Search

Abstract: Faustini crater (41 km diameter) hosts a large (664 km2) permanently shadowed region (PSR) with a high potential to harbor water-ice deposits. One of the 13 candidate Artemis III landing areas contains a portion of the crater rim and proximal ejecta. The ShadowCam instrument aboard the Korea Pathfinder Lunar Orbiter provides detailed images of the PSR within Faustini. We characterize the terrain and thermal environment within the Faustini PSR from ShadowCam images, Lunar Reconnaissance Orbiter thermal measurements and laser ranging, and thermal modeling. Our mapping revealed three distinct areas of the floor of Faustini based on elevations, slopes, and surface roughness. These units broadly correlate with temperatures; thus, they may be influenced by variations in volatile sublimation. Crater retention and topographic diffusion rates appear to be asymmetric across the floor, likely due to differences in maximum and average temperatures. Several irregular depressions and a pronounced lobate-rim crater are consistent with subsurface ice. However, differences in the thicknesses of deposited materials on the floor may also explain the asymmetry. Additionally, zones of elevated surface roughness across Faustini appear to result from overprinted crater ray segments, possibly from Tycho and Jackson craters. Mass wasting deposits and pitting on opposite sides of the crater wall may have resulted from the low-angle delivery of material ejected by the Shackleton crater impact event, suggesting that the Artemis III candidate landing region named “Faustini Rim A” will contain material from Shackleton.

Genitourinary (GU) malignancies, including prostate, urothelial, kidney, testicular, penile, and adrenocortical cancers, comprise a significant burden of cancers worldwide. While many practice-changing advances have been made in the management of GU malignancies in the last decade, there is still significant room for improvement. MicroRNAs (miRNAs) are noncoding RNAs that regulate post-transcription gene expression and which have been implicated in multiple mechanisms of carcinogenesis. Therefore, they have the potential to revolutionize personalized cancer therapy, with several ongoing preclinical and clinical studies underway to investigate their efficacy. In this review, we describe the current landscape of miRNAs as diagnostics, therapeutics, and biomarkers of response for GU malignancies, reflecting a novel frontier in cancer treatment.

Virus-like particles (VLPs) from bacteriophage MS2 provide a platform to study protein self-assembly and create engineered systems for drug delivery. Here, we aim to understand the impact of intersubunit interface mutations on the local and global structure and function of MS2-based VLPs. In previous work, our lab identified locally supercharged double mutants [T71K/G73R] that concentrate positive charge at capsid pores, enhancing uptake into mammalian cells. To study the effects of particle size on cellular internalization, we combined these double mutants with a single point mutation [S37P] that was previously reported to switch particle geometry from T = 3 to T = 1 icosahedral symmetry. These new variants retained their enhanced cellular uptake activity and could deliver small-molecule drugs with efficacy levels similar to our first-generation capsids. Surprisingly, these engineered triple mutants exhibit increased thermostability and unexpected geometry, producing T = 3 particles instead of the anticipated T = 1 assemblies. Transmission electron microscopy revealed various capsid assembly states, including wild-type (T = 3), T = 1, and rod-like particles, that could be accessed using different combinations of these point mutations. Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.

Cells employ many large macromolecular machines for the execution and regulation of processes that are vital for cell and organismal viability. Interestingly, cells cannot synthesize these machines as functioning units. Instead, cells synthesize the molecular parts that must then assemble into the functional complex. Many important machines, including chaperones such as GroEL and proteases such as the proteasome, comprise protein rings that are stacked on top of one another. While there is some experimental data regarding how stacked-ring complexes such as the proteasome self-assemble, a comprehensive understanding of the dynamics of stacked-ring assembly is currently lacking. Here, we developed a mathematical model of stacked-trimer assembly and performed an analysis of the assembly of the stacked homomeric trimer, which is the simplest stacked-ring architecture. We found that stacked rings are particularly susceptible to a form of kinetic trapping that we term deadlock, in which the system gets stuck in a state where there are many large intermediates that are not the fully assembled structure but that cannot productively react. When interaction affinities are uniformly strong, deadlock severely limits assembly yield. We thus predicted that stacked rings would avoid situations where all interfaces in the structure have high affinity. Analysis of available crystal structures indicated that indeed the majority-if not all-of stacked trimers do not contain uniformly strong interactions. Finally, to better understand the origins of deadlock, we developed a formal pathway analysis and showed that, when all the binding affinities are strong, many of the possible pathways are utilized. In contrast, optimal assembly strategies utilize only a small number of pathways. Our work suggests that deadlock is a critical factor influencing the evolution of macromolecular machines and provides general principles for understanding the self-assembly efficiency of existing machines.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

IntroductionThe concept of patient-provider trust in prenatal adverse childhood experiences (ACEs) screening remains unexplored. This concept analysis illuminates the role of trust in prenatal ACE screening to improve patient-provider relationships, increase patient uptake of ACE screening, and ensure that ACE screening is implemented in a strengths-based, trauma-informed way.MethodsA concept analysis was conducted using the Rodgers' evolutionary method to define the antecedents, attributes, and consequences of this construct. The databases searched were PubMed, PsychInfo, and Scopus between 2010 and 2021. A total of 389 articles were retrieved using the search terms prenatal, adverse childhood experiences screening, adverse childhood experiences, and adverse childhood experiences questionnaire. Included articles for detailed review contained prenatal screening, trauma screening (ACE or other), trust or building trust between patient and health care provider, patient engagement, and shared decision making. Excluded articles were those not in the context of prenatal care and that were exclusively about screening with no discussion about the patient-provider relationship or patient perspectives. A total of 32 articles were reviewed for this concept analysis.ResultsWe define trust in prenatal ACE screening as a network of evidence-based attributes that include the timing of the screening, patient familiarity with the health care provider, cultural competence, demystifying trauma, open dialogue between the patient and health care provider, and patient comfort and respect.DiscussionThis concept analysis elucidates the importance of ACE screening and provides suggestions for establishing trust in the context of prenatal ACE screening. Results give insight and general guidance for health care providers looking to implement ACE screening in a trauma-informed way. Further research is needed to evaluate pregnant patients' attitudes toward ACE screening and how a health care provider's trauma history might influence their care. More inquiry is needed to understand the racial, ethnic, and cultural barriers to ACE screening.

Relaxor ferroelectric polymers exhibiting a giant electrocaloric effect (ECE) can potentially be used to create next-generation solid-state coolers. Under an electric field, poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) terpolymer goes through a large dipolar entropy change producing a high adiabatic temperature change (ΔTECE). This work resolves the molecular origins of the large entropy change behind the electric field-induced dipole switching. A Fourier transform infrared spectroscopy equipped with a high voltage source is used to operandoly observe the characteristic molecular vibrational modes. A short-range trans (T) conformation of the CF2-CH2 dyads interrupted by a gauche (G) conformation, e.g., TTTG in the terpolymer chain, undergoes a dynamic transformation that leads to a corresponding ΔTECE whenever an electric field is applied. The molecular dynamics simulation also proves that the energy barrier that the transformation from TTTGs into a long T sequence overcomes is smaller than that for all other conformations. A mixed solvent system is used to obtain T3G-enriched terpolymer films exhibiting a 4.02 K ΔTECE at 60 MVm−1 and these films are employed to manufacture a 2-layer-cascaded cooling device that achieves a 6.7 K temperature lift, the highest reported value for a 2-layer cascaded device made of fluoropolymers.

The chemical and isotopic characteristics of a solidified pluton represent the integration of magmatic and sub-solidus processes operating across a range of spatial and temporal scales during pluton construction, crystallization, and cooling. Disentangling these processes and understanding where chemical and isotopic signatures were acquired requires the combination of multiple tools tracing processes at different time and length scales. We combine whole-rock oxygen and Sr-Nd isotopes, zircon oxygen isotopes and trace elements, and mineral compositions with published high-precision U-Pb zircon geochronology to evaluate differentiation within the bimodal Guadalupe Igneous Complex, Sierra Nevada, California (USA). The complex was constructed in ~300 k.y. between 149 and 150 Ma. Felsic magmas crystallized as centimeter- to meter-sized segregations in gabbros in the lower part of the complex and as granites and granophyres structurally above the gabbros. A central mingling zone separates the mafic and felsic units. Pluton-wide δ18O(whole-rock), δ18O(zircon), and Sr-Nd isotopic ranges are too large to be explained by in situ, closed-system differentiation, instead requiring open-system behavior at all scales. Low δ18O(whole-rock) and δ18O(zircon) values indicate assimilation of hydrothermally altered marine host rocks during ascent and/or emplacement. In situ differentiation processes operated on a smaller scale (meters to tens of meters) for at least ~200 k.y. via (1) percolation and segregation of chemically and isotopically diverse silicic interstitial melt from a heterogeneous gabbro mush; (2) crystal accumulation; and (3) sub-solidus, high-temperature, hydrothermal alteration at the shallow roof of the complex to modify the chemical and isotopic characteristics. Whole-rock and mineral chemistry in combination with geochronology allows deciphering open-system differentiation processes at the outcrop to pluton scale from magmatic to sub-solidus temperatures over time scales of hundreds of thousands to millions of years.

During HIV infection of CD4+ T cells, ubiquitin pathways are essential to viral replication and host innate immune response; however, the role of specific E3 ubiquitin ligases is not well understood. Proteomics analyses identified 116 single-subunit E3 ubiquitin ligases expressed in activated primary human CD4+ T cells. Using a CRISPR-based arrayed spreading infectivity assay, we systematically knocked out 116 E3s from activated primary CD4+ T cells and infected them with NL4-3 GFP reporter HIV-1. We found 10 E3s significantly positively or negatively affected HIV infection in activated primary CD4+ T cells, including UHRF1 (pro-viral) and TRAF2 (anti-viral). Furthermore, deletion of either TRAF2 or UHRF1 in three JLat models of latency spontaneously increased HIV transcription. To verify this effect, we developed a CRISPR-compatible resting primary human CD4+ T cell model of latency. Using this system, we found that deletion of TRAF2 or UHRF1 initiated latency reactivation and increased virus production from primary human resting CD4+ T cells, suggesting these two E3s represent promising targets for future HIV latency reversal strategies.ImportanceHIV, the virus that causes AIDS, heavily relies on the machinery of human cells to infect and replicate. Our study focuses on the host cell's ubiquitination system which is crucial for numerous cellular processes. Many pathogens, including HIV, exploit this system to enhance their own replication and survival. E3 proteins are part of the ubiquitination pathway that are useful drug targets for host-directed therapies. We interrogated the 116 E3s found in human immune cells known as CD4+ T cells, since these are the target cells infected by HIV. Using CRISPR, a gene-editing tool, we individually removed each of these enzymes and observed the impact on HIV infection in human CD4+ T cells isolated from healthy donors. We discovered that 10 of the E3 enzymes had a significant effect on HIV infection. Two of them, TRAF2 and UHRF1, modulated HIV activity within the cells and triggered an increased release of HIV from previously dormant or "latent" cells in a new primary T cell assay. This finding could guide strategies to perturb hidden HIV reservoirs, a major hurdle to curing HIV. Our study offers insights into HIV-host interactions, identifies new factors that influence HIV infection in immune cells, and introduces a novel methodology for studying HIV infection and latency in human immune cells.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.

IntroductionLimited data exist on factors associated with concurrent use patterns of electronic nicotine delivery systems (ENDS) and cigarettes. We examined longitudinally perceptions and experiences with ENDS in relationship to concurrent use patterns among established, recent smokers who recently initiated ENDS.MethodsParticipant recruitment took place using paid digital advertisements on social media. Between December 2020 and October 2021, 303 adults aged ≥21 years from across the US who currently or recently smoked and had initiated ENDS use within the past 30 days or reinitiated ENDS use after more than one year of non-use were surveyed. Multinomial logistic regressions were conducted to analyze association between the outcome of current use pattern at follow-up at 1 month [rejectors (discontinued ENDS, continued smoking), primary smokers (concurrent users, mostly smoke), dual user (similar smoking and ENDS use), primary vapers (concurrent users, mostly vape), and switchers (discontinued smoking, continued using ENDS) or quitters (discontinued both smoking and ENDS] and perceptions of and experiences with ENDS predictors at baseline.ResultsAt follow-up at 1 to 2 months after initiating ENDS, 20% were rejectors, 31% were primary smokers, 13% were dual users, 19% were primary vapers, and 17% were switchers/quitters. Perceiving ENDS as less harmful than smoking or being uncertain and as equally or more enjoyable smoking, experiencing a lot or complete reduction in cravings to smoking and in irritability with ENDS use, liking the taste of ENDS, and being satisfied with vaping were associated with higher odds of quitting smoking compared to rejecting ENDS or mostly smoking at follow-up at 1 month.ConclusionsFindings highlight the importance of initial ENDS perceptions and experiences when examining tobacco outcomes and potentially for developing policies and interventions targeting smoking cessation. ENDS initiators are differentiating into distinct use patterns based on these factors within a short period of time.

BACKGROUND: Cancer health research relies on large-scale cohorts to derive generalizable results for different populations. While traditional epidemiological cohorts often use costly random sampling or self-motivated, preselected groups, a shift toward health system-based cohorts has emerged. However, such cohorts depend on participants remaining within a single system. Recent consumer engagement models using smartphone-based communication, driving projects, and social media have begun to upend these paradigms. METHODS: We initiated the Healthy Oregon Project (HOP) to support basic and clinical cancer research. HOP study employs a novel, cost-effective remote recruitment approach to effectively establish a large-scale cohort for population-based studies. The recruitment leverages the unique email account, the HOP website, and social media platforms to direct smartphone users to the study app, which facilitates saliva sample collection and survey administration. Monthly newsletters further facilitate engagement and outreach to broader communities. RESULTS: By the end of 2022, the HOP has enrolled approximately 35,000 participants aged 18-100 years (median = 44.2 years), comprising more than 1% of the Oregon adult population. Among those who have app access, ∼87% provided consent to genetic screening. The HOP monthly email newsletters have an average open rate of 38%. Efforts continue to be made to improve survey response rates. CONCLUSION: This study underscores the efficacy of remote recruitment approaches in establishing large-scale cohorts for population-based cancer studies. The implementation of the study facilitates the collection of extensive survey and biological data into a repository that can be broadly shared and supports collaborative clinical and translational research.

BackgroundVariations in survival among patients with oligodendroglioma are unexplained by known prognostic factors. To assess the impact of peripheral immune profiles on prognosis, we applied immunomethylomics analyses-DNA methylation of archived whole blood samples, to characterize immune cells.MethodsWe compared the proportions of immune cells from patients with oligodendroglioma to other glioma subtypes and controls. We used recursive partitioning analysis (RPA) within the oligodendrogliomas to correlate with survival.ResultsPatients with oligodendrogliomas (141) were median age at diagnosis of 44 years; 57% male; 75% White; 60% prior chemotherapy; and 25% on dexamethasone at sample collection. Patients with oligodendrogliomas had immune profiles more similar to controls than other glioma subtypes, though with notably lower B-cells. RPA of patients with oligodendrogliomas delineated 2 survival groups based on an interaction between age and B-naïve cells. Patients with longer survival (median 24.2 years) were ≤42 years of age with higher B-naïve cells versus worse survival (median 16.9 years) who were ≤42 years of age with lower B-naïve cells or >42 years of age (P = .00032). Patients with worse survival also had lower CD4- and CD8-naïve T-cells. Similar immune profiles were observed in an independent cohort of oligodendroglioma patients prior to surgery.ConclusionsPeripheral blood immune profiles in oligodendroglioma suggested that younger patients with lower B-naïve cells experienced shorter survival. Though our findings lack of validation cohort and use a heterogenous patient population, they suggest peripheral blood immune profiles may be prognostic for patients with glioma and warrant further investigation.

PurposePersistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors.MethodsA prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic.ResultsIn the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms.ConclusionsOur findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization.Implications for cancer survivorsEarly identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization.

Improved hygiene depends on the accessibility and availability of effective disinfectant solutions. These disinfectant solutions are unavailable to many communities worldwide due to resource limitations, among other constraints. Safe and effective chlorine-based disinfectants can be produced via simple electrolysis of salt water, providing a low-cost and reliable option for on-site, local production of disinfectant solutions to improve sanitation and hygiene. This study reports on a system (herein called "Electro-Clean") that can produce concentrated solutions of hypochlorous acid (HOCl) using readily available, low-cost materials. With just table salt, water, graphite welding rods, and a DC power supply, the Electro-Clean system can safely produce HOCl solutions (~1.5 liters) of up to 0.1% free chlorine (i.e.,1000 ppm) in less than two hours at low potential (5 V DC) and modest current (~5 A). Rigorous testing of free chlorine production and durability of the Electro-Clean system components, described here, has been verified to work in multiple locations around the world, including microbiological tests conducted in India and Mexico to confirm the biocidal efficacy of the Electro-Clean solution as a surface disinfectant. Cost estimates are provided for making HOCl locally with this method in the USA, India, and Mexico. Findings indicate that Electro-Clean is an affordable alternative to off-the-shelf commercial chlorinator systems in terms of first costs (or capital costs), and cost-competitive relative to the unit cost of the disinfectant produced. By minimizing dependence on supply chains and allowing for local production, the Electro-Clean system has the potential to improve public health by addressing the need for disinfectant solutions in resource-constrained communities.

BACKGROUND: There is evidence for a significant excess of kinetic upper limb tremor in non-FXTAS female FMR1 premutation carriers. The present study explores the possibility that this tremor is associated with various other features reminiscent of those occurring in syndromic FXTAS. SAMPLE/METHODS: This study analyzed the data from an Australian cohort of 48 asymptomatic premutation women. We utilized spiral drawings from CRST, representing action tremor; the CRST total tremor; and ICARS- kinetic tremors/cerebellar ataxia scales. Cognitive tests (involving executive functioning) included SDMT, TMT, two subtests of the WAIS-III: MR and Similarities. Spearman Rank correlations assessed the relationships between the above measures, and the Chi-square tested hypothesis about the association between the white matter hyperintensities (wmhs) in the splenium of corpus callosum assessed from MR images and spiral drawings scores. RESULTS: The spiral drawing scores were significantly correlated with all three non-verbal cognitive test scores, and with the CRST scores; the latter correlated with all four cognitive test measures. Similarities (verbal) scores correlated with CRST, ICARS, and with the remaining cognitive scores. Ordered spiral scores categories were significantly associated with the degree of splenium involvement. CONCLUSION: This study showed that, in non-FXTAS premutation female carriers, sub-symptomatic forms of kinetic tremor were associated with a broader motor, and cognitive (especially executive) dysfunction.

The study compared concerns, anxiety, mindsets, and belonging in introductory statistics among Latine students across three higher education institutions. Students at the Predominantly White Institution voiced more concerns about R-coding and lack of prior knowledge. Students at the Hispanic-Serving Institutions voiced more concerns about math anxiety and social comparison and had more fixed mindsets, yet higher levels of belonging—pointing toward the value of exploring Latine students’ experiences across different contexts and providing tailored interventions.

Dravet syndrome is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, scn1lab mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in scn1lab mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behaviour and (ii) an electrophysiology-based assay, using in vivo local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our scn1lab zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.

Abstract: Background: Fatigue and neurocognitive impairment are highly prevalent in patients with glioma, significantly impacting health-related quality of life. Despite the presumed association between these two factors, evidence remains sparse. Therefore, we aimed to investigate this relationship using multinational data. Methods: We analyzed data on self-reported fatigue and neurocognitive outcomes from postoperative patients with glioma from the University of California San Francisco (n = 100, UCSF) and Amsterdam University Medical Center (n = 127, Amsterdam UMC). We used multiple linear regression models to assess associations between fatigue and seven (sub)domains of neurocognitive functioning and latent profile analysis to identify distinct patterns of fatigue and neurocognitive functioning. Results: UCSF patients were older (median age 49 vs. 43 years, P = .002), had a higher proportion of grade 4 tumors (32% vs. 18%, P = .03), and had more neurocognitive deficits (P = .01). While the number of clinically fatigued patients was similar between sites (64% vs. 58%, P = .12), fatigue and the number of impaired neurocognitive domains were not correlated (P = .16–.72). At UCSF, neurocognitive domains were not related to fatigue, and at Amsterdam UMC attention and semantic fluency explained only 4–7% of variance in fatigue. Across institutions, we identified four distinct patterns of neurocognitive functioning, which were not consistently associated with fatigue. Conclusions: Although individual patients might experience both fatigue and neurocognitive impairment, the relationship between the two is weak. Consequently, both fatigue and neurocognitive functioning should be independently assessed and treated with targeted therapies.

Lung neuroendocrine tumors (NETs) have few known predictors of survival. We investigated associations of sociodemographic, clinicopathologic, and treatment factors with overall survival (OS) and lung cancer-specific survival (LCSS) for incident lung NET cases (typical or atypical histology) in the California Cancer Registry (CCR) from 1992 to 2019. OS was estimated with the Kaplan-Meier method and compared by sociodemographic and disease factors univariately with the log-rank test. We used sequential Cox proportional hazards regression for multivariable OS analysis. LCSS was estimated using Fine-Gray competing risks regression. There were 6038 lung NET diagnoses (5569 typical, 469 atypical carcinoid); most were women (70%) and non-Hispanic White (73%). In our multivariable model, sociodemographic factors were independently associated with OS, with better survival for women (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.57-0.68, P < 0.001), married (HR 0.76, 95% CI 0.70-0.84, P < 0.001), and residents of high socioeconomic status (SES) neighborhoods (HRQ5vsQ1 0.73, 95% CI 0.62-0.85, P < 0.001). Compared to cases with private insurance, OS was worse for cases with Medicare (HR 1.24, 95% CI 1.10-1.40, P < 0.001) or Medicaid/other public insurance (HR 1.45, 95% CI 1.24-1.68, P < 0.001). In our univariate model, non-Hispanic Black Californians had worse OS than other racial/ethnic groups, but differences attenuated after adjusting for stage at diagnosis. In our LCSS models, we found similar associations between sex and marital status on survival, but no differences in outcomes by SES or insurance. By race/ethnicity, American Indian cases had worse LCSS. In summary, beyond disease-related and treatment variables, sociodemographic factors were independently associated with survival in lung NETs.

Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 Å-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity.

Background  The surgical burden in low- and middle-income countries (LMICs) as reported by the number of surgical cases per capita is great. To improve global health and help address this burden, there has been a rise in surgical outreach to LMICs. In high-income countries, an electronic health record (EHR) is used to document and communicate data critical to the quality of care and patient safety. Despite this, there is little guidance or precedence on the data elements or processes for utilizing an EHR on outreach trips. We validated data elements and process steps for utilizing an EHR for hand surgery outreach trips. Methods  We conducted a literature review to identify data elements collected during surgical outreach trips. A future-state process map for the collection and documentation of data elements within an EHR was developed through literature review and semistructured interviews with experts in global outreach. An expert consortium completed a modified RAND/University of California at Los Angeles Delphi process to evaluate the importance and feasibility of each data element and process step. Results  In total, 65 data elements (e.g., date of birth) and 24 process steps (e.g., surgical site marking) were validated for use in an EHR for hand surgery outreach trips to LMICs. Conclusion  This validated portfolio of data elements/process steps can serve as the foundation for pilot testing of an EHR to document and communicate critical patient data on hand surgery outreach trips. Utilization of an EHR during outreach trips to LMICs may serve to improve the safety and quality of care provided. The validated data elements/process steps can serve as a guide for EHR development and implementation of other surgical specialties.

Immortal time bias is a well-recognized bias in clinical epidemiology but is rarely discussed in environmental epidemiology. Under the target trial framework, this bias is formally conceptualized as a misalignment between the start of study follow-up (time 0) and treatment assignment. This misalignment can occur when attained duration of follow-up is encoded into treatment assignment using minimums, maximums, or averages. The bias can be exacerbated in the presence of time trends commonly found in environmental exposures. Using lung cancer cases from the California Cancer Registry (2000-2010) linked with estimated concentrations of particulate matter less than or equal to 2.5 μm in aerodynamic diameter (PM2.5), we replicated previous studies that averaged PM2.5 exposure over follow-up in a time-to-event model. We compared this approach with one that ensures alignment between time 0 and treatment assignment, a discrete-time approach. In the former approach, the estimated overall hazard ratio for a 5-μg/m3 increase in PM2.5 was 1.38 (95% confidence interval: 1.36, 1.40). Under the discrete-time approach, the estimated pooled odds ratio was 0.99 (95% confidence interval: 0.98, 1.00). We conclude that the strong estimated effect in the former approach was likely driven by immortal time bias, due to misalignment at time 0. Our findings highlight the importance of appropriately conceptualizing a time-varying environmental exposure under the target trial framework to avoid introducing preventable systematic errors.

During May 2018‒December 2022, we reviewed transfusion-transmitted sepsis cases in the United States attributable to polymicrobial contaminated apheresis platelet components, including Acinetobacter calcoaceticus‒baumannii complex or Staphylococcus saprophyticus isolated from patients and components. Transfused platelet components underwent bacterial risk control strategies (primary culture, pathogen reduction or primary culture, and secondary rapid test) before transfusion. Environmental samples were collected from a platelet collection set manufacturing facility. Seven sepsis cases from 6 platelet donations from 6 different donors were identified in patients from 6 states; 3 patients died. Cultures identified Acinetobacter calcoaceticus‒baumannii complex in 6 patients and 6 transfused platelets, S. saprophyticus in 4 patients and 4 transfused platelets. Whole-genome sequencing showed environmental isolates from the manufacturer were closely related genetically to patient and platelet isolates, indicating the manufacturer was the most probable source of recurrent polymicrobial contamination. Clinicians should maintain awareness of possible transfusion-transmitted sepsis even when using bacterial risk control strategies.

Establishing the temporal sequence of the Middle-Late Jurassic Yanliao Biota is essential as it anchors the timing of many key evolutionary innovations in vertebrates. Lack of sufficiently reliable high-precision ages of fossil-bearing horizons hinders our ability to reconstruct the tempo and mode of vertebrate evolution. Here, we frame a temporal sequence of Yanliao Biota with precise age constraints for iconic vertebrates, proposing that the major vertebrate-bearing strata span from 164 Ma to 157 Ma in age. The increasing ecological diversity of mammaliaforms is well illustrated by the Middle-Late Jurassic Yanliao Biota and Early Cretaceous Jehol Biota. Incorporation of the updated temporal frameworks in Bayesian tip-dated mammaliaform phylogeny reveals that Triassic haramiyidans are separate from Jurassic taxa and unrelated to crown Mammalia. Tip-dated phylogeny supports a long-fuse model for mammal evolution, featured by a Late Triassic root and Middle-Late Jurassic interordinal diversification of crown Mammalia, showing consistency with molecular-based timetrees in divergence timing.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

The short-lived radionuclide aluminium-26 (26Al) isotope is a major heat source for early planetary melting. The aluminium-26 - magnesium-26 (26Al-26Mg) decay system also serves as a high-resolution relative chronometer. In both cases, however, it is critical to establish whether 26Al was homogeneously or heterogeneously distributed throughout the solar nebula. Here we report a precise lead-207 - lead-206 (207Pb-206Pb) isotopic age of 4565.56 ± 0.12 million years (Ma) for the andesitic achondrite Erg Chech 002. Our analysis, in conjunction with published 26Al-26Mg data, reveals that the initial 26Al/27Al in the source material of this achondrite was notably higher than in various other well-preserved and precisely dated achondrites. Here we demonstrate that the current data clearly indicate spatial heterogeneity of 26Al by a factor of 3-4 in the precursor molecular cloud or the protoplanetary disk of the Solar System, likely associated with the late infall of stellar materials with freshly synthesized radionuclides.

Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

BACKGROUND: Breast cancer risk models guide screening and chemoprevention decisions, but the extent and effect of variability among models, particularly at the individual level, is uncertain. OBJECTIVE: To quantify the accuracy and disagreement between commonly used risk models in categorizing individual women as average vs. high risk for developing invasive breast cancer. DESIGN: Comparison of three risk prediction models: Breast Cancer Risk Assessment Tool (BCRAT), Breast Cancer Surveillance Consortium (BCSC) model, and International Breast Intervention Study (IBIS) model. SUBJECTS: Women 40 to 74 years of age presenting for screening mammography at a multisite health system between 2011 and 2015, with 5-year follow-up for cancer outcome. MAIN MEASURES: Comparison of model discrimination and calibration at the population level and inter-model agreement for 5-year breast cancer risk at the individual level using two cutoffs (≥ 1.67% and ≥ 3.0%). KEY RESULTS: A total of 31,115 women were included. When using the ≥ 1.67% threshold, more than 21% of women were classified as high risk for developing breast cancer in the next 5 years by one model, but average risk by another model. When using the ≥ 3.0% threshold, more than 5% of women had disagreements in risk severity between models. Almost half of the women (46.6%) were classified as high risk by at least one of the three models (e.g., if all three models were applied) for the threshold of ≥ 1.67%, and 11.1% were classified as high risk for ≥ 3.0%. All three models had similar accuracy at the population level. CONCLUSIONS: Breast cancer risk estimates for individual women vary substantially, depending on which risk assessment model is used. The choice of cutoff used to define high risk can lead to adverse effects for screening, preventive care, and quality of life for misidentified individuals. Clinicians need to be aware of the high false-positive and false-negative rates and variation between models when talking with patients.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

Background Severe cases of carpal tunnel syndrome (CTS) are treated with surgical decompression, for which regional nerve blocks are often administered. There is little data about complications associated with these regional techniques for this surgery. The primary objective was to assess the association of ultrasound-guided regional anesthesia nerve blocks in patients undergoing carpal tunnel release with symptom resolution. Methods This single-institution, retrospective study analyzed all patients undergoing open carpal tunnel release from March 2018 to November 2020. Primary exposure was either regional anesthesia (median and ulnar nerve blocks) or non-regional anesthesia (general anesthesia or local infiltration by surgeon). The primary outcome measurement was symptom resolution at postoperative follow-up at 30-60 days. Secondary outcomes were postoperative surgical site infection, time in operating room (minutes), and post-anesthesia care unit (PACU) length of stay (min). The primary outcome was analyzed using multivariable logistic regression. Results A total of 417 patients were included in this study. Of these, 269 (64.5%) subjects received regional anesthesia as their primary anesthetic. When adjusting for confounders, the use of regional anesthesia was not associated with symptoms not improving at postoperative visit (OR 0.52, 95% CI 0.22 - 1.26, P = 0.15), postoperative surgical site infection (OR 1.47, 95% CI 0.44 - 4.85, p = 0.53), or operating room time duration (p = 0.09). However, the use of regional anesthesia was associated with an approximately 15-minute decrease in PACU length of stay (p < 0.001). Conclusions Regional anesthesia is a safe, effective, and time-efficient method for anesthesia in patients undergoing open carpal tunnel release.

Oil supply-side policies—setbacks, excise taxes and carbon taxes—are increasingly considered for decarbonizing the transportation sector. Understanding not only how such policies reduce oil extraction and greenhouse gas (GHG) emissions but also which communities receive the resulting health benefits and labour-market impacts is crucial for designing effective and equitable decarbonization pathways. Here we combine an empirical field-level oil-production model, an air pollution model and an employment model to characterize spatially explicit 2020–2045 decarbonization scenarios from various policies applied to California, a major oil producer with ambitious decarbonization goals. We find setbacks generate the largest avoided mortality benefits from reduced air pollution and the largest lost worker compensation, followed by excise and carbon taxes. Setbacks also yield the highest share of health benefits and the lowest share of lost worker compensation borne by disadvantaged communities. However, currently proposed setbacks may fail to meet California’s GHG targets, requiring either longer setbacks or additional supply-side policies.

PurposeWe sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors.MethodsThis prospective cohort study included patients surgically treated for stage I-IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0-6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics.ResultsA total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42-0.79; p

Accurate characterization of microcalcifications (MCs) in 2D digital mammography is a necessary step toward reducing the diagnostic uncertainty associated with the callback of indeterminate MCs. Quantitative analysis of MCs can better identify MCs with a higher likelihood of ductal carcinoma in situ or invasive cancer. However, automated identification and segmentation of MCs remain challenging with high false positive rates. We present a two-stage multiscale approach to MC segmentation in 2D full-field digital mammograms (FFDMs) and diagnostic magnification views. Candidate objects are first delineated using blob detection and Hessian analysis. A regression convolutional network, trained to output a function with a higher response near MCs, chooses the objects which constitute actual MCs. The method was trained and validated on 435 screening and diagnostic FFDMs from two separate datasets. We then used our approach to segment MCs on magnification views of 248 cases with amorphous MCs. We modeled the extracted features using gradient tree boosting to classify each case as benign or malignant. Compared to state-of-the-art comparison methods, our approach achieved superior mean intersection over the union (0.670 ± 0.121 per image versus 0.524 ± 0.034 per image), intersection over the union per MC object (0.607 ± 0.250 versus 0.363 ± 0.278) and true positive rate of 0.744 versus 0.581 at 0.4 false positive detections per square centimeter. Features generated using our approach outperformed the comparison method (0.763 versus 0.710 AUC) in distinguishing amorphous calcifications as benign or malignant.

PurposeLimited data exist to help surgeons decide between active surveillance (AS) versus treatment for men with favorable intermediate risk (FIR) prostate cancer. To estimate the theoretical excess risk of prostate cancer-specific mortality (PCSM) with AS versus radical prostatectomy (RP), we determined the risk of PCSM in FIR men undergoing RP and modeled the PCSM risk for AS using a range of increased PSCM scenarios ranging from 1.25x to 2x higher relative to RP.Materials and methodsWe retrospectively reviewed data from men undergoing RP from 1988 to 2017 at 8 Veterans Affairs hospitals within the SEARCH cohort. Men with FIR PC were identified using the NCCN risk criteria. Risk of PCSM at 5, 10, and 15 years after RP was estimated. Using these estimates, PCSM was then modeled for AS using a range of increased risk of PCSM relative to RP ranging from 1.25x to 2x higher.ResultsFor the 920 FIR men identified, 5-, 10-, and 15-year survival estimates for PCSM after RP were 99.9%, 99.0%, and 97.8%, respectively. If the risk of PCSM on AS were 1.25-2x greater than RP, there would be 0.54%-2.17% excess risk of PCSM at 15 years.ConclusionsThe risk of death for FIR after RP is very low. Assuming even modestly increased PCSM with AS versus RP, the excess risk of death for AS in FIR is low even up to 15 years. These data support the consideration of AS as a relatively safe alternative to RP in FIR men, though prospective randomized trials are needed to validate these findings.

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Hexahydro-1,3,5-trinitro-1,3,5-triazine, or Royal Demolition Explosive (RDX), is a major component of plastic explosives such as C-4. Acute exposures from intentional or accidental ingestion are a documented clinical concern, especially among young male U.S. service members in the armed forces. When ingested in large enough quantity, RDX causes tonic-clonic seizures. Previous in silico and in vitro experiments predict that RDX causes seizures by inhibiting α1β2γ2 γ-aminobutyric acid type A (GABAA) receptor-mediated chloride currents. To determine whether this mechanism translates in vivo, we established a larval zebrafish model of RDX-induced seizures. After a 3 h of exposure to 300 µM RDX, larval zebrafish exhibited a significant increase in motility in comparison to vehicle controls. Researchers blinded to experimental group manually scored a 20-min segment of video starting at 3.5 h post-exposure and found significant seizure behavior that correlated with automated seizure scores. Midazolam (MDZ), an nonselective GABAAR positive allosteric modulator (PAM), and a combination of Zolpidem (α1 selective PAM) and compound 2-261 (β2/3-selective PAM) were effective in mitigating RDX-triggered behavioral and electrographic seizures. These findings confirm that RDX induces seizure activity via inhibition of the α1β2γ2 GABAAR and support the use of GABAAR-targeted anti-seizure drugs for the treatment of RDX-induced seizures.

Background Gender-affirming pelvic surgery (GAPS) can be associated with significant postoperative pelvic pain. Given the lack of available peripheral nerve blocks to the perineum, intrathecal morphine (ITM) injection could offer a potent analgesic modality for this patient population. No prior studies to date have been performed examining the analgesic effects of intrathecal morphine for these patients. Methods This retrospective case-control study aims to understand the postoperative analgesic effects of intrathecal morphine for these patients with a historical comparison group of patients who did not receive intrathecal morphine. Results Fourteen patients presented for gender-affirming pelvic surgery over an eight-month period at a single institution and were offered intrathecal morphine for postoperative analgesia. Their analgesic results were compared to a similar historical group of 13 patients who were not offered or declined intrathecal morphine. Conclusions Intrathecal morphine injection is a potent analgesic modality for patients presenting for gender-affirming pelvic surgery.

Baseline child characteristics may predict treatment outcomes in children with or at elevated likelihood of developing autism (EL-ASD). Little is known about the role of child sensory and language features on treatment outcome. Participants were randomly assigned to a parent-mediated intervention or control condition. Analyses explored the relationship between baseline child sensory and language characteristics and changes in ASD symptoms over approximately 9 months. Higher baseline sensory hyporeactivity was significantly related to less improvement in social communication (SC) for the treatment group only. More baseline atypical vocalizations were significantly related to less improvement on SC across treatment and control groups. This work provides an initial framework to encourage the tailoring of interventions for EL-ASD children, suggesting sensory reactivity and atypical vocalizations may be useful behaviors to consider in treatment planning.

In recent years, psychedelics have garnered significant interest as therapeutic agents for treating diverse neuropsychiatric disorders. However, the potential for these compounds to produce developmental neurotoxicity has not been rigorously assessed, and much of the available safety data is based on epidemiological studies with limited experimental testing in laboratory animal models. Moreover, the experimental safety data available thus far have focused on adult organisms, and the few studies conducted using developing organisms have tested a limited number of compounds, precluding direct comparisons between various chemical scaffolds. In the present study, 13 psychoactive compounds of different chemical or pharmacological classes were screened in a larval zebrafish model for teratological and behavioral abnormalities following acute and chronic developmental exposures. We found that the psychedelic tryptamines and ketamine were less neurotoxic to larval zebrafish than LSD and psychostimulants. Our work, which leverages the advantage of using zebrafish for higher throughput toxicity screening, provides a robust reference database for comparing the neurotoxicity profiles of novel psychedelics currently under development for therapeutic applications.

BACKGROUND: Nongovernmental organizations (NGOs) from high-income countries provide surgical outreach for patients in low and middle-income countries (LMICs); however, these efforts lack a coordinated measurement of their ability to build capacity. While the World Health Organization and others recommend outreach trips that aim to build the capacity of the local health-care system, no guidance exists on how to accomplish this. The objective of this paper is to establish a framework and a blueprint to guide the operations of NGOs that provide outreach to build orthopaedic surgical capacity in LMICs. METHODS: We conducted a qualitative analysis of semistructured interviews with 16 orthopaedic surgeons and administrators located in 7 countries (6 LMICs) on the necessary domains for capacity-building; the analysis was guided by a literature review of capacity-building frameworks. We subsequently conducted a modified nominal group technique with a consortium of 10 U.S.-based surgeons with expertise in global surgical outreach, which was member-checked with 8 new stakeholders from 4 LMICs. RESULTS: A framework with 7 domains for capacity-building in global surgical outreach was identified. The domains included professional development, finance, partnerships, governance, community impact, culture, and coordination. These domains were tiered in a hierarchical system to stratify the level of capacity for each domain. A blueprint was developed to guide the operations of an organization seeking to build capacity. CONCLUSIONS: The developed framework identified 7 domains to address when building capacity during global orthopaedic surgical outreach. The framework and its tiered system can be used to assess capacity and guide capacity-building efforts in LMICs. The developed blueprint can inform the operations of NGOs toward activities that focus on building capacity in order to ensure a measured and sustained impact.

Youth in the United States are experiencing mental health concerns at alarming rates. Considering the nation's legacy of racism and growing recognition of the impact of social determinants of health on educational and mental health inequities, it is imperative to re-envision how we approach mental health screening in schools to center equity. A focus on mental health screening for the sole purpose of identifying individual at-risk students ignores key contextual considerations, is ineffective in addressing health and educational inequities, and has the potential to perpetuate oppressive practices in schools. Equity-focused mental health screening requires a shift from individual- and deficit-focused approaches to systems- and holistic-focused approaches that (a) identify strengths and stressors among individuals, groups, and communities; (b) dismantle structural forms of oppression; and (c) promote positive mental health outcomes for minoritized youth. Integrating recommendations from the educational equity literature and critical school mental health frameworks, this paper identifies core considerations for equitable school mental health screening and provides guiding principles for each phase of the screening process, from screening readiness to execution to follow up. To implement these recommendations and transform school-based mental health care, schools should (a) incorporate multiple perspectives; (b) prioritize student, family, and community voices; and (c) build collaborative partnerships to co-construct a vision for equitable school mental health.

The Diviner Lunar Radiometer Experiment on the Lunar Reconnaissance Orbiter (LRO) has been mapping the surface temperatures of the Moon since 5 July 2009. Diviner has since collected over 500 billion radiometric measurements with excellent spatial and local time coverage. However, the most recently published high-resolution Diviner global maps only use data collected from 2009 to 2016. In this work, we compile ∼13 years of Diviner data to produce improved global maps of nighttime brightness temperature, bolometric temperature, regolith temperature, and rock abundance (RA). Errors in Diviner's pointing have been corrected and past effective field of view modeling has been optimized to improve data georeferencing without spatial interpolation. We estimate an effective resolution of ∼330 m longitudinally and ∼700 m latitudinally at the equator, which corresponds to an improvement of ∼3.5× longitudinally and ∼1.3× latitudinally. In addition, we develop a thermal model that accounts for indirect scattering and emission from surrounding topography. The resulting temperature anomaly maps better highlight variations in temperature caused by thermophysical properties by removing most topographic effects. These improvements allow for the identification of smaller and fainter thermal features than was previously possible. The improved effective resolution of Diviner maps allows for excellent spatial correlation with other high-resolution data sets. To demonstrate this, we compare Diviner RA to a manual survey of boulders in the Apollo 17 landing site region. We show that Diviner RA correlates well with the areal fraction of rocks larger than ∼1–2 m in diameter visible in LRO Camera imagery.

The U.S. Department of Energy (DOE) has been a long-standing leader in driving advances in science and technology through advanced computing. However, DOE laboratories are currently facing urgent workforce challenges, particularly in terms of underrepresentation from key communities, including people of color, women, persons with disabilities, and first-generation scholars. This paper introduces the work carried out as part of the Exascale Computing Project (ECP) Broadening Participation Initiative, which aims to address workforce challenges through a lens that considers the distinct needs and culture of high-performance computing (HPC). The work focuses on three main efforts: hosting Intro to HPC Bootcamps, expanding the Sustainable Research Pathways (SRP) internship and workforce development program, and establishing an HPC Workforce Development and Retention Action Group. The paper also highlights various workforce efforts throughout the computational science community and explores opportunities for future work aimed at broadening participation in HPC.

BACKGROUND: Peripheral blood vessels in pigs are not easily accessible, making placement of intravenous catheters difficult. Alternative methods to intravenous administration of fluids, such as administering fluids via the rectum (proctoclysis), are warranted in pigs. HYPOTHESIS: Administration of polyionic crystalloid fluids via proctoclysis results in hemodilution changes similar to intravenous administration. The objectives of this study were to evaluate the tolerance for proctoclysis in pigs and compare analytes before and after intravenous or proctoclysis therapy. ANIMALS: Six healthy, growing, academic institution-owned pigs. METHODS: Randomized, cross-over design clinical trial, with 3 treatments (control, intravenous, and proctoclysis) with a 3-day washout period. The pigs were anesthetized and jugular catheters were placed. A polyionic fluid (Plasma-Lyte A 148) was administered at 4.4 mL/kg/h during the intravenous and proctoclysis treatments. Laboratory analytes, including PCV, plasma, and serum total solids, albumin, and electrolytes were measured over 12 h at T0 , T3 , T6 , T9 , and T12 . Effects of treatment and time on analytes were determined by analysis of variance. RESULTS: Proctoclysis was tolerated by pigs. Albumin concentrations decreased during the IV treatment between T0 and T6 (least square mean of 4.2 vs 3.9 g/dL; 95% CI of mean difference = -0.42, -0.06; P = .03). Proctoclysis did not significantly affect any laboratory analytes at any time points (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Proctoclysis did not demonstrate hemodilution similar to intravenous administration of polyionic fluids. Proctoclysis might not be an effective alternative to the intravenous administration of polyionic fluids in healthy euvolemic pigs.