics, and infection kinetics over the entire course of infection, allowing measurements that were not previously possible. This suite of replication competent reporter viruses increases the ease, speed, and adaptability of standard assays and has the potential to accelerate multiple areas of human adenovirus research.IMPORTANCEIn this work, we developed a versatile toolbox of nine HAdV-C5 reporter viruses and validated their functions in cell culture. These reporter viruses provide a rapid and quantitative readout of various aspects of viral infection and replication based on EGFP, mCherry, or NanoLuc measurement. The utility of these reporter viruses could also be extended for use in 3D cell culture, organoids, live cell imaging, or animal models, and provides a conceptual framework for the development of new reporter viruses representing other clinically relevant HAdV species.

Effects of low-load resistance training with blood flow restriction on muscle fiber myofibrillar and extracellular area.

Blood flow restriction applied during low-load resistance training (LL-BFR) induces a similar increase in the cross-sectional area of muscle fibers (fCSA) compared to traditional high-load resistance training (HL-RT). However, it is unclear whether LL-BFR leads to differential changes in myofibrillar spacing in muscle fibers and/or extracellular area compared to HL-RT. Therefore, this study aimed to investigate whether the hypertrophy of type I and II fibers induced by LL-BFR or HL-RT is accompanied by differential changes in myofibrillar and non-myofibrillar areas. In addition, we examined if extracellular spacing was differentially affected between these two training protocols. Twenty recreationally active participants were assigned to LL-BFR or HL-RT groups and underwent a 6-week training program. Muscle biopsies were taken before and after the training period. The fCSA of type I and II fibers, the area occupied by myofibrillar and non-myofibrillar components, and extracellular spacing were analyzed using immunohistochemistry techniques. Despite the significant increase in type II and mean (type I + II) fCSA (p < 0.05), there were no significant changes in the proportionality of the myofibrillar and non-myofibrillar areas [∼86% and ∼14%, respectively (p > 0.05)], indicating that initial adaptations to LL-BFR are primarily characterized by conventional hypertrophy rather than disproportionate non-myofibrillar expansion. Additionally, extracellular spacing was not significantly altered between protocols. In summary, our study reveals that LL-BFR, like HL-RT, induces skeletal muscle hypertrophy with proportional changes in the areas occupied by myofibrillar, non-myofibrillar, and extracellular components.

Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. SIGNIFICANCE: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.

Hyperpolarized 13 C metabolic imaging of the human abdomen with spatiotemporal denoising.

PURPOSE: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 13 C MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach. METHODS: Denoising performance was first evaluated using the simulated [1-13 C]pyruvate dynamics at different noise levels to determine optimal kglobal and klocal parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1-13 C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients). RESULTS: The parameterization of kglobal = 0.2 and klocal = 0.9 denoises abdominal HP data while retaining image fidelity when evaluated by RMSE. The kPX (conversion rate of pyruvate-to-metabolite, X = lactate or alanine) difference was shown to be <20% with respect to ground-truth metabolic conversion rates when there is adequate SNR (SNRAUC > 5) for downstream metabolites. In both human cohorts, there was a greater than nine-fold gain in peak [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine apparent SNRAUC . The improvement in metabolite SNR enabled a more robust quantification of kPL and kPA . After denoising, we observed a 2.1 ± 0.4 and 4.8 ± 2.5-fold increase in the number of voxels reliably fit across abdominal FOVs for kPL and kPA quantification maps. CONCLUSION: Spatiotemporal denoising greatly improves visualization of low SNR metabolites particularly [1-13 C]alanine and quantification of [1-13 C]pyruvate metabolism in large FOV HP 13 C MRI studies of the human abdomen.

Assessing data analysis techniques in a high-throughput meiosis-like induction detection system.

BACKGROUND: Strategies to understand meiotic processes have relied on cytogenetic and mutant analysis. However, thus far in vitro meiosis induction is a bottleneck to laboratory-based plant breeding as factor(s) that switch cells in crops species from mitotic to meiotic divisions are unknown. A high-throughput system that allows researchers to screen multiple candidates for their meiotic induction role using low-cost microfluidic devices has the potential to facilitate the identification of factors with the ability to induce haploid cells that have undergone recombination (artificial gametes) in cell cultures. RESULTS: A data analysis pipeline and a detailed protocol are presented to screen for plant meiosis induction factors in a quantifiable and efficient manner. We assessed three data analysis techniques using spiked-in protoplast samples (simulated gametes mixed into somatic protoplast populations) of flow cytometry data. Polygonal gating, which was considered the "gold standard", was compared to two thresholding methods using open-source analysis software. Both thresholding techniques were able to identify significant differences with low spike-in concentrations while also being comparable to polygonal gating. CONCLUSION: Our study provides details to test and analyze candidate meiosis induction factors using available biological resources and open-source programs for thresholding. RFP (PE.CF594.A) and GFP (FITC.A) were the only channels required to make informed decisions on meiosis-like induction and resulted in detection of cell population changes as low as 0.3%, thus enabling this system to be scaled using microfluidic devices at low costs.

Structural and functional validation of a highly specific Smurf2 inhibitor.

Smurf1 and Smurf2 are two closely related member of the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase family and play important roles in the regulation of various cellular processes. Both were initially identified to regulate transforming growth factor-ß and bone morphogenetic protein signaling pathways through regulating Smad protein stability and are now implicated in various pathological processes. Generally, E3 ligases, of which over 800 exist in humans, are ideal targets for inhibition as they determine substrate specificity; however, there are few inhibitors with the ability to precisely target a particular E3 ligase of interest. In this work, we explored a panel of ubiquitin variants (UbVs) that were previously identified to bind Smurf1 or Smurf2. In vitro binding and ubiquitination assays identified a highly specific Smurf2 inhibitor, UbV S2.4, which was able to inhibit ligase activity with high potency in the low nanomolar range. Orthologous cellular assays further demonstrated high specificity of UbV S2.4 toward Smurf2 and no cross-reactivity toward Smurf1. Structural analysis of UbV S2.4 in complex with Smurf2 revealed its mechanism of inhibition was through targeting the E2 binding site. In summary, we investigated several protein-based inhibitors of Smurf1 and Smurf2 and identified a highly specific Smurf2 inhibitor that disrupts the E2-E3 protein interaction interface.

HIV Pre-Exposure Prophylaxis: New and Upcoming Drugs to Address the HIV Epidemic.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to utilize PrEP. PrEP options continue to expand as new administration modalities offer the potential to tailor PrEP use for individual success. We have provided the evidence for new and emerging antiretroviral agents for PrEP (cabotegravir, lenacapavir, dapivirine, and broadly neutralizing antibodies), divided into pharmacology, animal model, and human data, accompanied by a summary and suggested place in therapy. Cabotegravir is a US Food and Drug Administration (FDA)-approved intramuscular injection given every 2 months with a strong body of evidence demonstrating efficacy for HIV PrEP, lenacapavir administered subcutaneously every 6 months is currently under investigation for HIV PrEP, dapivirine vaginal ring is an available PrEP option for women in certain areas of Africa, and broadly neutralizing monoclonal antibodies have been challenged in demonstrating efficacy in phase 1-2 study for HIV PrEP to date. Clinical literature for individual agents is discussed with data from major studies summarized in tables. This review provides a detailed overview of recently available and premier candidate PrEP drugs.

Exploiting the endogenous yeast nuclear proteome to identify short linear motifs in vivo.

Peptide-domain interactions mediated by short linear motifs (SLiMs) play crucial roles in cellular biology. The simplicity of SLiMs poses challenges in their computational identification. Existing high-throughput methods for discovering SLiMs lack cellular context as they are typically performed in vitro. We developed a functional selection method using yeast to identify peptides that interact with the endogenous yeast nuclear proteome. Remarkably, peptides selected for in yeast also mediated nuclear import in human cells. Notably, the identified peptides did not resemble classical nuclear localization sequences. This platform has the potential to identify and investigate motifs that interact with the nuclear proteome of yeast and human and to aid in the identification and understanding of alternative protein nuclear import mechanisms.

Assessing the association between on-field heading technique and head impact kinematics in a cohort of female youth soccer players.

There is concern that exposure to soccer headers may be associated with neurological sequelae. Training proper heading technique represents a coachable intervention that may reduce head acceleration exposure. The objective was to assess relationships between heading technique and head kinematics in female youth soccer players. Fourteen players (mean age = 14.4 years) wore instrumented mouthpieces during practices and games. Headers were reviewed by three raters to assign a technique score. Mixed models and LASSO regression evaluated associations of technique with peak linear acceleration (PLA), rotational acceleration (PRA), rotational velocity (PRV), and head impact power ratio (HIP Ratio) while adjusting for session type and ball delivery. Two hundred eighty-nine headers (n = 212 standing, n = 77 jumping) were analyzed. Technique score (p = 0.043) and the technique score - session type interaction (p = 0.004) were associated with PRA of standing headers, whereby each 10-unit increase in technique score was associated with an 8.6% decrease in PRA during games but a 5.1% increase in PRA during practices. Technique was not significantly associated with any other kinematic metrics; however, peak kinematics tended to decrease as technique score increased. LASSO regression identified back extension and shoulder/hip alignment as important predictors of peak kinematics. Additional research on heading technique and head acceleration is recommended.

Pushing the agenda for intravenous push administration in outpatient parenteral antimicrobial therapy.

Intravenous push (IVP) antimicrobial administration refers to rapid bolus infusion of medication. This drug delivery method offers improved patient convenience, superior patient and nursing satisfaction, and cost savings when used in outpatient parenteral antimicrobial therapy (OPAT). Antimicrobial agents must demonstrate optimal physiochemical and pharmacologic characteristics, as well as sufficient syringe stability, to be administered in this manner. Additionally, impacts on medication tolerability, patient safety, and effectiveness must be considered. This narrative review summarizes the available data and practical implications of IVP administration of antimicrobials in the OPAT setting.

Bacillus subtilis NrnB is expressed during sporulation and acts as a unique 3'-5' exonuclease.

All cells employ a combination of endo- and exoribonucleases to degrade long RNA polymers to fragments 2-5 nucleotides in length. These short RNA fragments are processed to monoribonucleotides by nanoRNases. Genetic depletion of nanoRNases has been shown to increase abundance of short RNAs. This deleteriously affects viability, virulence, and fitness, indicating that short RNAs are a metabolic burden. Previously, we provided evidence that NrnA is the housekeeping nanoRNase for Bacillus subtilis. Herein, we investigate the biological and biochemical functions of the evolutionarily related protein, B. subtilis NrnB (NrnBBs). These experiments show that NrnB is surprisingly different from NrnA. While NrnA acts at the 5' terminus of RNA substrates, NrnB acts at the 3' terminus. Additionally, NrnA is expressed constitutively under standard growth conditions, yet NrnB is selectively expressed during endospore formation. Furthermore, NrnA processes only short RNAs, while NrnB unexpectedly processes both short RNAs and longer RNAs. Indeed, inducible expression of NrnB can even complement the loss of the known global 3'-5' exoribonucleases, indicating that it acts as a general exonuclease. Together, these data demonstrate that NrnB proteins, which are widely found in Firmicutes, Epsilonproteobacteria and Archaea, are fundamentally different than NrnA proteins and may be used for specialized purposes.

A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-type glioblastoma.

Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P = 0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P = 0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P < 0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1ß was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation.

Integrating biomechanics with stakeholder perspectives to inform safety in grassroots dirt track racing.

Grassroots dirt track racing is a foundational part of motorsports with a high risk of severe injury. This study aimed to gather perspectives and experiences of motorsports drivers surrounding safety and head acceleration events experienced during grassroots dirt track racing to inform strategies to improve driver safety. Thirteen drivers (n=9 who primarily race on dirt tracks; n=4 who primarily race on pavement tracks) with prior dirt track racing experience participated in separate, group-specific focus groups and/or one-on-one interviews where video, simulations of head motion, and head acceleration data were shared. Peak kinematics of laps and crash contact scenarios were recorded, and head perturbations (i.e., deviations in head motion relative to its moving-average trajectory) were quantified for each lap and presented through guided discussion. Responses were summarized using Rapid Assessment Process. Audio recordings and field notes were collected from focus groups and interviews and analyzed across 25 domains. Drivers described dirt track racing as short, fast bursts of racing. Benefits of dirt track racing for driver development were described, including learning car control. Drivers acknowledged risks of racing and expressed confidence in safety equipment but identified areas for improvement. Drivers observed lateral bouncing of the head in video and simulations but recognized that such motions were not noticed while racing. Track conditions and track type were identified as factors influencing head perturbations. Mean PLA (5.5 g) and PRV (3.07 rad/s) of perturbations experienced during racing laps and perturbation frequencies of 5 and 7 perturbations per second were reported. Generally, drivers accurately estimated the head acceleration magnitudes but were surprised by the frequency and maximum magnitude of perturbations. Maximum perturbation magnitudes (26.8 g and 19.0 rad/s) were attributed to hitting a "rut" in the dirt. Drivers described sudden stops, vertical loads due to landing from a large height, and impacts to the vehicle frame as crash events they physically feel the most. Summary statistics for crashes (medians = 7.30 g, 6.94 rad/s) were reported. Typical impact magnitudes measured in other sports (e.g., football) were provided for context. Upon reviewing the biomechanics, drivers were surprised that crash accelerations were relatively low compared to other contact/collision sports. Pavement drivers noted limited safety features in dirt track racing compared to pavement, including rigidity of vehicle frames, seat structure, seatbelt integration, and lack of oversight from sanctioning bodies. Most drivers felt seat inserts and head and neck restraints are important for injury prevention; however, usage of seat inserts and preferred head and neck restraint system differed among drivers. Drivers described their perspectives and experiences related to safety and identified strategies to improve safety in grassroots dirt track racing. Drivers expressed support for future safety research.

Driver head kinematics in grassroots dirt track racing crashes: A pilot analysis.

Motorsport athletes experience head acceleration loading during crashes; however, there is limited literature quantifying the frequency and magnitude of these loads, particularly at the grassroots level of the sport. Understanding head motion experienced during crash events in motorsport is necessary to inform interventions to improve driver safety. This study aimed to quantify and characterize driver head and vehicle kinematics during crashes in open-wheel grassroots dirt track racing. Seven drivers (ages 16-22, n = 2 female) competing in a national midget car series were enrolled in this study over two racing seasons and were instrumented with custom mouthpiece sensors. Drivers' vehicles were outfitted with an incident data recorder (IDR) to measure vehicle acceleration. Forty-one crash events were verified and segmented into 139 individual contact scenarios via film review. Peak resultant linear acceleration (PLA) of the vehicle and PLA, peak rotational acceleration (PRA), and peak rotational velocity (PRV) of the head were quantified and compared across the part of the vehicle contacted (i.e., tires or chassis), the vehicle location contacted (e.g., front, left, bottom), the external object contacted (i.e., another vehicle, wall, or the track), and the principal direction of force (PDOF). The median (95th percentile) PLA, PRA, and PRV of the head and PLA of the vehicle were 12.3 (37.3) g, 626 (1799) rad/s2, 8.92 (18.6) rad/s, and 23.2 (88.1) g, respectively. Contacts with a non-horizontal PDOF (n = 98, 71%) and contact with the track (n = 96, 70%) were common in the data set. Contact to the left side of the vehicle, with the track, and with a non-horizontal PDOF tended to have the greatest head kinematics compared to other factors in each sub-analysis. Results from this pilot study can inform larger studies of head acceleration exposure during crashes in the grassroots motorsports environment and may ultimately support evidence-based driver safety interventions.

Overcoming roadblocks for in vitro nurseries in plants: induction of meiosis.

Efforts to increase genetic gains in breeding programs of flowering plants depend on making genetic crosses. Time to flowering, which can take months to decades depending on the species, can be a limiting factor in such breeding programs. It has been proposed that the rate of genetic gain can be increased by reducing the time between generations by circumventing flowering through the in vitro induction of meiosis. In this review, we assess technologies and approaches that may offer a path towards meiosis induction, the largest current bottleneck for in vitro plant breeding. Studies in non-plant, eukaryotic organisms indicate that the in vitro switch from mitotic cell division to meiosis is inefficient and occurs at very low rates. Yet, this has been achieved with mammalian cells by the manipulation of a limited number of genes. Therefore, to experimentally identify factors that switch mitosis to meiosis in plants, it is necessary to develop a high-throughput system to evaluate a large number of candidate genes and treatments, each using large numbers of cells, few of which may gain the ability to induce meiosis.

Head Impact Exposure in Female Collegiate Soccer by Activity Type.

Soccer, one of the most popular sports in the world, has one of the highest rates of sports-related concussions. Additionally, soccer players are frequently exposed to nonconcussive impacts from intentionally heading the ball, a fundamental component of the sport. There have been many studies on head impact exposure in soccer, but few focus on soccer practices or practice activities. This study aimed to characterize the frequency and magnitude of head impacts in National Collegiate Athletic Association Division I female soccer practice activities using a custom-fit instrumented mouthpiece. Sixteen players were instrumented over the course of 54 practice sessions. Video analysis was performed to verify all mouthpiece-recorded events and classify practice activities. Category groupings of practice activities include technical training, team interaction, set pieces, position-specific, and other. Differences in head impact rates and peak resultant kinematics were observed across activity types and category groupings. Technical training had the highest impact rate compared to other category groupings. Impacts occurring during set piece activities had the highest mean kinematic values. Understanding drill exposure can help inform coaches on training plans aimed to reduce head impact exposure for their athletes.

Diffusion basis spectrum imaging as an adjunct to conventional MRI leads to earlier diagnosis of high-grade glioma tumor progression versus treatment effect.

Background: Following chemoradiotherapy for high-grade glioma (HGG), it is often challenging to distinguish treatment changes from true tumor progression using conventional MRI. The diffusion basis spectrum imaging (DBSI) hindered fraction is associated with tissue edema or necrosis, which are common treatment-related changes. We hypothesized that DBSI hindered fraction may augment conventional imaging for earlier diagnosis of progression versus treatment effect. Methods: Adult patients were prospectively recruited if they had a known histologic diagnosis of HGG and completed standard-of-care chemoradiotherapy. DBSI and conventional MRI data were acquired longitudinally beginning 4 weeks post-radiation. Conventional MRI and DBSI metrics were compared with respect to their ability to diagnose progression versus treatment effect. Results: Twelve HGG patients were enrolled between August 2019 and February 2020, and 9 were ultimately analyzed (5 progression, 4 treatment effect). Within new or enlarging contrast-enhancing regions, DBSI hindered fraction was significantly higher in the treatment effect group compared to progression group (P = .0004). Compared to serial conventional MRI alone, inclusion of DBSI would have led to earlier diagnosis of either progression or treatment effect in 6 (66.7%) patients by a median of 7.7 (interquartile range = 0-20.1) weeks. Conclusions: In the first longitudinal prospective study of DBSI in adult HGG patients, we found that in new or enlarging contrast-enhancing regions following therapy, DBSI hindered fraction is elevated in cases of treatment effect compared to those with progression. Hindered fraction map may be a valuable adjunct to conventional MRI to distinguish tumor progression from treatment effect.