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Abstract Objective Intranasal medications have been proposed as adjuncts to out‐of‐hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows. Methods We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands‐only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group. Results Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment (p = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. −9.1 cpm, 95% CI −16.6, −1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. −7.5%, 95% CI −12.0, −2.9). Among FRs, we found no significant CPR2 delays (mean diff. −2.1 s, 95% CI −15.9, 11.7), which persisted after adjustment (p = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. −5.3 cpm, 95% CI −12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. −1.6%, 95% CI −7.4, 4.3%) Conclusions INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality.

Methicillin-resistant Staphylococcus aureus (MRSA) infections in neonates can result in significant morbidity and mortality. However, comparatively to adults, neonatal MRSA data remains relatively scarce. Additionally, while evidence-driven practices for adults have seen considerable progress, neonatal infection prevention strategies remain poorly described. The Leeds Newborn Service adopted a series of infection prevention and control (IPC) measures following a rise in MRSA cases in 2008–2009. This narrative review presents IPC measures for neonatal MRSA and methicillin-sensitive Staphylococcus aureus (MSSA) infections and reflects upon local challenges and successes of these interventions. Our experience underscores the importance of an adaptive, evidence-based strategy, tailored to the neonatal population. Effectively addressing MRSA/MSSA requires continuous monitoring with sustained targeted interventions. Our key learning points highlight the intertwined difficulties of specific neonatal requirements and lack of definitive IPC guidance, suggesting a holistic approach is key for successful IPC outcomes in the neonatal intensive care unit setting.

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that θ_{13}>0. The measured value of θ_{13} is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable of making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti)neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EUROν Design Study consortium. EUROν coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EUROν baseline accelerator facility will provide 10^{21} muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.

We present a new design study of the neutrino Super Beam based on the Superconducting Proton Linac at CERN. This beam is aimed at megaton mass physics, a large water Cherenkov detector, proposed for the Laboratoire Souterrain de Modane in France, with a baseline of 130 km. The aim of this proposed facility is to study CP violation in the neutrino sector. In the study reported here, we have developed the conceptual design of the neutrino beam, especially the target and the magnetic focusing device. Indeed, this beam presents several unprecedented challenges, related to the high primary proton beam power (4 MW), the high repetition rate (50 Hz), and the low kinetic energy of the protons (4.5 GeV). The design is completed by a study of all the main components of the system, starting from the transport system to guide the beam to the target up to the beam dump. This is the first complete study of a neutrino beam based on a pebble-bed target capable of standing the large heat deposition of MW class proton beams.

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ^{+} and μ^{-} beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular ^{6}He and ^{18}Ne, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive.

Summary: Optogenetics is a rapidly advancing technology combining photochemical, optical, and synthetic biology to control cellular behavior. Together, sensitive light-responsive optogenetic tools and human pluripotent stem cell differentiation models have the potential to fine-tune differentiation and unpick the processes by which cell specification and tissue patterning are controlled by morphogens. We used an optogenetic bone morphogenetic protein (BMP) signaling system (optoBMP) to drive chondrogenic differentiation of human embryonic stem cells (hESCs). We engineered light-sensitive hESCs through CRISPR-Cas9-mediated integration of the optoBMP system into the AAVS1 locus. The activation of optoBMP with blue light, in lieu of BMP growth factors, resulted in the activation of BMP signaling mechanisms and upregulation of a chondrogenic phenotype, with significant transcriptional differences compared to cells in the dark. Furthermore, cells differentiated with light could form chondrogenic pellets consisting of a hyaline-like cartilaginous matrix. Our findings indicate the applicability of optogenetics for understanding human development and tissue engineering.

Approximate methods for radiative transfer equations that are fast, reliable, and accurate are essential for the understanding of atmospheres of exoplanets and brown dwarfs. The simplest and most popular choice is the “two-stream method,” which is often used to produce simple yet effective models for radiative transfer in scattering and absorbing media. Toon et al. (hereafter, Toon89) outlined a two-stream method for computing reflected light and thermal spectra that was later implemented in the open-source radiative transfer model PICASO . In Part I of this series, we developed an analytical spherical harmonics method for solving the radiative transfer equation for reflected solar radiation that was implemented in PICASO to increase the accuracy of the code by offering a higher-order approximation. This work is an extension of this spherical harmonics derivation, to study thermal emission spectroscopy. We highlight the model differences in the approach for thermal emission and benchmark the four-term method (SH4) against Toon89 and a high-stream discrete-ordinates method, CDISORT . By comparing the spectra produced by each model, we demonstrate that the SH4 method provides a significant increase in accuracy, compared to Toon89, which can be attributed to the increased order of approximation and to the choice of phase function. We also explore the trade-off between computational time and model accuracy. We find that our four-term method is twice as slow as our two-term method, but is up to five times more accurate, when compared with CDISORT . Therefore, SH4 provides excellent improvement in model accuracy with minimal sacrifice in numerical expense.

Introduction: Case-based learning (CBL) utilizes authentic clinical cases that connect theory to practice. CBL has been shown to result in deeper learning and high engagement of adult learners. An open-source, web-based CBL module was created to help learners develop the cognitive foundation of ectopic pregnancy management in the low-resource setting. We present psychometric evidence that supports the use of this web-based CBL in the low-resource setting. Methods: The case scenario comprising 20 topics in ectopic pregnancy management was created by an Ethiopian team member and hosted on an interactive web-based platform. The module was reviewed by Ethiopian, Cameroonian, and US surgeons and OB/GYN team members for content, relevance, and clarity, followed by a psychometrician for clarity, bias, relevance, and alignment. Twenty participants (3-Mbingo Baptist Hospital-Cameroon, 6-Soddo Christian Hospital-Ethiopia, 3-Southern Illinois University (SIU), and 8-University of Michigan (UM)) then completed the module. Four attending surgeons (2 OB/GYN, 2 general surgery) were designated experts while 10 medical students and 6 residents were designated novices. The module included a 10-item dichotomously scored pre-test, the CBL content, and the same, but shuffled, post-test. Pre- and post-test summed scores were compared using paired Student's t-tests, while differences in scores across participants' experience levels and sites were analyzed using a many-facet Rasch model. Results: Findings indicated a statistically significant improvement in participants’ mean summed scores from pre-test (M = 6.7, SD = 2.2) to post-test (M = 9.0, SD = 1.5), t(20) = – 4.76, P < 0.0001 and confirmed by Rasch analysis, P < 0.001. An adequate distribution of difficulty was demonstrated and 80% of questions had high discrimination value between experts and novices, d = | 0.87, 1.40 |. There was no difference in scores across specialties. Following the module, expert scores (M = 9.7) were higher than novice scores (M = 9.0), but the difference was not statistically significant. Conclusion: Our findings suggest that using a web-based CBL module could be used to effectively improve understanding of the management of ectopic pregnancy in the low-resource setting, especially for nascent surgeons. The concept of a web-based CBL module has special attraction in the low-resource setting as it may target the adult surgical learner in remote regions where established technologies and existing experts are unavailable.

ABSTRACT Intestinal colonization with pathogens and antimicrobial-resistant organisms (AROs) is associated with increased risk of infection. Fecal microbiota transplant (FMT) has successfully been used to cure recurrent Clostridioides difficile infection (rCDI) and to decolonize intestinal AROs. However, FMT has significant practical barriers to safe and broad implementation. Microbial consortia represent a novel strategy for ARO and pathogen decolonization, with practical and safety advantages over FMT. We undertook an investigator-initiated analysis of stool samples collected from previous interventional studies of a microbial consortium, microbial ecosystem therapeutic (MET-2), and FMT for rCDI before and after treatment. Our aim was to assess whether MET-2 was associated with decreased Pseudomonadota (Proteobacteria) and antimicrobial resistance gene (ARG) burden with similar effects to FMT. Participants were selected for inclusion if baseline stool had Pseudomonadota relative abundance ≥10%. Pre- and post-treatment Pseudomonadota relative abundance, total ARGs, and obligate anaerobe and butyrate-producer relative abundances were determined by shotgun metagenomic sequencing. MET-2 administration had similar effects to FMT on microbiome outcomes. The median Pseudomonadota relative abundance decreased by four logs after MET-2 treatment, a greater decrease than that observed after FMT. Total ARGs decreased, while beneficial obligate anaerobe and butyrate-producer relative abundances increased. The observed microbiome response remained stable over 4 months post-administration for all outcomes. IMPORTANCE Overgrowth of intestinal pathogens and AROs is associated with increased risk of infection. With the rise in antimicrobial resistance, new therapeutic strategies that decrease pathogen and ARO colonization in the gut are needed. We evaluated whether a microbial consortium had similar effects to FMT on Pseudomonadota abundances and ARGs as well as obligate anaerobes and beneficial butyrate producers in individuals with high Pseudomonadota relative abundance at baseline. This study provides support for a randomized, controlled clinical trial of microbial consortia (such as MET-2) for ARO decolonization and anaerobe repletion.

IntroductionMental health difficulties in early childhood can have a debilitating and ongoing impact throughout an individual’s life; emotion regulation can serve as a protective factor. Therefore, evidence-based prevention programs that teach children effective skills and strategies for emotion regulation are needed.MethodsAs part of the Aussie Optimism pilot study evaluating the “I Spy Feelings” program, this study aims to assess the short-term effects of the program on emotion regulation in pre-primary aged children after 2 months via a longitudinal cluster randomized controlled trial. Participants included parents (N = 73) of 5- to 6-year-old children attending four different Catholic primary schools. Children from two of the schools were allocated to the intervention group where they participated in the program (N = 33), while children from the other two schools were allocated to the control group where they did not (N = 40). At each time point, all parents completed abridged Children’s Emotional Management Scales measuring how well parents believe their child is able to cope with anger, sadness and worry.ResultsA significant intervention effect 2 months after intervention was found for the outcome of anger coping such that parents whose children were in the intervention group reported significantly greater improvement in their children’s ability to cope with anger compared to parents whose children were in the control group. No significant effect was found for the outcome of sadness, and results for the worry subscale were inconclusive due to unacceptable internal consistency.DiscussionThe present study provides insight into the benefit of programs designed to enhance the emotion regulation skills of very young children. Further follow-up is needed to assess whether the “I Spy Feelings” program has lasting effects.

Abstract We previously demonstrated that P. aeruginosa isolates that persisted in children with cystic fibrosis (CF) despite inhaled tobramycin treatment had increased anti-Psl antibody binding in vitro compared to those successfully eradicated. We aimed to validate these findings by directly visualizing P. aeruginosa in CF sputum. This was a prospective observational study of children with CF with new-onset P. aeruginosa infection who underwent inhaled tobramycin eradication treatment. Using microbial identification passive clarity technique (MiPACT), P. aeruginosa was visualized in sputum samples obtained before treatment and classified as persistent or eradicated based on outcomes. Pre-treatment isolates were also grown as biofilms in vitro. Of 11 patients enrolled, 4 developed persistent infection and 7 eradicated infection. P. aeruginosa biovolume and the number as well as size of P. aeruginosa aggregates were greater in the sputum of those with persistent compared with eradicated infections (p

Abstract Introduction Glaucoma is the leading cause of irreversible blindness worldwide and is often undetected in resource-limited settings. Early screening and treatment of elevated intraocular pressure (IOP) reduces both the development and progression of visual field defects. IOP screening in developing countries is limited by access to ophthalmic equipment, trained ophthalmic staff, and follow up. High-volume cataract surgery outreaches in resource-limited countries provide ample opportunity for glaucoma screening, intervention and follow up. Methods This prospective cross-sectional study took place during a cataract outreach campaign sponsored by the Himalayan Cataract Project (HCP) in partnership with Felege Hiwot Hospital in Bahir Dar, Ethiopia, during April 5th – April 10th 2021. IOP was measured on the surgical eye of patients before undergoing small incision cataract surgery (SICS) using rebound tonometry with an iCare tonometer model IC100. Results Intraocular pressure (IOP) was measured in 604 eyes of 595 patients who received SICS. Mean IOP was 12.1 mmHg (SD = 5.0 mmHg). A total of 29 patients had an IOP greater than 21 mmHg representing 4.8% of total IOP measurements. A total of 17 patients received oral acetazolamide prior to surgery to acutely lower IOP. Six of these patients had their surgery delayed due to elevated IOP and 9 patients received excisional goniotomy at the time of SICS. A temporal approach during SCIS was taken for all patients with elevated IOP to allow for possible trabeculectomy at a future date. Discussion IOP screening during high-volume cataract outreach campaigns can be performed safely, accurately and on a large scale with minimal resources and supplemental training. Pre-operative IOP measurement can improve surgical care at the time of cataract surgery as well as help establish long-term follow up for patients with glaucoma.

Background The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it.Methods CD45RO+CD45RA− memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include naïve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) Vβ repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma.Results Depletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the naïve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses.Conclusion Our findings suggest that naïve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials: NCT01555892 and NCT04288726 using autologous and allogeneic EBVSTs to treat lymphoma and NCT04013802 using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.

The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral blood T-cells with overlapping peptide libraries spanning the EBV lymphoma antigens, LMP1, LMP2, and EBNA 1, followed by retroviral vector transduction to express the C7R. The C7R increased STAT5 signaling in EBVSTs and enhanced their expansion over 30 days of culture in the presence or absence of exogenous cytokines. C7R-EBVSTs maintained EBV antigen specificity but were dependent on TCR stimulation for continued expansion. C7R-EBVSTs produced more rapid lymphoma control in a murine xenograft model than unmodified EBVSTs and persisted for longer. The findings have led to a clinical trial, evaluating C7R-EBVSTs for the treatment of refractory or relapsed EBV-positive lymphoma (NCT04664179).

Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including ‘delta’ and ‘omicron’). The feasibility of making and safely utilizing such virus-specific T cells clinically was assessed by administering partially HLA-matched, third-party, cryopreserved SARS-CoV-2-specific T cells (ALVR109) in combination with other antiviral agents to four individuals who were hospitalized with COVID-19. This study establishes the feasibility of preparing and delivering off-the-shelf, SARS-CoV-2-directed, virus-specific T cells to patients with COVID-19 and supports the clinical use of these products outside of the profoundly immune compromised setting (ClinicalTrials.gov number, NCT04401410).

Purpose: Adoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC. Materials and methods: MultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally recurrent unresectable BC of all subtypes and infused at a fixed dose level of 2 × 10 7 /m 2 . Patients received two infusions of cells 4 weeks apart and safety and clinical activity were determined. Cells were administered in an outpatient setting and without prior lymphodepleting chemotherapy. Results: All patients had estrogen receptor/progesterone receptor positive BC, with one patient also having human epidermal growth factor receptor 2-positive. There were no treatment-related toxicities and the infusions were well tolerated. Of the 10 heavily pre-treated patients enrolled and infused with multiTAA T cells, nine had disease progression while one patient with 10 lines of prior therapies experienced prolonged (5 months) disease stabilization that was associated with the in vivo expansion and persistence of T cells directed against the targeted antigens. Furthermore, antigen spreading and the endogenous activation of T cells directed against a spectrum of non-targeted tumor antigens were observed in 7/10 patients post-multiTAA infusion. Conclusion: MultiTAA T cells were well tolerated and induced disease stabilization in a patient with refractory BC. This was associated with in vivo T-cell expansion, persistence, and antigen spreading. Future directions of this approach may include additional strategies to enhance the therapeutic benefit of multiTAA T cells in patients with BC.

ABSTRACT Short-read sequencing can provide detection of multiple genomic determinants of antimicrobial resistance from single bacterial genomes and metagenomic samples. Despite its increasing application in human, animal, and environmental microbiology, including human clinical trials, the performance of short-read Illumina sequencing for antimicrobial resistance gene (ARG) detection, including resistance-conferring single nucleotide polymorphisms (SNPs), has not been systematically characterized. Using paired-end 2 × 150 bp (base pair) Illumina sequencing and an assembly-based method for ARG prediction, we determined sensitivity, positive predictive value (PPV), and sequencing depths required for ARG detection in an Escherichia coli isolate of sequence type (ST) 38 spiked into a synthetic microbial community at varying abundances. Approximately 300,000 reads or 15× genome coverage was sufficient to detect ARGs in E. coli ST38, with comparable sensitivity and PPV to ~100× genome coverage. Using metagenome assembly of mixed microbial communities, ARG detection at E. coli relative abundances of 1% would require assembly of approximately 30 million reads to achieve 15× target coverage. The minimum sequencing depths were validated using public data sets of 948 E. coli genomes and 10 metagenomic rectal swab samples. A read-based approach using k-mer alignment (KMA) for ARG prediction did not substantially improve minimum sequencing depths for ARG detection compared to assembly of the E. coli ST38 genome or the combined metagenomic samples. Analysis of sequencing depths from recent studies assessing ARG content in metagenomic samples demonstrated that sequencing depths had a median estimated detection frequency of 84% (interquartile range: 30%–92%) for a relative abundance of 1%. IMPORTANCE Systematically determining Illumina sequencing performance characteristics for detection of ARGs in metagenomic samples is essential to inform study design and appraisal of human, animal, and environmental metagenomic antimicrobial resistance studies. In this study, we quantified the performance characteristics of ARG detection in E. coli genomes and metagenomes and established a benchmark of ~15× coverage for ARG detection for E. coli in metagenomes. We demonstrate that for low relative abundances, sequencing depths of ~30 million reads or more may be required for adequate sensitivity for many applications.

The Saturnian moon Enceladus presents a unique opportunity to sample the contents of a subsurface liquid water ocean in situ via the continuous plume formed over its south polar terrain using a multi-flyby mission architecture. Previous analyses of the plume’s composition by Cassini revealed an energy-rich system laden with salts and organic compounds, representing an environment containing most of the ingredients for life as we know it. Following in the footsteps of the Cassini-Huygens mission, we present Astrobiology eXploration at Enceladus (AXE), a New Frontiers class Enceladus mission concept study carried out during the 2021 NASA Planetary Science Summer School program at the Jet Propulsion Laboratory, California Institute of Technology. We demonstrate that a scientifically compelling geophysical and life-detection mission to Enceladus can be carried out within the constraints of a New Frontiers-5 cost cap using a modest instrument suite, requiring only a narrow angle, high-resolution telescopic imager, a mass spectrometer, and a high-gain antenna for radio communications and gravity science measurements. Using a multi-flyby mission architecture, AXE would evaluate the habitability and potential for life at Enceladus through a synergistic combination of in situ chemical analysis measurements aimed at directly detecting the presence of molecular biosignatures, along with geophysical and geomorphological investigations to contextualize chemical biosignatures and further evaluate the habitability of Enceladus over geologic time.

A significant challenge in radiative transfer theory for atmospheres of exoplanets and brown dwarfs is the derivation of computationally efficient methods that have adequate fidelity to more precise, numerically demanding solutions. In this work, we extend the capability of the first open-source radiative transfer model for computing the reflected light of exoplanets at any phase geometry, PICASO (Planetary Intensity Code for Atmospheric Spectroscopy Observations). Until now, PICASO has implemented two-stream approaches to the solving the radiative transfer equation for reflected light, in particular following the derivations of Toon et al. In order to improve the model accuracy, we have considered higher-order approximations of the phase functions; namely, we have increased the order of approximation from two to four, using spherical harmonics. The spherical harmonics approximation decouples spatial and directional dependencies by expanding the intensity and phase function into a series of spherical harmonics, or Legendre polynomials, allowing for analytical solutions for low-order approximations to optimize computational efficiency. We rigorously derive the spherical harmonics method for reflected light and benchmark the four-term method (SH4) against Toon et al. and two independent and higher-fidelity methods ( CDISORT and doubling method). On average, the SH4 method provides an order-of-magnitude increase in accuracy, compared to Toon et al. Finally, we implement SH4 within PICASO and observe only a modest increase in computational time, compared to two-stream methods (20% increase).