Intrafraction Imaging Can Replace the Midtreatment Cone Beam Tomography for Lung Stereotactic Ablative Radiation Therapy Patients for Increased Treatment Efficiency.

Purpose: To determine the feasibility of replacing the mid treatment cone beam computed tomography (MT CBCT) image with Intrafraction Imaging (IFI) acquired concurrently during dose delivery in lung Stereotactic Ablative Body Radiation therapy (SABR) patients, and thus improve treatment efficiency. Methods and Materials: A review of departmental imaging data was performed on ten lung SABR patients treated with dual arc volumetric modulated arc therapy (VMAT) on an Elekta Versa HD linear accelerator with XVI imaging software.IFI data was extracted and a database of the translational (TX, TY, TZ) and the rotational (RX, RY, RZ) position errors was created for retrospective comparison, with the values of the MT CBCT for the same patients, treated between March 2021 and March 2022 at our center. The data was evaluated for correlation between the values in all 6° of freedom. Results: The inter-class correlation (ICC) coefficient for Tx was 0.89 (95% CI, 0.80-0.94), Ty was 0.69 (95% CI, 0.49-0.82), Tz was 0.89 (95% CI, 0.82-0.95) in the translational planes, and Rx was 0.79 (95% CI, 0.65-0.88), Ry was 0.79 (95% CI, 0.65-0.88), and Rz was 0.91 (95% CI, 0.84-0.95) in rotational planes.The Bland-Altman (BA) statistics for Tx had a bias of -1.22 × 10-3, with an upper limit of agreement (UOA) of 0.07, and a lower limit of agreement (LOA) of -0.07, for Ty the bias was 0.01 (UOA: 0.18; LOA: -0.16), Tz bias was 2.6 × 10-3(UOA: 0.10; LOA: -0.09), Rx bias was 0.09 (UOA: 0.82; LOA: -0.64), Ry bias was -0.04 (UOA: 1.08; LOA: -1.16) and Rz was -0.03 (UOA: 0.44; LOA: -0.51). Conclusions: The ICC was excellent for Tx, Tz, Rx, y, z, and good for Ty. The data demonstrated promising correlation between IFI and MT CBCT values, and therefore supports the use of IFI for clinical decision making and improving treatment efficiency.

The unknown unknown: A framework for assessing environmental DNA assay specificity against unsampled taxa.

Taxon-specific quantitative PCR (qPCR) assays are commonly used for environmental DNA sampling-based inference of animal presence. These assays require thorough validation to ensure that amplification truly indicates detection of the target taxon, but a thorough validation is difficult when there are potentially many non-target taxa, some of which may have incomplete taxonomies. Here, we use a previously published, quantitative model of cross-amplification risk to describe a framework for assessing qPCR assay specificity when there is missing information and it is not possible to assess assay specificity for each individual non-target confamilial. In this framework, we predict assay specificity against unsampled taxa (non-target taxa without sequence data available) using the sequence information that is available for other confamilials. We demonstrate this framework using four case study assays for: (1) An endemic, freshwater arthropod (meltwater stonefly; Lednia tumana), (2) a globally distributed, marine ascidian (Didemnum perlucidum), (3) a continentally distributed freshwater crustacean (virile crayfish; Faxonius virilis, deanae and nais species complex) and (4) a globally distributed freshwater teleost (common carp; Cyprinus carpio and its close relative C. rubrofuscus). We tested the robustness of our approach to missing information by simulating application of our framework for all possible subsamples of 20-all non-target taxa. Our results suggest that the modelling framework results in estimates which are largely concordant with observed levels of cross-amplification risk using all available sequence data, even when there are high levels of data missingness. We explore potential limitations and extensions of this approach for assessing assay specificity and provide users with an R Markdown template for generating reproducible reports to support their own assay validation efforts.

A novel combination treatment for fragile X syndrome predicted using computational methods.

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx's data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.

Lessons learned from a non-traditional application process: Integrating user experiences to inform admission application design.

PURPOSE: The research aim was to gather applicant expectations and perspectives with a user-centered approach during a pilot application process for a new dental school. The goal was to inform future admissions practices at our institution and for programs broadly. METHODS: The High Point University admission team developed an electronic application external to current centralized services that was launched from May to August 2022. Participants who completed the application were requested to complete an electronic survey of closed- and open-ended questions about the factors influencing their application decisions, feedback about how to optimize the experience, and their overall satisfaction using a Net Promoter Score. RESULTS: A total of 303 applicants (79% response rate) completed the survey about their application experience. The most influential reason for applying to the program was the optional Dental Admissions Test requirement (43%). Participants frequently referenced a need for a more human-centered process focused on the candidate rather than their numerical values and that the process should be smooth, straight-forward, short, easy, and simple. Participants requested that experiences should be weighed the most in the application process followed by letters of recommendation. Most applicants were "promoters" (68%) for the program with a Net Promoter Score of 62. Moreover, 32% and 45% rated the application process as the best or better application experience compared to other programs. CONCLUSION: Programs can benefit from collecting applicant's (i.e., users) opinions and feedback about their expectations and experiences to inform more user-centered application processes.

The first clinical implementation of real-time 6 degree-of-freedom image-guided radiotherapy for liver SABR patients.

PURPOSE: Multiple survey results have identified a demand for improved motion management for liver cancer IGRT. Until now, real-time IGRT for liver has been the domain of dedicated and expensive cancer radiotherapy systems. The purpose of this study was to clinically implement and characterise the performance of a novel real-time 6 degree-of-freedom (DoF) IGRT system, Kilovoltage Intrafraction Monitoring (KIM) for liver SABR patients. METHODS/MATERIALS: The KIM technology segmented gold fiducial markers in intra-fraction x-ray images as a surrogate for the liver tumour and converted the 2D segmented marker positions into a real-time 6DoF tumour position. Fifteen liver SABR patients were recruited and treated with KIM combined with external surrogate guidance at three radiotherapy centres in the TROG 17.03 LARK multi-institutional prospective clinical trial. Patients were either treated in breath-hold or in free breathing using the gating method. The KIM localisation accuracy and dosimetric accuracy achieved with KIM + external surrogate were measured and the results were compared to those with the estimated external surrogate alone. RESULTS: The KIM localisation accuracy was 0.2±0.9 mm (left-right), 0.3±0.6 mm (superior-inferior) and 1.2±0.8 mm (anterior-posterior) for translations and -0.1◦±0.8◦ (left-right), 0.6◦±1.2◦ (superior-inferior) and 0.1◦±0.9◦ (anterior-posterior) for rotations. The cumulative dose to the GTV with KIM + external surrogate was always within 5% of the plan. In 2 out of 15 patients, >5% dose error would have occurred to the GTV and an organ-at-risk with external surrogate alone. CONCLUSIONS: This work demonstrates that real-time 6DoF IGRT for liver can be implemented on standard radiotherapy systems to improve treatment accuracy and safety. The observations made during the treatments highlight the potential false assurance of using traditional external surrogates to assess tumour motion in patients and the need for ongoing improvement of IGRT technologies.

An empirical potential for simulating hydrogen isotope retention in highly irradiated tungsten.

We describe the parameterization of a tungsten-hydrogen empirical potential designed for use with large-scale molecular dynamics simulations of highly irradiated tungsten containing hydrogen isotope atoms, and report test results. Particular attention has been paid to getting good elastic properties, including the relaxation volumes of small defect clusters, and to the interaction energy between hydrogen isotopes and typical irradiation-induced defects in tungsten. We conclude that the energy ordering of defects changes with the ratio of H atoms to point defects, indicating that this potential is suitable for exploring mechanisms of trap mutation, including vacancy loop to plate-like void transformations.

Hearing voices among Russian patients with schizophrenia.

There has been relatively little work which systematically examines whether the content of hallucinations in individuals diagnosed with schizophrenia varies by cultural context. The work that exists finds that it does. The present project explores the way auditory hallucinations, or "voices," manifest in a Russian cultural context. A total of 28 individuals, diagnosed with schizophrenia, who reported hearing voices at the Republican Clinical Psychiatric Hospitals in Kazan, Russia, were interviewed about their experience of auditory hallucinations. The voices reported by our Russian participants did appear to have culturally specific content. Commands tended to be non-violent and focused on chores or other activities associated with daily life (byt). Many patients also reported sensory hallucinations involving other visions, sounds, and smells which sometimes reflected Russian folklore themes. For the most part, religious themes did not appear in patients' auditory vocal hallucinations, though nearly all patients expressed adherence to a religion. These findings support research that finds that the content, and perhaps the form, of auditory hallucinations may be shaped by local culture.

Wearing the Same Jersey? The Impact of Players' Cultural Diversity and Shared Team Tenure on National Soccer Team Performance.

In the present paper, we empirically analyze a dataset from national soccer teams between 2004 and 2019 to investigate the impact of team members' cultural diversity on final team outcomes. Further, we examine the role of shared team tenure as a proxy of tacit knowledge and within team communications in relation to the cultural diversity-team performance relationship. After addressing a potential endogeneity issue, results from multiple instrumental variable estimation methods implied a higher level of cultural diversity enhanced on-field performance. Meanwhile, increased level of shared team tenure further strengthened the effect associated with cultural diversity on team performance.

Microstructure of a heavily irradiated metal exposed to a spectrum of atomic recoils.

At temperatures below the onset of vacancy migration, metals exposed to energetic ions develop dynamically fluctuating steady-state microstructures. Statistical properties of these microstructures in the asymptotic high exposure limit are not universal and vary depending on the energy and mass of the incident ions. We develop a model for the microstructure of an ion-irradiated metal under athermal conditions, where internal stress fluctuations dominate the kinetics of structural evolution. The balance between defect production and recombination depends sensitively not only on the total exposure to irradiation, defined by the fluence, but also on the energy of the incident particles. The model predicts the defect content in the high dose limit as an integral of the spectrum of primary knock-on atom energies, with the finding that low energy ions produce a significantly higher amount of damage than high energy ions at comparable levels of exposure to radiation.

Exercise Training Prevents the Loss of Wall Thickness and Lowers Expression of Alzheimer's Related Proteins in 3xTg Mouse Jejunum.

Growing evidence has demonstrated the benefits of regular exercise on cardiovascular, neural, and cognitive function in humans with Alzheimer's disease (AD). However, the consequences of AD on gastrointestinal morphology and the effects of regular exercise, which plays an important role against the development of certain gastrointestinal-related diseases, are still poorly understood. Therefore, to assess the changes in intestinal structure in a mouse model of AD and the impact of exercise, 2-month-old 3xTg-AD male mice were subjected to treadmill running 5 days per week for a period of 5 months. Jejunum from 3xTg-AD mice analyzed by histochemical methods revealed significant alterations in morphology. Compared to age-matched wild-type (WT) mice, villi length and crypt depth were increased, and collagen content of jejunum was elevated in 3xTg-AD mice. Jejunum wall dimensions, expressed as total wall thickness, outer longitudinal thickness, and inner circular thickness were decreased in 3xTg-AD compared to WT. Smooth muscle actin expression in jejunal wall was decreased in 3xTg-AD. Most of these aberrations were improved with exercise. Western blot expression of cyclin dependent kinase 5 (CDK5, involved in neural cell death and hyperphosphorylation of tau), was elevated in 3xTg-AD jejunum. This was associated with a 4-fold increase in tau5 expression. Exercise prevented the increase in expression of CDK5 and tau5. Expression of caspase 3 (an apoptotic marker) was elevated in 3xTg-AD jejunum and exercise prevented this. The results of our study indicate that the abnormalities in jejunum of the 3xTg mouse model of AD were prevented with exercise training.

Alternating 1-Phenyl-2,2,2-Trifluoroethanol Conformational Landscape With the Addition of One Water: Conformations and Large Amplitude Motions.

The 1:1 adduct of 1-phenyl-2,2,2-trifluoroethanol (PhTFE), a chiral fluoroalcohol, with water was investigated using chirped pulse Fourier transform microwave spectroscopy and computational methods. While PhTFE itself was predicted to have three minima, I (gauche+), II (trans), and III (gauche-), only I and II were stable and only I was observed experimentally. A systematic search of the PhTFE···H2O conformational landscape identified 110 stable minima, 14 of which are within a 15 kJ mol-1 energy window. Rotational spectra of the two PhTFE···H2O conformers along with several deuterium and 18O isotopologues were assigned, and the isotopic data were used to verify the corresponding structures. In the two observed monohydrate conformers, one contains PhTFE I where the water subunit is inserted into the existing intramolecular OH···F contact of I, and the binary adduct is stabilized by two intermolecular contacts: OH···OW and HW···F, whereas the other contains PhTFE II where the water subunit interacts with both the alcohol hydrogen and phenyl ring of II, demonstrating that interaction with water sufficiently stabilizes II for its observation in a jet expansion. Interestingly, the predicted electric dipole moment components at the identified minima deviate considerably from the experimental ones. Such deviations were analyzed in terms of dynamic effects associated with the large amplitude motions of the unbound HW. In addition, tunnelling effects associated with the exchange of the bonded and nonbonded HW were also discussed.

Shadow Stadia and the Circular Economy.

Most attention on stadium or arena-anchored development projects is placed on the scope and construction of the new sports facility, while less emphasis is on the facility left behind, which we describe as shadow stadia. Some shadow stadia are repurposed for mixed use development, others are demolished but have delayed redevelopment plans, while some remain abandoned and empty for years after the professional sports team or event is no longer present in the facility. The environmental impacts of shadow stadia are not fully understood, as limited research exists on how the immediate neighborhood anchored by pre-existing venues cope in the shadows of these new development plans and the loss of a sport venue and its events. Green strategies such as the circular economy may extend the lifecycle of existing sport faciltiies. To contribute to this discussion further, this perspective article will first discuss current advances in the academic literature on the circular economy. Second, it will present a comprehensive categorization of shadow stadia globally and future opportunities on integrating circularity into best practices. By doing so, this perspective article highlights several areas of future investigation that should be considered and planned for when major league sports teams and city leaders move their team and build new facilities.

Arena-Anchored Urban Development Projects and the Visitor Economy.

Cities of all sizes are actively engaged in developing various urban infrastructure projects. A common strategy used in larger North American cities is employing arena-anchored urban development projects, where a professional sports team is used as an anchor tenant of a sports facility to generate development in the city. One means of relocating economic activity is to increase visitation to the desired redevelopment area. In this paper we used the visitor economy as a lens to explore how arena-anchored projects and the professional sports teams that play there fit into a local city's tourism economy. To conduct this study, a multi case study design was used to draw data from two cities: Columbus, Ohio, and Detroit, Michigan. Interviews were goal directed and conducted in person with leaders in Columbus (n = 9) and Detroit (n = 10), and inductive and deductive approaches to coding were undertaken in the form of content analysis. The results indicate that growing the visitor economy through arena anchored urban development relies on planned placemaking via the strategic approach of bundling diverse amenities together. These findings provide valuable feedback to those cities considering arena development projects, and how the arenas may be combined with other civic amenities to undergird the local visitor economy.

eDNAssay: A machine learning tool that accurately predicts qPCR cross-amplification.

Environmental DNA (eDNA) sampling is a highly sensitive and cost-effective technique for wildlife monitoring, notably through the use of qPCR assays. However, it can be difficult to ensure assay specificity when many closely related species co-occur. In theory, specificity may be assessed in silico by determining whether assay oligonucleotides have enough base-pair mismatches with nontarget sequences to preclude amplification. However, the mismatch qualities required are poorly understood, making in silico assessments difficult and often necessitating extensive in vitro testing-typically the greatest bottleneck in assay development. Increasing the accuracy of in silico assessments would therefore streamline the assay development process. In this study, we paired 10 qPCR assays with 82 synthetic gene fragments for 530 specificity tests using SYBR Green intercalating dye (n = 262) and TaqMan hydrolysis probes (n = 268). Test results were used to train random forest classifiers to predict amplification. The primer-only model (SYBR Green results) and full-assay model (TaqMan probe-based results) were 99.6% and 100% accurate, respectively, in cross-validation. We further assessed model performance using six independent assays not used in model training. In these tests the primer-only model was 92.4% accurate (n = 119) and the full-assay model was 96.5% accurate (n = 144). The high performance achieved by these models makes it possible for eDNA practitioners to more quickly and confidently develop assays specific to the intended target. Practitioners can access the full-assay model online via eDNAssay (https://NationalGenomicsCenter.shinyapps.io/eDNAssay), a user-friendly tool for predicting qPCR cross-amplification.

α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans.

Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of α-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to cases of Lewy body disorders. However, the link between APE1 and α-synuclein is unexplored. We report that knockdown or inhibition of APE1 amplified inclusion formation in primary hippocampal cultures challenged with preformed α-synuclein fibrils. Fibril infusions into the mouse olfactory bulb/anterior olfactory nucleus (OB/AON) elicited a modest decrease in APE1 expression in the brains of male mice but an increase in females. Similarly, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women. Preformed fibril infusions of the mouse OB/AON induced more robust base excision repair of DNA lesions in females than males. No fibril-mediated loss of APE1 expression was observed in male mice when the antioxidant N-acetylcysteine was added to their diet. These findings reveal a potential sex-biased link between α-synucleinopathy and APE1 in mice and humans. Further studies are warranted to determine how this multifunctional protein modifies α-synuclein inclusions and, conversely, how α-synucleinopathy and biological sex interact to modify APE1.

New Media, Digitalization, and the Evolution of the Professional Sport Industry.

The professional sport industry achieved tremendous success in the traditional broadcast media age, established a multi-sided market and an effective business model for revenue growth. However, the emergence and proliferation of the new media technologies have drastically changed the media landscape, creating a much more complicated cross-media environment that unites popularity and personalization, structure and agency. Such a changing environment creates transformations within the professional sport industry, and adapting to these transformations will lead to the evolution of the professional sport industry and its success in the digital media age.

Current status of ischemic stroke treatment: From thrombolysis to potential regenerative medicine.

Ischemic stroke is a major cause of death and disability worldwide and is expected to increase in the future with the aging population. Currently, there are no clinically available treatments for damage sustained during an ischemic stroke, but much research is being conducted in this area. In this review, we will introduce current ischemic stroke treatments along with their limitations, as well as research on potential short and long-term future treatments. There are advantages and disadvantages in these potential treatments, but our understanding of these methods and their effectiveness in clinical trials are improving. We are confident that some future treatments introduced in this review will become commonly used in clinical settings in the future.