Enhancing the Effectiveness of the Telescope Assembly Alignment Simulator

SOFIA - Stratospheric Observatory for Infrared Astronomy is a 747sp Boeing aircraft modified to carry a 2.7m telescope. This unique aircraft uses infrared light to study the hidden universe, create a greater understanding of local galaxies and observe the past of our universe. To enhance the effectiveness of the telescope on SOFIA, a baseline of an ideal science instrument needs to be established in a lab setting to help reduce time and make things more efficient when SOFIA is flying. This baseline can be done using the TAAS – Telescope Assembly Alignment Simulator, an instrument that simulates the telescope on SOFIA. In this project, the research team uses the Focus Chop Light Source (FCLS) instrument to mimic a blackbody source on the TAAS. There are 6 different sized aperture holes on the FCLS. These sizes represent different magnitudes of starlight. Optimization of the light path for the TAAS is needed to ensure an ideal baseline

CD28 costimulation in T cells: requirements, outcomes and regulation

The costimulatory receptor CD28 and its inhibitory counterpart CTLA-4 share the same ligands and comprise a crucial checkpoint in T cell activation. CTLA-4 removes its ligands from antigen presenting cells by trans-endocytosis, which reduces the availability of costimulatory ligands for CD28 engagement to regulate T cell activation. This project examined the functional implications of reducing the availability of costimulatory molecules for CD4 T cell responses, and investigated the use of trans-endocytosis by other T cell receptors. Surprisingly, it was revealed that PD-1 and OX40 can also internalise their ligands, although perhaps not via the same mechanism as CTLA-4 trans-endocytosis. It was also shown that altering the availability of CD28 ligands affects the extent of T cell proliferation, suggesting that CTLA-4 trans-endocytosis can finely tune the T cell response. Furthermore, it was observed that CD28 costimulation is not always required for T cell activation and proliferation, but CD28 engagement is required for the optimal upregulation of a number of effector proteins and for TH2 cytokine production. Interestingly, T cells activated in the absence of CD28 signalling were not classically anergic. Strikingly, it was also found that memory T cells are dependent on CD28 costimulation

Optimizing the Telescope Assembly Alignment Simulator for SOFIA

The Stratospheric Observatory for Infrared Astronomy (SOFIA) conducts research on a modified Boeing 747sp aircraft. By using a variety of infrared science instruments mounted on a 2.7 meter telescope, researchers can make discoveries about the galactic center, star formation, and various topics associated with a deeper understanding of our universe. To efficiently collect data through the SOFIA instruments, the instruments must be tested and prepared prior to being placed on the aircraft. Therefore, with the use of the Telescope Assembly Alignment Simulator (TAAS), researchers can design and construct improvements needed for these instruments to efficiently perform while in flight. The TAAS simulates an infrared light source through several different installed plates, The Large Chop Hot Plate (LCHP), the Small Chop Hot Plate (SCHP), and the Focus Chopping Light Source (FCLS). This research project focuses on creating a deeper characterization and optimization for the TAAS as well as improving the overall test instrument in order to make refinements on instruments with wide fields of view, such as HAWC+. The research team specifically realigned the TAAS aperture through the use of an infrared camera and the computer software, TAAS FCLS Alignment, and used the focus light source to eliminate aberrations that were discovered by on recent HAWC+ observations. Likewise, the team made developments on the FCLS as needed for the new instrument installments

RSL Rover

The goal of this project was to design and implement an unmanned vehicle that can assess the air quality and general state of a post-fire environment. To do this, we equipped Santa Clara University\u27s Polaris 6x6 Ranger with appropriate sensors and cameras to determine how safe the environment is for humans to enter. We also used GPS and laser scans to generate a 3D map that operators can use to define certain zones as particularly dangerous. Finally, we incorporated partially-autonomous sensing capabilities that will allow the operator to easily drive the vehicle. The result was a rugged, advanced, and intuitive vehicle that can be used to protect fire responders from any lingering hazards during the investigation of a post-fire environment. This vehicle is accompanied by a powerful operating system and localization techniques that will allow any future research groups to help this vehicle evolve into a fully autonomous system

1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept

Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell–mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment

Artificial intelligence-based decision support software to improve the efficacy of acute stroke pathway in the NHS: an observational study

IntroductionIn a drip-and-ship model for endovascular thrombectomy (EVT), early identification of large vessel occlusion (LVO) and timely referral to a comprehensive center (CSC) are crucial when patients are admitted to an acute stroke center (ASC). Several artificial intelligence (AI) decision-aid tools are increasingly being used to facilitate the rapid identification of LVO. This retrospective cohort study aimed to evaluate the impact of deploying e-Stroke AI decision support software in the hyperacute stroke pathway on process metrics and patient outcomes at an ASC in the United Kingdom.MethodsExcept for the deployment of e-Stroke on 01 March 2020, there were no significant changes made to the stroke pathway at the ASC. The data were obtained from a prospective stroke registry between 01 January 2019 and 31 March 2021. The outcomes were compared between the 14 months before and 12 months after the deployment of AI (pre-e-Stroke cohort vs. post-e-Stroke cohort) on 01 March 2020. Time window analyses were performed using Welch’s t-test. Cochran–Mantel–Haenszel test was used to compare changes in disability at 3 months assessed by modified Rankin Score (mRS) ordinal shift analysis, and Fisher’s exact test was used for dichotomised mRS analysis.ResultsIn the pre-e-Stroke cohort, 19 of 22 patients referred received EVT. In the post-e-Stroke cohort, 21 of the 25 patients referred were treated. The mean door-in-door-out (DIDO) and door-to-referral times in pre-e-Stroke vs. post-e-Stroke cohorts were 141 vs. 79 min (difference 62 min, 95% CI 96.9–26.8 min, p < 0.001) and 71 vs. 44 min (difference 27 min, 95% CI 47.4–5.4 min, p = 0.01), respectively. The adjusted odds ratio (age and NIHSS) for mRS ordinal shift analysis at 3 months was 3.14 (95% CI 0.99–10.51, p = 0.06) and the dichotomized mRS 0–2 at 3 months was 16% vs. 48% (p = 0.04) in the pre- vs. post-e-Stroke cohorts, respectively.ConclusionIn this single-center study in the United Kingdom, the DIDO time significantly decreased since the introduction of e-Stroke decision support software into an ASC hyperacute stroke pathway. The reduction in door-in to referral time indicates faster image interpretation and referral for EVT. There was an indication of an increased proportion of patients regaining independent function after EVT. However, this should be interpreted with caution given the small sample size. Larger, prospective studies and further systematic real-world evaluation are needed to demonstrate the widespread generalisability of these findings

Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of “vitamin D status”. However, utilization of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1α-hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we now show that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact resulting in the generation and release of 1,25(OH)(2)D(3) which subsequently affects T cell responses. In most tissues, vitamin D binding protein (DBP) acts as a carrier to enhance the utilization of vitamin D. However, we show that DBP modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of “free” 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure. Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients. Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54–1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection. Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK

BACKGROUND: Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. METHODS: In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. FINDINGS: Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8-4·4]; p<0·0001). INTERPRETATION: The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions. FUNDING: Kidney Research UK