Background: Epstein-Barr virus (EBV) infection is believed to be a critical prerequisite for the development of multiple sclerosis (MS). This study aims to investigate whether anti-EBV titres are elevated before the onset of MS symptoms in people with radiologically isolated syndrome (pwRIS) and to evaluate their association with markers of adverse clinical outcomes. Methods: Epstein-Barr nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) titres were quantified in a cohort of 47 pwRIS and 24 healthy controls using Enzyme-Linked Immuno-Sorbent Assay. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light protein (NfL) were measured using single-molecule array. MRI lesion metrics and the development of MS symptoms over time were also evaluated. Results: EBNA1 titres were higher pwRIS compared to healthy controls (p=0.038), while VCA titres were not (p=0.237). A positive correlation was observed between EBNA1 titres and plasma GFAP in pwRIS (p=0.005). Neither EBNA1 nor VCA titres correlated with NfL. MRI lesion measures and the development of MS symptoms did not show any significant relationship with EBNA1 or VCA titres. Conclusions: Eelevated EBNA1 titres are detectable prior to MS symptom onset and correlate with GFAP, a biomarker associated with worse clinical outcomes. However, their role in disease progression and clinical outcomes requires further investigation.

Background: Our prior six-year review (n=2165) revealed 24% of patients undergoing posterior decompression surgeries (laminectomy or discectomy) sought emergency department (ED) care within three months post-surgery. We established an integrated Spine Assessment Clinic (SAC) to enhance patient outcomes and minimize unnecessary ED visits through pre-operative education, targeted QI interventions, and early post-operative follow-up. Methods: We reviewed 13 months of posterior decompression data (n=205) following SAC implementation. These patients received individualized, comprehensive pre-operative education and follow-up phone calls within 7 days post-surgery. ED visits within 90 days post-surgery were tracked using provincial databases and compared to our pre-SAC implementation data. Results: Out of 205 patients, 24 (11.6%) accounted for 34 ED visits within 90 days post-op, showing a significant reduction in ED visits from 24% to 11.6%, and decreased overall ED utilization from 42.1% to 16.6% (when accounting for multiple visits by the same patient). Early interventions including wound monitoring, outpatient bloodwork, and prescription adjustments for pain management, helped mitigate ED visits. Patient satisfaction surveys (n=62) indicated 92% were “highly satisfied” and 100% would recommend the SAC. Conclusions: The SAC reduced ED visits after posterior decompression surgery by over 50%, with pre-operative education, focused QI initiatives, and its individualized, proactive approach.

Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

Background: In multiple sclerosis (MS), soluble mediators of neuroinflammation are released by activated lymphocytes and resident immune cells, leading to demyelination and neurodegeneration. Radiologically isolated syndrome (RIS) is an entity in which white matter lesions fulfilling criteria for MS occur in individuals without any suggestive symptoms. The exact nature of pro- and anti-inflammatory cytokines in blood, and their association with disease activity in RIS/MS requires further clarification. Methods: Plasma was collected and cryopreserved from healthy controls (HCs), people with RIS and relapsing-remitting MS (RRMS) at the Barlo MS Centre. All samples were analyzed with OLink Target 96 Inflammation Multiplex Immunoassay Panel. Results: Individuals with RIS (p=0.0001; p= 0.0007; p= 0.0012) and RRMS (p<0.0001; p= 0.0003; p= 0.00112) had significantly higher concentrations of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and chemokine ligand 23 (CCL23) in plasma compared to HCs, and patients with RRMS (p=0.0087) had significantly higher concentrations of HGF compared to individuals with RIS. Conclusions: Our study demonstrates that HGF, IL-6 and CCL23 are significantly increased in the plasma of patients with RIS and RRMS compared to HCs. Our observations suggest that the biology of MS is present in those with RIS, and these neuroinflammatory mediators may serve as a biomarker of disease activity.

Background: Nipocalimab is a human IgG1 monoclonal antibody targeting FcRn that selectively reduces IgG levels without impacting antigen presentation, T- and B-cell functions. This study describes the effect of nipocalimab on vaccine response. Methods: Open-label, parallel, interventional study randomized participants 1:1 to receive intravenous 30mg/kg nipocalimab at Week0 and 15mg/kg at Week2 and Week4 (active) or no drug (control). On Day 3, participants received Tdap and PPSV®23 vaccinations and were followed through Wk16. Results: Twenty-nine participants completed the study and are included (active, n=15; control, n=14). Participants with a positive anti-tetanus IgG response was comparable between groups at Wk2 and Wk16, but lower at Wk4 (nipocalimab 3/15 [20%] vs control 7/14 [50%]; P=0.089). All maintained anti-tetanus IgG above the protective threshold (0.16IU/mL) through Wk16. While anti-pneumococcal-capsular-polysaccharide (PCP) IgG levels were lower during nipocalimab treatment, the percent increase from baseline at Wk2 and Wk16 was comparable between groups. Post-vaccination, anti-PCP IgG remained above 50mg/L and showed a 2-fold increase from baseline throughout the study in both groups. Nipocalimab co-administration with vaccines was safe and well-tolerated. Conclusions: These findings suggest that nipocalimab does not impact the development of an adequate IgG response to T-cell–dependent/independent vaccines and that nipocalimab-treated patients can follow recommended vaccination schedules.

Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.

The Australian SKA Pathfinder (ASKAP) offers powerful new capabilities for studying the polarised and magnetised Universe at radio wavelengths. In this paper, we introduce the Polarisation Sky Survey of the Universe’s Magnetism (POSSUM), a groundbreaking survey with three primary objectives: (1) to create a comprehensive Faraday rotation measure (RM) grid of up to one million compact extragalactic sources across the southern $\sim50$% of the sky (20,630 deg$^2$); (2) to map the intrinsic polarisation and RM properties of a wide range of discrete extragalactic and Galactic objects over the same area; and (3) to contribute interferometric data with excellent surface brightness sensitivity, which can be combined with single-dish data to study the diffuse Galactic interstellar medium. Observations for the full POSSUM survey commenced in May 2023 and are expected to conclude by mid-2028. POSSUM will achieve an RM grid density of around 30–50 RMs per square degree with a median measurement uncertainty of $\sim$1 rad m$^{-2}$. The survey operates primarily over a frequency range of 800–1088 MHz, with an angular resolution of 20” and a typical RMS sensitivity in Stokes Q or U of 18 $\mu$Jy beam$^{-1}$. Additionally, the survey will be supplemented by similar observations covering 1296–1440 MHz over 38% of the sky. POSSUM will enable the discovery and detailed investigation of magnetised phenomena in a wide range of cosmic environments, including the intergalactic medium and cosmic web, galaxy clusters and groups, active galactic nuclei and radio galaxies, the Magellanic System and other nearby galaxies, galaxy halos and the circumgalactic medium, and the magnetic structure of the Milky Way across a very wide range of scales, as well as the interplay between these components. This paper reviews the current science case developed by the POSSUM Collaboration and provides an overview of POSSUM’s observations, data processing, outputs, and its complementarity with other radio and multi-wavelength surveys, including future work with the SKA.

In 2010, USAID catalyzed the formation of One Health University Networks as part of a holistic response designed to promote the One Health approach for addressing complex health challenges. This globally connected One Health University network now includes the African One Health University Network (AFROHUN) and the Southeast Asia University Network (SEAOHUN) and has representation from over 120 universities in 17 countries across Africa and Southeast Asia. Over more than 15 years of USAID investment, these networks have trained more than 85,000 students, in-service professionals and faculty around the world in One Health principles and collaborative problem solving, grounded in One Health core competencies. These One Health practitioners have gone on to contribute to improved global health security in their communities and countries. The evolution and maturation of these networks is a testament to a strong vision and dedication to the task by leadership and donors. As the global academic community continues to refine and adapt training methodologies for ‘future ready’ individuals, resources and examples from One Health University Networks stand as a legacy to build upon.

This paper investigates the association between potential serum biomarkers and diabetes status in older Australians by employing traditional and machine learning methods. Data from Sydney Memory and Ageing Study (MAS) were interrogated cross-sectionally in 801 participants aged 70–90 years (n = 801). Twenty-eight serum biomarkers and 6 other factors were investigated as potential indicators that may distinguish diabetes status. Diabetes status was categorised as No-Diabetes, Pre-diabetes, and Type 2 diabetes (T2D). Diabetes is defined as follows when using fasting plasma glucose: no diabetes/ normal: < 5.6 mmol/L; prediabetes: 5.6–6.9 mmol/L; and diabetes: ≥ 7 mmol/L(1). Variable selection was executed using two distinct regression methods (i) multinomial logistic regression with backward selection and (ii) machine learning using elasticNet regression. Multiple imputation was used to address missing data. Age and sex were included as a priori covariates in the multinomial regression model. Using a multinomial logistic regression, Malondialdehyde (MDA), Macrophage inhibiting cytokine 1 (MIC1), and vitamin E were associated with diabetes status. MDA was strongly associated with diabetes with relative risk ratio (RRR) of 4.78 (95% CI = 3.39, 6.75; p < 0.001) when comparing to no diabetes, surpassing usual markers insulin, triglycerides, and waist-to-hip (WHR). Diabetes was associated with lower vitamin E levels, compared to no diabetes, with an RRR of 0.54 (95% CI:0.38, 0.75; p < 0.001). Comparing diabetes to prediabetes, RRR for lower vitamin E levels was 0.71 (95% CI: 0.51, 0.98; p = 0.035). MIC1 distinguished between diabetes and prediabetes status (RRR: 1.84; 95% CI:1.41, 2.41; p < 0.001). Consistent with the traditional methods, machine learning also identified MDA as being associated with T2D, with an odds ratio (OR) of 1.9, followed hierarchically by insulin (OR = 1.23), WHR (OR = 1.22) and triglyceride (OR = 1.13). Higher serum Vitamin E were associated with a lower risk of being in diabetes category (OR = 0.84). MIC1, urate, IL1b, HDL, and carotene were identified by the machine learning model, but showed minimal association. These results suggest that the oxidative stress and inflammation markers distinguish the state of having T2D.

Objectives/Goals: Inclusive physical activity (PA) interventions could improve trans and gender diverse (TGD) adolescents’ PA levels, perceived social support from peers and adults, and mental health, but no stakeholder-informed interventions exist. We describe parents’ impressions of TGD adolescent children’s PA experiences and advice for a PA intervention. Methods/Study Population: We conducted individual Zoom interviews with parents of 13- to 20-year-old TGD adolescents (n = 15). All parents were recruited from a gender healthcare clinic. All children self-identified as TGD, an umbrella term including people who have a gender identity different from social expectations for their assigned sex. We asked questions regarding children’s current and historical participation in PA, parents’ perceptions of barriers to PA for their TGD children, and parents’ desired intervention components. After each interview, parent participants were compensated $100 for their time. We analyzed interview transcripts, focusing on insights to incorporate in an intervention. This study was approved by the University’s Institutional Review Board. Results/Anticipated Results: Parents shared rich histories of their children’s PA participation, compounding barriers to PA, numerous benefits of PA, and a range of preferences for program activities and inclusive practices (e.g., safety protocols, training for adult leaders). They also emphasized the need for TGD youth to build social connectedness through PA. Discussion/Significance of Impact: We gathered concrete advice from parents on creating a PA intervention, which we will use to build a social PA program that meets TGD adolescents’ needs. Addressing health disparities and improving PA, social support, and mental health among TGD adolescents will require such stakeholder input to improve upon existing PA and sports opportunities.

Water hyacinth is a highly invasive aquatic species in the southern United States that requires intensive management through frequent herbicide applications. Quantifying management success in large-scale operations is challenging with traditional survey methods that rely on boat-based teams and can be time-consuming and labor-intensive. In contrast, an unmanned aerial system (UAS) allows a single operator to survey a waterbody more efficiently and rapidly, enhancing both coverage and data collection. Therefore, the objective of this research was to develop remote sensing techniques to assess herbicide efficacy for water hyacinth control in an outdoor mesocosm study. Experiments were conducted in spring and summer 2023 to compare and correlate data from visual evaluations of herbicide efficacy against nine vegetation indices (VIs) derived from UAS-based red-green-blue imagery. Penoxsulam, carfentrazone, diquat, 2,4-D, florpyrauxifen-benzyl, and glyphosate were applied at two rates, and experimental units were evaluated for 6 wk. The carotenoid reflectance index (CRI) had the highest Spearman’s correlation coefficient with visually evaluated efficacy for 2,4-D, diquat, and florpyrauxifen benzyl (> −0.77). The visible atmospherically resistance index (VARI) had the highest correlation with carfentrazone and penoxsulam treatments (> −0.70), and the excess greenness minus redness index had the highest correlation for glyphosate treatments (> −0.83). CRI had the highest correlation coefficient with the most herbicide treatments, and it was the only VI tested that did not include the red band. These VIs were satisfactory predictors of mid-range visually evaluated herbicide efficacy values but were poorly correlated with extremely low and high values, corresponding to nontreated and necrotic plants. Future research should focus on applying findings to real-world (nonexperimental) field conditions and testing imagery with spectral bands beyond the visible range.

We construct a Divisia money measure for U.K. households and private non-financial corporations and a corresponding dual user cost index employing a consistent methodology from 1977 up to the present. Our joint construction of both the Divisia quantity index and the Divisia price dual facilitates an investigation of structural vector autoregresssion models (SVARs) over a long sample period of the type of non-recursive identifications explored by Belongia and Ireland (2016, 2018), as well as the block triangular specification advanced by Keating et al. (2019). An examination of the U.K. economy reveals that structures that consider a short-term interest rate to be the monetary policy indicator generate unremitting price puzzles. In contrast, we find sensible economic responses in various specifications that treat our Divisia measure as the indicator variable.

We provide an assessment of the Infinity Two fusion pilot plant (FPP) baseline plasma physics design. Infinity Two is a four-field period, aspect ratio $A = 10$, quasi-isodynamic stellarator with improved confinement appealing to a max-$J$ approach, elevated plasma density and high magnetic fields ($ \langle B\rangle = 9$ T). Here $J$ denotes the second adiabatic invariant. At the envisioned operating point ($800$ MW deuterium-tritium (DT) fusion), the configuration has robust magnetic surfaces based on magnetohydrodynamic (MHD) equilibrium calculations and is stable to both local and global MHD instabilities. The configuration has excellent confinement properties with small neoclassical transport and low bootstrap current ($|I_{bootstrap}| \sim 2$ kA). Calculations of collisional alpha-particle confinement in a DT FPP scenario show small energy losses to the first wall (${\lt}1.5 \,\%$) and stable energetic particle/Alfvén eigenmodes at high ion density. Low turbulent transport is produced using a combination of density profile control consistent with pellet fueling and reduced stiffness to turbulent transport via three-dimensional shaping. Transport simulations with the T3D-GX-SFINCS code suite with self-consistent turbulent and neoclassical transport predict that the DT fusion power$P_{{fus}}=800$ MW operating point is attainable with high fusion gain ($Q=40$) at volume-averaged electron densities $n_e\approx 2 \times 10^{20}$ m$^{-3}$, below the Sudo density limit. Additional transport calculations show that an ignited ($Q=\infty$) solution is available at slightly higher density ($2.2 \times 10^{20}$ m$^{-3}$) with $P_{{fus}}=1.5$ GW. The magnetic configuration is defined by a magnetic coil set with sufficient room for an island divertor, shielding and blanket solutions with tritium breeding ratios (TBR) above unity. An optimistic estimate for the gas-cooled solid breeder designed helium-cooled pebble bed is TBR $\sim 1.3$. Infinity Two satisfies the physics requirements of a stellarator fusion pilot plant.