Rotating curved spacetime signatures from a giant quantum vortex.

Gravity simulators1 are laboratory systems in which small excitations such as sound2 or surface waves3,4 behave as fields propagating on a curved spacetime geometry. The analogy between gravity and fluids requires vanishing viscosity2-4, a feature naturally realized in superfluids such as liquid helium or cold atomic clouds5-8. Such systems have been successful in verifying key predictions of quantum field theory in curved spacetime7-11. In particular, quantum simulations of rotating curved spacetimes indicative of astrophysical black holes require the realization of an extensive vortex flow12 in superfluid systems. Here we demonstrate that, despite the inherent instability of multiply quantized vortices13,14, a stationary giant quantum vortex can be stabilized in superfluid 4He. Its compact core carries thousands of circulation quanta, prevailing over current limitations in other physical systems such as magnons5, atomic clouds6,7 and polaritons15,16. We introduce a minimally invasive way to characterize the vortex flow17,18 by exploiting the interaction of micrometre-scale waves on the superfluid interface with the background velocity field. Intricate wave-vortex interactions, including the detection of bound states and distinctive analogue black hole ringdown signatures, have been observed. These results open new avenues to explore quantum-to-classical vortex transitions and use superfluid helium as a finite-temperature quantum field theory simulator for rotating curved spacetimes19.

Placental transcriptomic signatures of prenatal and preconceptional maternal stress.

Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes.

Human Enteroid Monolayers: A Novel, Functionally-Stable Model for Investigating Oral Drug Disposition.

To further the development of an in vitro model which faithfully recapitulates drug disposition of orally administered drugs, we investigated the utility of human enteroid monolayers to simultaneously assess intestinal drug absorption and first-pass metabolism processes. We cultured human enteroid monolayers from three donors, derived via biopsies containing duodenal stem cells that were propagated and then differentiated atop permeable Transwell® inserts, and confirmed transformation into a largely enterocyte population via RNA-seq analysis and immunocytochemical (ICC) assays. Proper cell morphology was assessed and confirmed via bright field microscopy and ICC imaging of tight junction proteins and other apically and basolaterally localized proteins. Enteroid monolayer barrier integrity was demonstrated by elevated transepithelial electrical resistance (TEER) that stabilized after 10 days in culture and persisted for 42 days. These results were corroborated by low paracellular transport probe permeability at 7 and 21 days in culture. The activity of a prominent drug metabolizing enzyme, CYP3A, was confirmed at 7, 21, and 42 days culture under basal, 1α,25(OH)2 vitamin D3-induced, and 6',7'-dihydroxybergamottin-inhibited conditions. The duration of these experiments is particularly noteworthy, as this is the first study assessing drug metabolizing enzymes and transporters (DMET) expression/function for enteroids cultured for greater than 12 days. The sum of these results suggests enteroid monolayers are a promising ex vivo model to investigate and quantitatively predict an orally administered drug's intestinal absorption and/or metabolism. Significance Statement This study presents a novel ex vivo model of the human intestine, human intestinal organoid (enteroid) monolayers, that maintain barrier function and metabolic functionality for up to 42-days in culture. The incorporation of both barrier integrity and metabolic function over an extended period within the same model is an advancement over historically used in vitro systems, which either lack one or both of these attributes or have limited viability.

Exploring the association between cognitive activity and symptom resolution following concussion in adolescents aged 11-17 years.

OBJECTIVE: As opposed to postconcussion physical activity, the potential influence of cognitive activity on concussion recovery is not well characterised. This study evaluated the intensity and duration of daily cognitive activity reported by adolescents following concussion and examined the associations between these daily cognitive activities and postconcussion symptom duration. METHODS: This study prospectively enrolled adolescents aged 11-17 years with a physician-confirmed concussion diagnosis within 72 hours of injury from the emergency department and affiliated concussion clinics. Participants were followed daily until symptom resolution or a maximum of 45 days postinjury to record their daily cognitive activity (intensity and duration) and postconcussion symptom scores. RESULTS: Participants (n=83) sustained their concussion mostly during sports (84%), had a mean age of 14.2 years, and were primarily male (65%) and white (72%). Participants reported an average of 191 (SD=148), 166 (SD=151) and 38 (SD=61) minutes of low-intensity, moderate-intensity and high-intensity daily cognitive activity postconcussion while still being symptomatic. Every 10 standardised minutes per hour increase in moderate-intensity or high-intensity cognitive activities postconcussion was associated with a 22% greater rate of symptom resolution (adjusted hazard ratio (aHR) 1.22, 95% CI 1.01 to 1.47). Additionally, each extra day's delay in returning to school postconcussion was associated with an 8% lower rate of symptom resolution (aHR 0.92, 95% CI 0.85 to 0.99). CONCLUSION: In adolescents with concussion, more moderate-high intensity cognitive activity is associated with faster symptom resolution, and a delayed return to school is associated with slower symptom resolution. However, these relationships may be bidirectional and do not necessarily imply causality. Randomised controlled trials are needed to determine if exposure to early cognitive activity can promote concussion recovery in adolescents.

Managing an epidemic within a pandemic: orthopedic opioid prescribing trends during COVID-19.

INTRODUCTION: In response to the opioid epidemic, a multitude of policy and clinical-guideline based interventions were launched to combat physician overprescribing. However, the sudden rise of the Covid-19 pandemic disrupted all aspects of healthcare delivery. The purpose of this study was to evaluate how opioid prescribing patterns changed during the Covid-19 pandemic within a large multispecialty orthopedic practice. MATERIALS AND METHODS: A retrospective review of 1,048,559 patient encounters from January 1, 2015 to December 31, 2022 at a single orthopedic practice was performed. Primary outcomes were the percent of encounters with opioids prescribed and total morphine milligram equivalents (MMEs) per opioid prescription. Differences in outcomes were assessed by calendar year. Encounters were then divided into two groups: pre-Covid (1/1/2019-2/29/2020) and Covid (3/1/2020-12/31/2022). Univariate analyses were used to evaluate differences in diagnoses and outcomes between periods. Multivariate analysis was performed to assess changes in outcomes during Covid after controlling for differences in diagnoses. Statistical significance was assessed at p < 0.05. RESULTS: The percentage of encounters with opioids prescribed decreased from a high of 4.0% in 2015 to a low of 1.6% in 2021 and 2022 (p < 0.001). MMEs per prescription decreased from 283.6 ± 213.2 in 2015 to a low of 138.6 ± 100.4 in 2019 (p < 0.001). After adjusting for diagnoses, no significant differences in either opioid prescribing rates (post-COVID OR = 0.997, p = 0.893) or MMEs (post-COVID ß = 2.726, p = 0.206) were observed between the pre- and post-COVID periods. CONCLUSION: During the Covid-19 pandemic opioid prescribing levels remained below historical averages. While continued efforts are needed to minimize opioid overprescribing, it appears that the significant progress made toward this goal was not lost during the pandemic era.

Social vulnerability adversely affects emergency-department utilization but not patient-reported outcomes after total joint arthroplasty.

INTRODUCTION: Multiple studies demonstrate social deprivation is associated with inferior outcomes after total hip (THA) and total knee (TKA) arthroplasty; its effect on patient-reported outcomes is debated. The primary objective of this study evaluated the relationship between social vulnerability and the PROMIS-PF measure in patients undergoing THA and TKA. A secondary aim compared social vulnerability between patients who required increased resource utilization or experienced complications and those who didn't. MATERIALS AND METHODS: A retrospective review of 537 patients from March 2020 to February 2022 was performed. The Centers for Disease Control Social Vulnerability Index (SVI) were used to quantify socioeconomic disadvantage. The cohort was split into THA and TKA populations; univariate and multivariate analyses were performed to evaluate primary and secondary outcomes. Statistical significance was assessed at p < 0.05. RESULTS: 48.6% of patients achieved PROMIS-PF MCID at 1-year postoperatively. Higher levels of overall social vulnerability (0.40 vs. 0.28, p = 0.03) were observed in TKA patients returning to the ED within 90-days of discharge. Increased overall SVI (OR = 9.18, p = 0.027) and household characteristics SVI (OR = 9.57, p = 0.015) were independent risk factors for 90-day ED returns after TKA. In THA patients, increased vulnerability in the household type and transportation dimension was observed in patients requiring 90-day ED returns (0.51 vs. 0.37, p = 0.04). CONCLUSION: Despite an increased risk for 90-day ED returns, patients with increased social vulnerability still obtain good 1-year functional outcomes. Initiatives seeking to mitigate the effect of social deprivation on TJA outcomes should aim to provide safe alternatives to ED care during early recovery.

Characterization of Xenobiotic and Steroid Disposition Potential of Human Placental Tissue and Cell Lines (BeWo, JEG-3, JAR, and HTR-8/SVneo) by Quantitative Proteomics.

The placenta is a fetal organ that performs critical functions to maintain pregnancy and support fetal development, including metabolism and transport of xenobiotics and steroids between the maternal-fetal unit. In vitro placenta models are used to study xenobiotic and steroid disposition, but how well these models recapitulate the human placenta is not well understood. We first characterized the abundance of proteins involved in xenobiotic and steroid disposition in human placental tissue. In pooled human placenta, the following xenobiotic and steroid disposition proteins were detected (highest to lowest), 1) enzymes: glutathione S-transferase P, carbonyl reductase 1, aldo-keto reductase 1B1, hydroxysteroid dehydrogenases (HSD3B1 and HSD11B1), aromatase, epoxide hydrolase 1 (EPHX1) and steryl-sulfatase, and 2) transporters: monocarboxylate transporters (MCT1 and 4), organic anion transporting polypeptide 2B1, organic anion transporter 4, and breast cancer resistance protein (BCRP). Then, the tissue proteomics data were compared with four placental cell lines (BeWo, JEG-3, JAR, and HTR-8/SVneo). The differential global proteomics analysis revealed that the tissue and cell lines shared 1420 cytosolic and 1186 membrane proteins. Although extravillous trophoblast and cytotrophoblast marker proteins were detected in all cell lines, only BeWo and JEG-3 cells expressed the syncytiotrophoblast marker, chorionic somatomammotropin hormone 1. BeWo and JEG-3 cells expressed most target proteins including aromatase, HSDs, EPHX1, MCT1, and BCRP. JEG-3 cells treated with commonly detected phthalates in human biofluids showed dysregulation of steroid pathways. The data presented here show that BeWo and JEG-3 cells are closer to the placental tissue for studying xenobiotic and steroid disposition. SIGNIFICANCE STATEMENT: This is the first study to compare proteomics data of human placental tissue and cell lines (BeWo, JAR, JEG-3, and HTR-8/SVneo). The placental cell line and tissue proteomes are vastly different, but BeWo and JEG-3 cells showed greater resemblance to the tissue in the expression of xenobiotic and steroid disposition proteins. These data will assist researchers to select an optimum cell model for mechanistic investigations on xenobiotic and steroid disposition in the placenta.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Depression in Uveal Melanoma Survivorship: Examining Psychological Predictors of Adjustment in the First Year Following Diagnosis.

BACKGROUND: A rare cancer, uveal melanoma (UM) affects 5 in 1 million adults annually. Research on predictors of mental health in UM survivors is scarce. PURPOSE: In this prospective study, we tested models that postulate interactions between illness perceptions and coping processes in predicting depressive symptoms 1 year following UM diagnosis. METHODS: Participants' approach- and avoidance-oriented coping processes and illness perceptions specific to control and chronicity were assessed. Participants (N = 107) completed assessments prior to diagnosis (T0), and 1 week (T1), 3 months (T2), and 12 months after UM diagnosis (T3). RESULTS: At T1, a significant avoidance coping × chronicity perception interaction (b = 1.84, p = .03) indicated that the link between higher avoidance coping and greater T3 depressive symptoms was stronger for participants with prolonged chronicity perceptions (b = 17.13, p < .001). Chronicity perceptions at T2 interacted significantly with approach-oriented coping at all time points; the link between higher approach coping and lower T3 depressive symptoms was stronger for participants with prolonged chronicity perceptions at T2. Interactions between control perceptions and coping did not significantly predict T3 depressive symptoms. CONCLUSIONS: Findings lend partial support to predictive models that consider the combined, interacting influence of chronicity perceptions and coping processes on depressive symptoms in survivors of eye cancer.

The present study sought to identify psychological factors that were associated with depressive symptoms in adults diagnosed with uveal melanoma, a rare cancer. Understanding risk factors for depressive symptoms in cancer survivors is important, as heightened depressive symptoms have been shown to be associated with worse mental, physical, and disease-related outcomes in various cancer populations. In this study, uveal melanoma patients at University of California, Los Angeles were given questionnaires before their diagnosis, as well as 1 week, 3 months, and 1 year later. These questionnaires asked patients about their mental health, their efforts to cope with their cancer, and how they viewed their cancer. Adults with uveal melanoma were more likely to experience depressive symptoms 1 year after diagnosis when they had viewed their illness as more chronic in nature and also engaged in higher levels of cancer-related avoidance coping or lower levels of approach coping 3 months after their diagnosis. Findings highlight the impact that coping and perceptions of one's illness can have on mental health in the year following an uveal melanoma diagnosis. Future work should test whether mental health interventions targeting coping behaviors and/or illness perceptions can help to prevent or reduce depressive symptoms in uveal melanoma survivors.

Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles.

Atropisomeric, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. Using the isoindoles 5d-f as models, the stereochemistry and conformational folding of the systems were examined. Chiral UHPLC was used to analyze the rate of racemization and calculate the Gibbs free energy of enantiomerization (ΔG‡Enant). X-ray crystallography, 1H NMR spectroscopy, and DFT calculations were used to elucidate the three axes of chirality and clarify the structural factors contributing to ΔG‡Enant. Tandem rotation around the axes of chirality precludes the formation of diastereomers, with rotational restriction of the Caryl-Nsulfonamide bond determined as the moderator of atropisomeric stability in the system, affected primarily by steric hindrance as well as by π-stacking interactions facilitated by the folded conformation of the sulfonamide over the isoindole moiety.

Mono(2-ethylhexyl) phthalate induces transcriptomic changes in placental cells based on concentration, fetal sex, and trophoblast cell type.

Phthalates are ubiquitous plasticizer chemicals found in consumer products. Exposure to phthalates during pregnancy has been associated with adverse pregnancy and birth outcomes and differences in placental gene expression in human studies. The objective of this research was to evaluate global changes in placental gene expression via RNA sequencing in two placental cell models following exposure to the phthalate metabolite mono(2-ethylhexyl) phthalate (MEHP). HTR-8/SVneo and primary syncytiotrophoblast cells were exposed to three concentrations (1, 90, 180 µM) of MEHP for 24 h with DMSO (0.1%) as a vehicle control. mRNA and lncRNAs were quantified using paired-end RNA sequencing, followed by identification of differentially expressed genes (DEGs), significant KEGG pathways, and enriched transcription factors (TFs). MEHP caused gene expression changes across all concentrations for HTR-8/SVneo and primary syncytiotrophoblast cells. Sex-stratified analysis of primary cells identified different patterns of sensitivity in response to MEHP dose by sex, with male placentas being more responsive to MEHP exposure. Pathway analysis identified 11 KEGG pathways significantly associated with at least one concentration in both cell types. Four ligand-inducible nuclear hormone TFs (PPARG, PPARD, ESR1, AR) were enriched in at least three treatment groups. Overall, we demonstrated that MEHP differentially affects placental gene expression based on concentration, fetal sex, and trophoblast cell type. This study confirms prior studies, as enrichment of nuclear hormone receptor TFs were concordant with previously published mechanisms of phthalate disruption, and generates new hypotheses, as we identified many pathways and genes not previously linked to phthalate exposure.

The effect of reduced bone mineral density on elective total hip arthroplasty outcomes.

INTRODUCTION: Reduced bone mineral density (BMD) and disruption of normal bony architecture are the characteristics of osteopenia and osteoporosis and in patients undergoing total hip arthroplasty (THA) may cause failure of trabecular ingrowth. The purpose of this study is to evaluate the impact of reduced BMD on outcomes following primary elective THA. METHODS: A retrospective chart review of 650 elective THAs with a DEXA scan in their electronic health record (EHR) from 2011 to 2020 was conducted at an urban, academic center and a regional, health center. Patients were separated into three cohorts based on their t-score and the World Health Organizations definitions: normal (t-score ≥ - 1), osteopenia (t-score < - 1.0 and > - 2.5), and osteoporosis (t-score ≤ - 2.5). Demographic and outcome data were assessed. Subsidence was assessed for patients with non-cemented THAs. Regression models were used to account for demographic differences. RESULTS: 650 elective THAs, of which only 11 were cemented, were included in the study. Patients with osteopenia and osteoporosis were significantly older than those without (p = 0.002 and p < 0.0001, respectively) and had a lower BMI (p < 0.0001 and p < 0.0001, respectively). PFx was significantly greater in patients with osteoporosis when compared to those with normal BMD (6.5% vs. 1.0%; p = 0.04). No such difference was found between osteoporotic and osteopenic patients. The revision rate was significantly higher for osteoporotic patients than osteopenic patients (7.5% vs. 1.5%; p = 0.04). No such difference was found between the other comparison groups. CONCLUSION: Patients with osteoporosis were older with reduced BMI and had increased PFx after non-cemented elective THA. Understanding this can help surgeons formulate an appropriate preoperative plan for the treatment of patients with osteoporotic bone undergoing elective THA.

The effects of hypoalbuminemia in obese patients undergoing total joint arthroplasty.

INTRODUCTION: Total joint arthroplasty (TJA) is a highly effective surgery. However, poor nutritional status has been associated with worse outcomes. In orthopedics, nutrition status is commonly evaluated using serum albumin. When albumin levels fall below 3.0 g/dL, wound healing ability becomes impaired. Typically, malnutrition is associated with low BMI, but malnourished patients can also be obese. The goals of this study were to investigate the relationship between malnourishment represented through albumin levels of obese patients and likelihood of postoperative complications. METHODS: A retrospective review of patients undergoing primary TJA from 2016 to 2020 in the American College of Surgeons National Surgical Quality Improvement Program national database was performed. Patients with an albumin of < 3.5 g/dL were considered to have hypoalbuminemia and those with ≥ 3.5 g/dL were considered normal albumin. Univariate analysis was used to determine demographic and comorbidity differences between those with and without hypoalbuminemia. Outcomes of interest included length of stay, resource utilization, discharge disposition, and unplanned readmissions. Multivariate logistic regression examined albumin as a predictor of increased resource utilization and complications after controlling for possible confounding variables. RESULTS: Of the 79,784 patients, 4.96% of patients had low albumin. Those with hypoalbuminemia were nearly 1.5 years older than those with normal albumin, were more likely to be black, female, and had an overall increased comorbidity burden as shown by percent of patients with ASA > 3 (all p < 0.001). After risk adjustment, those with hypoalbuminemia and a BMI of 35 + had greater risk of complications and increased resource utilization. CONCLUSION: Our results demonstrated the prevalence of malnutrition increases as a patient's BMI increases. Further, hypoalbuminemia was associated with increased resource utilization and increased complication rates in all obese patients. We suggest screening albumin levels in obese patients preoperatively to give surgeons the best opportunity to optimize patient nutrition before undergoing surgery.

Phosphorylation of the RB C-terminus regulates condensin II release from chromatin.

The retinoblastoma tumor suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate and render RB inactive in late G1/S, promoting entry into S phase. Recently, monophosphorylated RB species were described to have distinct cell-cycle-independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output. We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK and RB S838/T841 phosphorylation. This signaling pathway disrupts RB and condensin II interaction with chromatin. Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

Temporal changes in the brain lipidome during neurodevelopment of Smith-Lemli-Opitz syndrome mice.

Neurodevelopment is an intricately orchestrated program of cellular events that occurs with tight temporal and spatial regulation. While it is known that the development and proper functioning of the brain, which is the second most lipid rich organ behind adipose tissue, greatly rely on lipid metabolism and signaling, the temporal lipidomic changes that occur throughout the course of neurodevelopment have not been investigated. Smith-Lemli-Opitz syndrome is a metabolic disorder caused by genetic mutations in the DHCR7 gene, leading to defective 3ß-hydroxysterol-Δ7-reductase (DHCR7), the enzyme that catalyzes the last step of the Kandutsch-Russell pathway of cholesterol synthesis. Due to the close regulatory relationship between sterol and lipid homeostasis, we hypothesize that altered or dysregulated lipid metabolism beyond the primary defect of cholesterol biosynthesis is present in the pathophysiology of SLOS. Herein, we applied our HILIC-IM-MS method and LiPydomics Python package to streamline an untargeted lipidomics analysis of developing mouse brains in both wild-type and Dhcr7-KO mice, identifying lipids at Level 3 (lipid species level: lipid class/subclass and fatty acid sum composition). We compared relative lipid abundances throughout development, from embryonic day 12.5 to postnatal day 0 and determined differentially expressed brain lipids between wild-type and Dhcr7-KO mice at specific developmental time points, revealing lipid metabolic pathways that are affected in SLOS beyond the cholesterol biosynthesis pathway, such as glycerolipid, glycerophospholipid, and sphingolipid metabolism. Implications of the altered lipid metabolic pathways in SLOS pathophysiology are discussed.

Radical-induced hetero-nuclear mixing and low-field 13C relaxation in solid pyruvic acid.

Radicals serve as a source of polarization in dynamic nuclear polarization, but may also act as polarization sink, in particular at low field. Additionally, if the couplings between the electron spins and different nuclear reservoirs are stronger than any of the reservoirs' couplings to the lattice, radicals can mediate hetero-nuclear polarization transfer. Here, we report radical-enhanced 13C relaxation in pyruvic acid doped with trityl. Up to 40 K, we find a linear carbon T1 field dependence between 5 mT and 2 T. We model the dependence quantitatively, and find that the presence of trityl accelerates direct hetero-nuclear polarization transfer at low fields, while at higher fields 13C relaxation is diffusion limited. Measurements of hetero-nuclear polarization transfer up to 600 mT confirm the predicted radical-mediated proton-carbon mixing.

Alpha oscillations and stimulus-evoked activity dissociate metacognitive reports of attention, visibility, and confidence in a rapid visual detection task.

Variability in the detection and discrimination of weak visual stimuli has been linked to oscillatory neural activity. In particular, the amplitude of activity in the alpha-band (8-12 Hz) has been shown to impact the objective likelihood of stimulus detection, as well as measures of subjective visibility, attention, and decision confidence. Here we investigate how preparatory alpha in a cued pretarget interval influences performance and phenomenology, by recording simultaneous subjective measures of attention and confidence (experiment 1) or attention and visibility (experiment 2) on a trial-by-trial basis in a visual detection task. Across both experiments, alpha amplitude was negatively and linearly correlated with the intensity of subjective attention. In contrast with this linear relationship, we observed a quadratic relationship between the strength of alpha oscillations and subjective ratings of confidence and visibility. We find that this same quadratic relationship links alpha amplitude with the strength of stimulus-evoked responses. Visibility and confidence judgments also corresponded with the strength of evoked responses, but confidence, uniquely, incorporated information about attentional state. As such, our findings reveal distinct psychological and neural correlates of metacognitive judgments of attentional state, stimulus visibility, and decision confidence when these judgments are preceded by a cued target interval.

Patients From Medically Underserved Areas Are at Increased Risk for Nonhome Discharge and Emergency Department Return After Total Joint Arthroplasty.

BACKGROUND: Maryland Health Enterprise Zones (MHEZs) were introduced in 2012 and encompass underserved areas and those with reduced access to healthcare providers. Across the United States many underserved and minority populations experience poorer total joint arthroplasty (TJA) outcomes seemingly because they reside in underserved areas. The purpose of this study is to identify and quantify the relationship between living in an MHEZ and TJA outcomes. METHODS: Retrospective review of 11,451 patients undergoing primary TJA at a single institution from July 1, 2014 to June 30, 2020 was conducted. Patients were classified based on whether they resided in an MHEZ. Statistical analyses were used to compare outcomes for TJA patients who live in MHEZ and those who do not. RESULTS: Of the 11,451 patients, 1057 patients lived in MHEZ and 10,394 patients did not. After risk adjustment, patients who live in an MHEZ were more likely to return to the emergency department within 90 days postoperatively and were less likely to be discharged home than those patients who do not live in an MHEZ. CONCLUSION: Total joint arthroplasty patients residing in MHEZ appear to present with poorer overall health as measured by increased American Society of Anesthesiologists and Hierarchical Condition Categories scores, and they are less likely to be discharged home and more likely to return to the emergency department within 90 days. Several factors associated with these findings such as socioeconomic factors, household composition, housing type, disability, and transportation may be modifiable and should be targets of future population health initiatives.

Effect of a Biopsychosocial Intervention or Postural Therapy on Disability and Health Care Spending Among Patients With Acute and Subacute Spine Pain: The SPINE CARE Randomized Clinical Trial.

Importance: Low back and neck pain are often self-limited, but health care spending remains high. Objective: To evaluate the effects of 2 interventions that emphasize noninvasive care for spine pain. Design, Setting, and Participants: Pragmatic, cluster, randomized clinical trial conducted at 33 centers in the US that enrolled 2971 participants with neck or back pain of 3 months' duration or less (enrollment, June 2017 to March 2020; final follow-up, March 2021). Interventions: Participants were randomized at the clinic-level to (1) usual care (n = 992); (2) a risk-stratified, multidisciplinary intervention (the identify, coordinate, and enhance [ICE] care model that combines physical therapy, health coach counseling, and consultation from a specialist in pain medicine or rehabilitation) (n = 829); or (3) individualized postural therapy (IPT), a postural therapy approach that combines physical therapy with building self-efficacy and self-management (n = 1150). Main Outcomes and Measures: The primary outcomes were change in Oswestry Disability Index (ODI) score at 3 months (range, 0 [best] to 100 [worst]; minimal clinically important difference, 6) and spine-related health care spending at 1 year. A 2-sided significance threshold of .025 was used to define statistical significance. Results: Among 2971 participants randomized (mean age, 51.7 years; 1792 women [60.3%]), 2733 (92%) finished the trial. Between baseline and 3-month follow-up, mean ODI scores changed from 31.2 to 15.4 for ICE, from 29.3 to 15.4 for IPT, and from 28.9 to 19.5 for usual care. At 3-month follow-up, absolute differences compared with usual care were -5.8 (95% CI, -7.7 to -3.9; P < .001) for ICE and -4.3 (95% CI, -5.9 to -2.6; P < .001) for IPT. Mean 12-month spending was $1448, $2528, and $1587 in the ICE, IPT, and usual care groups, respectively. Differences in spending compared with usual care were -$139 (risk ratio, 0.93 [95% CI, 0.87 to 0.997]; P = .04) for ICE and $941 (risk ratio, 1.40 [95% CI, 1.35 to 1.45]; P < .001) for IPT. Conclusions and Relevance: Among patients with acute or subacute spine pain, a multidisciplinary biopsychosocial intervention or an individualized postural therapy intervention, each compared with usual care, resulted in small but statistically significant reductions in pain-related disability at 3 months. However, compared with usual care, the biopsychosocial intervention resulted in no significant difference in spine-related health care spending and the postural therapy intervention resulted in significantly greater spine-related health care spending at 1 year. Trial Registration: ClinicalTrials.gov Identifier: NCT03083886.

An Unusual Case of Arm Pain in a Young Soccer Player: Herpes Zoster in the Pediatric Athlete.

ABSTRACT: Herpes zoster (HZ), shingles, is caused by the varicella-zoster virus (VZV). HZ develops as a reactivation of latent VZV and is characterized by a painful, vesicular rash typically manifesting in a dermatomal distribution on the arms, trunk or face. HZ occurs in individuals who had primary VZV disease (chickenpox) as a child or in those who have received live, attenuated VZV vaccine. HZ is common in the elderly and the immunocompromised, with age being the single greatest risk factor. The incidence of HZ in children is 74/100,000 person years for the unvaccinated and 38/100,000 person years for the vaccinated. We discuss the case of a 12-year-old soccer player with HZ who presented with right arm pain after a putative traumatic event. Diagnosis was made after two emergency department visits where the condition was not identified. HZ should be considered in the clinician's differential even in immunocompetent, vaccinated children.