Efficacy of late-onset antiviral treatment in immune-compromised hosts with persistent SARS-CoV-2 infection.

The immunocompromised are at high risk of prolonged SARS-CoV-2 infection and progression to severe COVID-19. However, efficacy of late-onset direct-acting antiviral (DAA) therapy with therapeutics in clinical use and experimental drugs to mitigate persistent viral replication is unclear. In this study, we employed an immunocompromised mouse model, which supports prolonged replication of SARS-CoV-2 to explore late-onset treatment options. Tandem immuno-depletion of CD4 + and CD8 + T cells in C57BL/6 mice followed by infection with SARS-CoV-2 variant of concern (VOC) beta B.1.351 resulted in prolonged infection with virus replication for five weeks after inoculation. Early-onset treatment with nirmatrelvir/ritonavir (paxlovid) or molnupiravir was only moderately efficacious, whereas the experimental therapeutic 4'-fluorourdine (4'-FlU, EIDD-2749) significantly reduced virus load in upper and lower respiratory compartments four days post infection (dpi). All antivirals significantly lowered virus burden in a 7-day treatment regimen initiated 14 dpi, but paxlovid-treated animals experienced rebound virus replication in the upper respiratory tract seven days after treatment end. Viral RNA was detectable 28 dpi in paxlovid-treated animals, albeit not in the molnupiravir or 4'-FlU groups, when treatment was initiated 14 dpi and continued for 14 days. Low-level virus replication continued 35 dpi in animals receiving vehicle but had ceased in all treatment groups. These data indicate that late-onset DAA therapy significantly shortens the duration of persistent virus replication in an immunocompromised host, which may have implications for clinical use of antiviral therapeutics to alleviate the risk of progression to severe disease in highly vulnerable patients. Importance: Four years after the onset of the global COVID-19 pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4 + and CD8 + T cell-depleted immunocompromised mouse model of SARS-CoV-2 infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-FlU. Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.

Fine-scale spatial and social patterns of SARS-CoV-2 transmission from identical pathogen sequences.

Pathogen genomics can provide insights into disease transmission patterns, but new methods are needed to handle modern large-scale pathogen genome datasets. Genetically proximal viruses indicate epidemiological linkage and are informative about transmission events. Here, we leverage pairs of identical sequences using 114,298 SARS-CoV-2 genomes collected via sentinel surveillance from March 2021 to December 2022 in Washington State, USA, with linked age and residence information to characterize fine-scale transmission. The location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postal codes with male prisons, consistent with transmission between prison facilities. Transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. This work improves our ability to characterize transmission from large pathogen genome datasets.

Quantum state tomography in a third-order integrated optical parametric oscillator.

We measured the covariance matrix of the fields generated in an integrated third-order optical parametric oscillator operating above threshold. We observed up to (2.3 ± 0.3) dB of squeezing in amplitude difference and inferred (4.9 ± 0.7) dB of on-chip squeezing, while an excess of noise for the sum of conjugated quadratures hinders the entanglement. The degradation of amplitude correlations and state purity for increasing the pump power is consistent with the observed growth of the phase noise of the fields, showing the necessity of strategies for phase noise control aiming at entanglement generation in these systems.

Wildfire smoke impacts lake ecosystems.

Wildfire activity is increasing globally. The resulting smoke plumes can travel hundreds to thousands of kilometers, reflecting or scattering sunlight and depositing particles within ecosystems. Several key physical, chemical, and biological processes in lakes are controlled by factors affected by smoke. The spatial and temporal scales of lake exposure to smoke are extensive and under-recognized. We introduce the concept of the lake smoke-day, or the number of days any given lake is exposed to smoke in any given fire season, and quantify the total lake smoke-day exposure in North America from 2019 to 2021. Because smoke can be transported at continental to intercontinental scales, even regions that may not typically experience direct burning of landscapes by wildfire are at risk of smoke exposure. We found that 99.3% of North America was covered by smoke, affecting a total of 1,333,687 lakes ≥10 ha. An incredible 98.9% of lakes experienced at least 10 smoke-days a year, with 89.6% of lakes receiving over 30 lake smoke-days, and lakes in some regions experiencing up to 4 months of cumulative smoke-days. Herein we review the mechanisms through which smoke and ash can affect lakes by altering the amount and spectral composition of incoming solar radiation and depositing carbon, nutrients, or toxic compounds that could alter chemical conditions and impact biota. We develop a conceptual framework that synthesizes known and theoretical impacts of smoke on lakes to guide future research. Finally, we identify emerging research priorities that can help us better understand how lakes will be affected by smoke as wildfire activity increases due to climate change and other anthropogenic activities.

A multispectral 3D live organoid imaging platform to screen probes for fluorescence guided surgery.

Achieving complete tumor resection is challenging and can be improved by real-time fluorescence-guided surgery with molecular-targeted probes. However, pre-clinical identification and validation of probes presents a lengthy process that is traditionally performed in animal models and further hampered by inter- and intra-tumoral heterogeneity in target expression. To screen multiple probes at patient scale, we developed a multispectral real-time 3D imaging platform that implements organoid technology to effectively model patient tumor heterogeneity and, importantly, healthy human tissue binding.

Depression, Contraception, and Ambivalence Concerning Fertility.

Individuals suffering from depression exhibit a higher rate of unintended pregnancies, which are associated with negative outcomes for both parents and children. Often, unintended pregnancies result from contraceptive mistakes. Here, we examine the relationship between depression and the consistency of contraceptive behavior, testing ambivalence as a possible mediator. The analyses were based on cross-sectional data from the second and third waves of the German Relationship and Family Panel Pairfam. A German-speaking sample without children (N = 190; 117 female, 73 male), who reported not attempting to conceive or become pregnant during the last 12 months, was analyzed in comparison with a propensity score matched sample. Ambivalence was operationalized as the difference between the ideal and realistic number of children in wave 2. Data from wave 3 were used to assess contraceptive behavior. Depressed mood in wave 2 and consistency of contraceptive behavior in wave 3 were negatively correlated. After including ambivalence in wave 2 as a mediator in the model, the direct path between depressed mood and consistency of contraceptive behavior remained significant, with no significant mediation found. For men only, we observed a significant negative association of ambivalence with the consistency of contraceptive behavior in the last 3 months. No significant relationship was found between depressed mood and ambivalence. We conclude that future research aiming to better understand the consistency of contraceptive behavior should incorporate measures of ambivalence.

Efficacy and Safety of Abrocitinib in Prurigo Nodularis and Chronic Pruritus of Unknown Origin: A Nonrandomized Controlled Trial.

Importance: Prurigo nodularis (PN) and chronic pruritus of unknown origin (CPUO) are chronic pruritic diseases that dramatically impair quality of life, but therapeutic options are limited. Abrocitinib, a Janus kinase 1 inhibitor, represents a promising therapy for both conditions. Objective: To assess the efficacy and safety of 200-mg oral abrocitinib administered once daily in adults with moderate to severe PN or CPUO. Design, Setting, and Participants: This phase 2, open-label, nonrandomized controlled trial conducted between September 2021 and July 2022 took place at a single center in the US. A total of 25 adult patients with moderate to severe PN or CPUO were screened. Ten patients with PN and 10 patients with CPUO were enrolled. All 20 patients completed the 12-week treatment period, 18 of whom completed the 4-week follow-up period. Intervention: Abrocitinib, 200 mg, by mouth once daily for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was the percent change in weekly Peak Pruritus Numerical Rating Scale (PP-NRS) scores from baseline to week 12. Key secondary end points included the percentage of patients achieving at least a 4-point reduction in weekly PP-NRS score from baseline to week 12 and the percent change in Dermatology Life Quality Index (DLQI) scores. Results: A total of 10 patients with PN (mean [SD] age, 58.6 [13.1] years; all were female) and 10 patients with CPUO (mean [SD] age, 70.7 [5.6] years; 2 were female) enrolled in the study. The mean (SD) baseline PP-NRS score was 9.2 (1.0) for PN and 8.2 (1.2) for CPUO. PP-NRS scores decreased by 78.3% in PN (95% CI, -118.5 to -38.1; P < .001) and 53.7% in CPUO (95% CI, -98.8 to -8.6; P = .01) by week 12. From baseline to week 12, 8 of 10 patients with PN and 6 of 10 patients with CPUO achieved at least a 4-point improvement on the PP-NRS. Both groups experienced significant improvement in quality of life as demonstrated by percent change in DLQI scores (PN: -53.2% [95% CI, -75.3% to -31.1%]; P = .002; CPUO: -49.0% [95% CI, -89.6% to -8.0%]; P = .02). The most common adverse event among patients was acneiform eruption in 2 of 20 patients (10%). No serious adverse events occurred. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that abrocitinib monotherapy may be effective and tolerated well in adults with PN or CPUO. Randomized, double-blind, placebo-controlled trials are warranted to validate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT05038982.

Seabird transported contaminants are dispersed in island ecosystems.

Seabirds are long-range transporters of nutrients and contaminants, linking marine feeding areas with terrestrial breeding and roosting sites. By depositing nutrient-rich guano, which acts as a fertiliser, seabirds can substantially influence the terrestrial environment in which they reside. However, increasing pollution of the marine environment has resulted in guano becoming similarly polluted. Here, we determined metal and metalloid concentrations (As, Cd, Cr, Cu, Hg, Pb) in Flesh-footed Shearwater (Ardenna carneipes) guano, soil, terrestrial flora, and primary consumers and used an ecological approach to assess whether the trace elements in guano were bioaccumulating and contaminating the surrounding environment. Concentrations in guano were higher than those of other Procellariiformes documented in the literature, which may be influenced by the high amounts of plastics that this species of shearwater ingests. Soil samples from shearwater colonies had significantly higher concentrations of all metals, except for Pb, than soils from control sites and formerly occupied areas. Concentrations in terrestrial primary producers and primary consumers were not as marked, and for many contaminants there was no significant difference observed across levels of ornithogenic input. We conclude that Flesh-footed Shearwaters are transporters of marine derived contaminants to the Lord Howe Island terrestrial environment.

Optical coherence elastography with osmotically induced strains: Preliminary demonstration for express detection of cartilage degradation.

Optical coherence elastography (OCE) demonstrated impressive abilities for diagnosing tissue types/states using differences in their biomechanics. Usually, OCE visualizes tissue deformation induced by some additional stimulus (e.g., contact compression or auxiliary elastic-wave excitation). We propose a new variant of OCE with osmotically induced straining (OIS-OCE) and demonstrate its application to assess various stages of proteoglycan content degradation in cartilage. The information-bearing signatures in OIS-OCE are the magnitude and rate of strains caused by the application of osmotically active solutions onto the sample surface. OCE examination of the induced strains does not require special tissue preparation, the osmotic stimulation is highly reproducible, and strains are observed in noncontact mode. Several minutes suffice to obtain a conclusion. These features are promising for intraoperative method usage when express assessment of tissue state is required during surgical operations. The "waterfall" images demonstrate the development of cumulative osmotic strains in control and degraded cartilage samples.

Characterization of treatment resistance and viral kinetics in the setting of single- versus dual-active monoclonal antibodies against SARS-CoV-2.

BACKGROUND: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for SARS-CoV-2 infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. METHODS: Participants were non-hospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. RESULTS: Study participants receiving single- and dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared to single-active mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p < 0.001) and day 7 (p < 0.01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P < 0.001), and more frequently detected in the setting of single-active compared to dual-active mAb treatment (7.2% vs 1.1%, p < 0.01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. CONCLUSION: Compared to single-active mAb therapy, dual-active mAbs led to similar clinical outcomes, but significantly faster viral load decline and a lower risk of emergent resistance.

Disentangling cell-intrinsic and extrinsic factors underlying gene expression evolution.

Chimeras have played a foundational role in biology, for example by enabling the classification of developmental processes into those driven intrinsically by individual cells versus those driven extrinsically by their extracellular environment. Here, we extend this framework to decompose evolutionary divergence in gene expression and other quantitative traits into cell-intrinsic, extrinsic, and intrinsic-extrinsic interaction components. Applying this framework to reciprocal rat-mouse chimeras, we found that the majority of gene expression divergence is attributable to cell-intrinsic factors, though extrinsic factors also play an integral role. For example, a rat-like extracellular environment extrinsically up-regulates the expression of a key transcriptional regulator of the endoplasmic reticulum (ER) stress response in some but not all cell types, which in turn strongly predicts extrinsic up-regulation of its target genes and of the ER stress response pathway as a whole. This effect is also seen at the protein level, suggesting propagation through multiple regulatory levels. We also demonstrate that our framework is applicable to a cellular trait, neuronal differentiation, and estimated the intrinsic and extrinsic contributions to its divergence. Finally, we show that imprinted genes are dramatically mis-expressed in species-mismatched environments, suggesting that mismatch between rapidly evolving intrinsic and extrinsic mechanisms controlling gene imprinting may contribute to barriers to interspecies chimerism. Overall, our conceptual framework opens new avenues to investigate the mechanistic basis of evolutionary divergence in gene expression and other quantitative traits in any multicellular organism.

The effect of gastrointestinal graft-versus-host disease and diarrhea on the pharmacokinetic profile of sotrovimab in hematopoietic stem cell transplant recipients.

BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics (PK) of the long-acting mAb sotrovimab targeting SARS-CoV-2 in hematopoietic cell transplant (HCT) recipients. METHODS: All participants received an intravenous infusion of sotrovimab within one week prior to initiating the pre-transplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks post-transplant. RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal (GI) graft-versus-host disease (GVHD) post-transplant. CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased GI clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.

Programmatic implementation of depression screening and remote mental health support sessions for persons recently diagnosed with TB in Lima, Peru during the COVID-19 pandemic.

Background: Few studies have explored a stepped care model for delivering mental health care to persons with tuberculosis (TB). Here, we evaluated depression screening and remote low-intensity mental health interventions for persons initiating TB treatment in Lima, Peru during the COVID-19 pandemic. Methods: We used the Patient Health Questionnaire 9 (PHQ-9) to screen participants for depressive symptoms (PHQ-9 ≥ 5). Participants with PHQ-9, 5-14 received remote Psychological First Aid (PFA) or Problem Management Plus (PM+). Participants were reevaluated 6 months after intervention completion. We then compared the change in median PHQ-9 scores before and after intervention completion. Those with PHQ-9 ≥ 15 were referred to higher-level care. Findings: We found that 62 (45.9%) of the 135 participants had PHQ-9 ≥ 5 at baseline. Then, 54 individuals with PHQ-9, 5-9 received PFA, of which 44 (81.5%) were reevaluated. We observed significant reductions in median PHQ-9 scores from 6 to 2 (r = 0.98; p < 0.001). Four participants with PHQ-9, 10-14 received PM+ but were unable to be reevaluated. Four participants with PHQ-9 ≥ 15 were referred to higher-level care. Conclusions: Depressive symptoms were common among persons recently diagnosed with TB. We observed improvements in depressive symptoms 6 months later for most participants who received remote sessions of PFA.

Pediatric Trauma Center Access, Regional Injury Burden, and Socioeconomic Disadvantage.

This cross-sectional study assesses whether populations in socioeconomically disadvantaged regions in the US lack timely access to pediatric trauma centers.

Oscillating latent dynamics in robot systems during walking and reaching.

Sensorimotor control of complex, dynamic systems such as humanoids or quadrupedal robots is notoriously difficult. While artificial systems traditionally employ hierarchical optimisation approaches or black-box policies, recent results in systems neuroscience suggest that complex behaviours such as locomotion and reaching are correlated with limit cycles in the primate motor cortex. A recent result suggests that, when applied to a learned latent space, oscillating patterns of activation can be used to control locomotion in a physical robot. While reminiscent of limit cycles observed in primate motor cortex, these dynamics are unsurprising given the cyclic nature of the robot's behaviour (walking). In this preliminary investigation, we consider how a similar approach extends to a less obviously cyclic behaviour (reaching). This has been explored in prior work using computational simulations. But simulations necessarily make simplifying assumptions that do not necessarily correspond to reality, so do not trivially transfer to real robot platforms. Our primary contribution is to demonstrate that we can infer and control real robot states in a learnt representation using oscillatory dynamics during reaching tasks. We further show that the learned latent representation encodes interpretable movements in the robot's workspace. Compared to robot locomotion, the dynamics that we observe for reaching are not fully cyclic, as they do not begin and end at the same position of latent space. However, they do begin to trace out the shape of a cycle, and, by construction, they are driven by the same underlying oscillatory mechanics.

Genicular nerve radiofrequency ablation: a systematic review of application for perioperative pain control in total knee arthroplasty and as treatment for chronic pain in well-appearing total knee arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) is a successful treatment for end-stage osteoarthritis, yet some patients still experience postoperative pain. Genicular nerve radiofrequency ablation (GNRFA) has become a potential modality to address pain in TKA. This systematic review aims to critically analyze the applicability of GNRFA in perioperative pain control prior to TKA, as well as a treatment modality for chronic painful well-appearing TKA. METHODS: PubMed, Medline, EMBASE, Google Scholar, Scopus, and COCHRANE databases, as well as the ClinicalTrials.gov register, were reviewed. The search included randomized controlled trials and cohort studies. The sample population focused on two cohorts; those who underwent TKA and utilized intentional GNRFA as a perioperative pain control modality, and those utilizing the treatment modality for chronic pain in well-appearing TKA. GNRFA was the intervention studied, and postoperative outcomes were compared with the control group, which consisted of those not receiving GNRFA. RESULT: Eight total publications were identified as relevant to this search. Among the pre-TKA studies, there was variability in results; these inconsistencies were attributed to a lack of standardization, especially with regard to type, timing, and targeted nerves with ablation. Likewise, while the results were improved among the population with chronic painful TKA receiving GNRFA, these inconsistencies still existed. CONCLUSIONS: Current evidence suggests GNRFA as a possible pre-TKA intervention to potentially minimize opioid consumption, patient-reported pain, length of stay, and increased range of motion and activity. However, the short-lived duration in the setting of chronically painful well-appearing TKA represents a major barrier that warrants further investigation. Limitations include small sample size, heterogeneity, lack of standardization of techniques among studies, and lack of direct comparison and meta-analysis. Further research should focus on the standardization of technique as well as analyzing various patient and health-system-related factors that correlate with sustained positive outcomes.

Orexin neurons track temporal features of blood glucose in behaving mice.

Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of >900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain's arousal orchestrators.

Noninvasive therapy of brain cancer using a unique systemic delivery methodology with a cancer terminator virus.

Primary, glioblastoma, and secondary brain tumors, from metastases outside the brain, are among the most aggressive and therapeutically resistant cancers. A physiological barrier protecting the brain, the blood-brain barrier (BBB), functions as a deterrent to effective therapies. To enhance cancer therapy, we developed a cancer terminator virus (CTV), a unique tropism-modified adenovirus consisting of serotype 3 fiber knob on an otherwise Ad5 capsid that replicates in a cancer-selective manner and simultaneously produces a potent therapeutic cytokine, melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24). A limitation of the CTV and most other viruses, including adenoviruses, is an inability to deliver systemically to treat brain tumors because of the BBB, nonspecific virus trapping, and immune clearance. These obstacles to effective viral therapy of brain cancer have now been overcome using focused ultrasound with a dual microbubble treatment, the focused ultrasound-double microbubble (FUS-DMB) approach. Proof-of-principle is now provided indicating that the BBB can be safely and transiently opened, and the CTV can then be administered in a second set of complement-treated microbubbles and released in the brain using focused ultrasound. Moreover, the FUS-DMB can be used to deliver the CTV multiple times in animals with glioblastoma  growing in their brain thereby resulting in a further enhancement in survival. This strategy permits efficient therapy of primary and secondary brain tumors enhancing animal survival without promoting harmful toxic or behavioral side effects. Additionally, when combined with a standard of care therapy, Temozolomide, a further increase in survival is achieved. The FUS-DMB approach with the CTV highlights a noninvasive strategy to treat brain cancers without surgery. This innovative delivery scheme combined with the therapeutic efficacy of the CTV provides a novel potential translational therapeutic approach for brain cancers.

Commercial Cannabidiol for Community-Based Young Adolescents: Predicting Medicinal Use.

Objectives: Cannabidiol (CBD) is rising in popularity, including as a potential medicinal product. Yet data on use of commercial CBD for medicinal or health reasons in adolescents are lacking. In this study we aim to detail characteristics of adolescents given commercial CBD for health reasons (health CBD [hCBD]) and to investigate predictors of use. Materials and Methods: The Adolescent Brain Cognitive Development (ABCD) Study is a population-based cohort study following U.S. healthy, community-based adolescents annually, with data from 2018 to 2022 (11- to 15-year-olds; N=11,189). Participants and caregivers completed questionnaires, including whether adolescents were given CBD with parent or doctor's permission. Participants reported past-month pain, attention problems, externalizing symptoms, internalizing symptoms, and total mental health problems. Caregivers reported youth sociodemographics, sleep problems, whether the youth had mental health treatment or sought medical treatment, and rules about recreational cannabis use. We describe youth given hCBD, and run generalized estimating equations predicting odd ratios (ORs) and 95% confidence intervals of adolescents given hCBD by mental health, physical health, or sociodemographics of factors. Results: Of the 11,189 participants across up to three waves of data, 48% were female. Mean age across waves was 12.8 years old (SD=1). In total, 307 (2.8%) were given hCBD. Common administration methods were oil (42%), topical (31%), and edibles (29%). Increased hCBD odds were associated with being older (OR=1.32 [1.17-1.49]), White (relative to Black, OR=05.97 [2.81-12.65] or Hispanic, OR=1.82 [1.17-2.82]), parents with some college (relative to no high school diploma, OR=3.55 [1.09-11.6]), internalizing symptoms (OR=1.81 [1.13-2.91]), mental health treatment (OR=1.76 [1.3-2.38]), pain (OR=1.38 [1.09-1.76]), medical treatment (OR=1.39 [1.08-1.79]), and sleep problems (OR=1.69 [1.27-2.25]). Rules against recreational cannabis decreased odds of hCBD (OR=1.75 [1.30-2.36]). Conclusions: Findings indicate some healthy adolescents are given hCBD, and predictors of use include mental and physical health concerns, being White, older, and parents with some college education. Providers should ask if their youth patients are being given CBD medicinally, and transparently discuss potential benefits, consequences, and unknowns of CBD.