Magnetic Field Modeling and Visualization of the Europa Clipper Spacecraft.

The goal of NASA's Europa Clipper Mission is to investigate the habitability of the subsurface ocean within the Jovian moon Europa using a suite of ten investigations. The Europa Clipper Magnetometer (ECM) and Plasma Instrument for Magnetic Sounding (PIMS) investigations will be used in unison to characterize the thickness and electrical conductivity of Europa's subsurface ocean and the thickness of the ice shell by sensing the induced magnetic field, driven by the strong time-varying magnetic field of the Jovian environment. However, these measurements will be obscured by the magnetic field originating from the Europa Clipper spacecraft. In this work, a magnetic field model of the Europa Clipper spacecraft is presented, characterized with over 260 individual magnetic sources comprising various ferromagnetic and soft-magnetic materials, compensation magnets, solenoids, and dynamic electrical currents flowing within the spacecraft. This model is used to evaluate the magnetic field at arbitrary points around the spacecraft, notably at the locations of the three fluxgate magnetometer sensors and four Faraday cups which make up ECM and PIMS, respectively. The model is also used to evaluate the magnetic field uncertainty at these locations via a Monte Carlo approach. Furthermore, both linear and non-linear gradiometry fitting methods are presented to demonstrate the ability to reliably disentangle the spacecraft field from the ambient using an array of three fluxgate magnetometer sensors mounted along an 8.5-meter (m) long boom. The method is also shown to be useful for optimizing the locations of the magnetometer sensors along the boom. Finally, we illustrate how the model can be used to visualize the magnetic field lines of the spacecraft, thus providing very insightful information for each investigation. Supplementary Information: The online version contains supplementary material available at 10.1007/s11214-023-00974-y.

Intranasal Anticholinergics for Treatment of Chronic Rhinitis: Systematic Review and Meta-Analysis.

OBJECTIVE: Topical intranasal anticholinergics are commonly prescribed for the relief of chronic rhinitis and associated symptoms, warranting thorough assessment of the supporting evidence. The present study aimed to evaluate the safety and efficacy of anticholinergic nasal sprays in the management of allergic and non-allergic rhinitis symptom severity and duration. METHODS: A search encompassing the Cochrane Library, PubMed/MEDLINE, and Scopus databases was conducted. Primary studies describing rhinorrhea, nasal congestion, and/or postnasal drip outcomes in rhinitis patients treated with an anticholinergic spray were included for review. RESULTS: The search yielded 1,029 unique abstracts, of which 12 studies (n = 2,024) met inclusion criteria for qualitative synthesis and 9 (n = 1,920) for meta-analysis. Median follow-up was 4 weeks and ipratropium bromide was the most extensively trialed anticholinergic. Compared to placebo, anticholinergic treatment was demonstrated to significantly reduce rhinorrhea severity scores (standardized mean difference [95% CI] = -0.77 [-1.20, -0.35]; -0.43 [-0.72, -0.13]) and duration (-0.62 [-0.95, -0.30]; -0.29 [-0.47, -0.10]) in allergic and non-allergic rhinitis patients respectively. Benefit was less consistent for nasal congestion, postnasal drip, and sneezing symptoms. Reported adverse effects included nasal mucosa dryness or irritation, epistaxis, headaches, and pharyngitis, though comparison to placebo found significantly greater risk for epistaxis only (risk ratio [95% CI] = 2.19 [1.22, 3.93]). CONCLUSION: Albeit treating other symptoms with less benefit, anticholinergic nasal sprays appear to be safe and efficacious in reducing rhinorrhea severity and duration in both rhinitis etiologies. This evidence supports their continued use in the treatment of rhinitis-associated rhinorrhea. LEVEL OF EVIDENCE: 1 Laryngoscope, 133:722-731, 2023.

Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown. METHODS: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis. RESULTS: Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls. CONCLUSIONS: Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

Alcoholic Liver Disease Epidemiology in the United States: A Retrospective Analysis of 3 US Databases.

OBJECTIVES: Alcoholic liver disease (ALD) prevalence, particularly the subset with advanced liver disease, is not well defined. Herein, we aim to provide a comprehensive assessment of ALD epidemiology across the spectrum of disease severity and across different settings using 3 unique US databases. METHODS: We performed a retrospective, observational study of US adults with ALD using 2001-2016 National Health and Nutrition Examination Survey (NHANES), 2007-2014 Nationwide Inpatient Sample (NIS), and 2007-2017 United Network for Organ Sharing (UNOS) registry. ALD in the NHANES was defined using clinical laboratory data and self-reported alcohol use, among which fibrosis-4 score of >2.67 defined stage ≥3 fibrosis. Alcoholic cirrhosis (AC) in the NIS was identified using International Classification of Diseases, Ninth Revision codes. ALD in the UNOS was identified using UNOS coding. RESULTS: From 2001-2002 to 2015-2016, the overall weighted ALD prevalence was stable from 8.8% to 8.1% (P = 0.102), whereas the proportion of ALD with stage ≥3 fibrosis increased from 2.2% (95% CI: 0.4-4.0) to 6.6% (95% CI: 2.0-9.9; P = 0.007) (NHANES). From 2007 to 2014, the number of hospitalizations among patients with AC per 1,000 increased by 32.8%, and the proportion of hospitalizations among the patients with AC with ≥3 cirrhosis complications increased from 11.6% in 2007 to 25.8% in 2014 (Ptrend < 0.0001) (NIS). From 2007 to 2017, the total number of adults with ALD listed for liver transplant increased by 63.4% and the proportion with concurrent hepatocellular carcinoma increased by 178% (UNOS). DISCUSSION: Among these 3 US databases, consistent observations of increasing ALD severity emphasize the urgent need for greater awareness about the consequences of unhealthy alcohol use and interventions aimed specifically at addressing alcohol use disorders.

Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli.

Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

Integrating Autism Care through a School-Based Intervention Model: A Pilot Study.

The purpose of this pilot study is to determine the feasibility of monitoring the progress of children with an autism spectrum disorder (ASD) both in school and at home to promote a school-based integrated care model between parents, teachers, and medical providers. This is a prospective cohort study. To monitor progress, outcome measures were administered via an online platform developed for caregivers and teachers of children (n = 30) attending a school specializing in neurodevelopmental disorders and using an integrated medical and education program. Longitudinal analysis showed improvements in a novel scale, the Teacher Autism Progress Scale (TAPS), which was designed to measure key autism-related gains in a school environment (2.1-point improvement, p = 0.004, ES = 0.324). The TAPS showed a strong and statistically significant correlation, with improvement in aberrant behavior (r = -0.50; p = 0.008) and social responsiveness (r = -0.70; p < 0.001). The results also showed non-statistically significant improvements in aberrant behavior, social responsiveness, and quality of life over time at both school and home. To assess feasibility of ongoing progress measurement, we assessed missing data, which showed caregivers were more likely to miss surveys during summer. Results demonstrate the value and feasibility of online, longitudinal data collection in school to assist with individualized education planning and collaborative care for children with ASD. Lessons learned in this pilot will support school outcomes researchers in developing more efficacious, collaborative treatment plans between clinicians, caregivers, and teachers.

Examining Clinics for Children with Autism: The Autism Translating To Treatment Study.

OBJECTIVES: Certain clinical providers specialize in providing complementary and integrative medicine (CIM) therapies for children with autism spectrum disorder (ASD). Because many of these providers and their patients/families have reported substantial improvement, the authors developed an online platform to carefully examine these clinical practices. The initial goal was to examine the feasibility of prospective data collection in this setting. The larger goals were to characterize the tests and treatments used in these clinics; examine associations between specific treatments, biomarkers, and improved outcomes; and identify promising treatments for future study. DESIGN: Prospective cohort study. SETTING: Four CIM clinics specializing in treating children with ASD. PATIENTS: Children with ASD age 2-8 years. INTERVENTIONS: The study protocol provided no interventions, but all interventions provided by the CIM clinical providers were recorded. OUTCOME MEASURES: Aberrant Behavior Checklist (ABC); Social Responsiveness Scale (SRS); and instruments that assessed sensory sensitivity, language, gastrointestinal (GI) symptoms, pediatric quality of life, and caregiver strain. RESULTS: Fourteen children were enrolled (mean age, 4.4 years). Over 3 months, the total behavior score (ABC) decreased (improved) from 110.8 to 103.8 (change, -7.0; 95% confidence interval [CI], -27.9 to 13.9), and the total social responsiveness score (SRS) decreased (improved) from 133.8 to 127.2 (change, -6.6; 95% CI, -30.5 to 17.3), but these changes were not statistically significant. Similarly, caregiver strain and pediatric quality of life decreased (improved) but by a nonsignificant amount. More severe GI symptoms and more severe ASD symptoms were associated with lower quality of life (p < 0.001). CONCLUSIONS: Barriers to successful data collection were identified. Despite these challenges, this study could confirm interesting associations between data elements, highlighting the future value of similar systems for improving evidence-based care in this population.

Quantification of Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Commercial Cows' Milk from California by Gas Chromatography-Triple Quadruple Mass Spectrometry.

We determined 12 polybrominated diphenyl ethers (PBDEs) and 19 polychlorinated biphenyls (PCBs) congeners in eight different brands of commercial whole milk (WM) and fat free milk (FFM) produced and distributed in California. Congeners were extracted using a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method, purified by gel permeation chromatography, and quantified using gas chromatography-triple quadruple mass spectrometry. PBDEs and PCBs were detected in all FFM and WM samples. The most prevalent PBDE congeners in WM were BDE-47 (geometric mean: 18.0 pg/mL, 0.51 ng/g lipid), BDE-99 (geometric mean: 9.9 pg/mL, 0.28 ng/g lipid), and BDE-49 (geometric mean: 6.0 pg/mL, 0.17 ng/g lipid). The dominant PCB congeners in WM were PCB-101(geometric mean: 23.6 pg/mL, 0.67 ng/g lipid), PCB-118 (geometric mean: 25.2 pg/mL, 0.72 ng/g lipid), and PCB-138 (geometric mean: 25.3 pg/mL, 0.72 ng/g lipid). The sum of all 19 PCB congeners in FFM and WM were several orders of magnitude below the U.S. FDA tolerance. The sum of PBDEs in milk samples suggest close proximity to industrial emissions, and confirm previous findings of elevated PBDE levels in California compared to other regions in the United States.