Search

Background: A three-antigen DNA-prime/chimpanzee adenovirus 63 (ChAd63) boost vaccine containing pre-erythrocytic Plasmodium falciparum (Pf) circumsporozoite protein (CSP), Pf apical membrane antigen-1 (AMA1) and malaria multiple epitopes (ME) fused to Pf thrombospondin-related adhesion protein (ME-TRAP) elicited higher vaccine efficacy (VE) in an open label, randomized Phase 1 trial against controlled human malaria infection (CHMI) than the two-antigen vaccine DNA/Human Adenovirus 5 (HuAd5) containing CSP and AMA1. The objective of this follow-up study was to determine whether responses to CSP, AMA1 or TRAP MHC Class I-restricted epitopes were associated with VE. Methodology: Protected (n = 6) and non-protected participants (n = 26) were screened in FluoroSpot interferon gamma (IFN-γ) and Granzyme B (GzB) assays using antigen-specific 15mer peptide subpools spanning CSP (n = 9 subpools), AMA1 (n = 12 subpools), and TRAP (n = 11 subpools). Individual antigen-specific 15mers in the subpools with strong responses were then deconvoluted, evaluated for activities, and MHC Class I-restricted epitopes within the active 15mers were predicted using NetMHCpan algorithms. The predicted epitopes were synthesized and evaluated in the FluoroSpot IFN-γ and GzB assays. Results: Protected and some non-protected participants had similar responses to individual antigen-specific peptide subpools, which did not distinguish only protected participants. However, deconvoluted antigen-specific positive subpools with high magnitudes of responses revealed individual 15mer peptides containing specific and/or predicted MHC Class I (HLA) epitopes. Responses to epitopes were either IFN-γ-only, IFN-γ and GzB, or GzB-only. Due to limitation of cells, most of the analysis concentrated on the identification of protection associated AMA1 epitopes, since most of the predominant pool specific responses were generated against AMA1 15mer subpools. Furthermore, we previously identified protection associated HLA class I-restricted epitopes in a previous gene-based vaccine trial. Seven predicted minimal epitopes in AMA1 were synthesized and upon testing, five recalled responses from protected participants confirming their possible contribution and association with protection, and two recalled responses from non-protected participants. Two protection-associated epitopes were promiscuous and may have also contributed to protection by recognition of different HLA alleles. In addition, strongly positive antigen-specific 15mers identified within active antigen-specific subpools contained 39 predicted but not tested epitopes were identified in CSP, AMA1 and TRAP. Finally, some non-protected individuals recognized HLA-matched protection-associated minimal epitopes and we discuss possible reasons. Other factors such as HLA allele fine specificity or interaction between other HLA alleles in same individual may also influence protective efficacy. Conclusions: This integrated approach using immunoassays and bioinformatics identified and confirmed AMA1-MHC Class I-restricted epitopes and a list of predicted additional epitopes which could be evaluated in future studies to assess possible association with protection against CHMI in the Phase 1 trial participants. The results suggest that identification of protection-associated epitopes within malaria antigens is feasible and can help design potent next generation multi-antigen, multi-epitope malaria vaccines for a genetically diverse population and to develop robust assays to measure protective cellular immunity against pre-erythrocytic stages of malaria. This approach can be used to develop vaccines for other novel emerging infectious disease pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Food insecurity among college students, combined with limited nutrition knowledge and barriers to healthy eating, significantly impacts diet quality and fruit and vegetable intake. Efforts to address these issues are further complicated by the challenges of accurately and efficiently collecting dietary data in research settings. This study aimed to explore the relationship between nutrition knowledge and fruit/vegetable intake using skin, plasma, and dietary carotenoid levels as biomarkers. Methods: Undergraduate and graduate students aged 18 years and older (n = 166) from a California public university were recruited. The sample was predominately female (n = 133, 80%), with 30 males (18%) and three individuals (2%) identifying as non-binary. Food security was assessed using the USDA's 10-item Adult Food Security Survey Module and nutrition knowledge through a validated questionnaire. Biological data included blood samples and skin carotenoid measurements (Veggie Meter®). Dietary quality (HEI-2015) and carotenoid intake were assessed through Diet ID™, a photo-based assessment tool. Results: The mean nutrition knowledge scores were 36.55 ± 8.83 out of 58 points, and the mean skin carotenoid score was 307.07 ± 110.22. Higher knowledge scores were associated with increased plasma carotenoids, HEI-score, and Diet ID™ total carotenoids. Food security classification did not significantly impact nutrition knowledge but did influence HEI scores and skin carotenoid levels, with very low food security linked to poorer diet quality and lower carotenoid levels. Conclusions: Nutrition knowledge may serve as a significant predictor of fruit and vegetable intake in university students. Despite this correlation, the impact of overall diet quality is potentially hindered by an individual's food security status. Therefore, while knowledge is critical, addressing food insecurity is essential for enhancing diet quality among college students. [ABSTRACT FROM AUTHOR]

Background In Ontario, Canada, province-wide initiatives supporting safer opioid prescribing in primary care include voluntary audit and feedback reports and academic detailing. In this process evaluation, we aimed to determine the fidelity of delivery and receipt of the interventions, the observed change strategies used by physicians, potential mechanisms of action, and how complementary the initiatives can be to each other. Method Semi-structured interviews were conducted with academic detailers and with physicians who received both interventions. Academic detailer interviews were coded using the Behavior Change Technique Taxonomy; physician interviews were coded to the Theoretical Domain Framework. Change strategies were summarized based on academic detailer intentions and physician-reported practice changes. Potential mechanisms of action were identified using the Theories and Techniques Tool and the literature. Patient partners informed the interpretation of results through ongoing group discussions of preliminary findings. Results Interviews were conducted with eight academic detailers and 12 physicians. Change strategies described by academic detailers to support physicians’ opioid prescribing included problem solving , instructions on how to perform the behavior , adding objects to the environment , credible source , shaping knowledge , and social support. Physicians mentioned that academic detailing validated current opioid practices or increased their belief about capabilities and their intentions , mediated by increased skills and the impact of environmental context and resources . Potential mechanisms of action included behavioral regulation , behavioral cueing , and general attitudes/beliefs. On its own, receiving the audit and feedback report did not lead to changes in beliefs about prescribing practices; however, for some physicians, it provided validation and reassurance. Physicians saw unrealized potential for complementarity. Conclusions New interventions are often implemented in a complex ecosystem with other competing interventions. In this study, we show how examining the fidelity of the intervention from initial design through to delivery can identify opportunities for potential optimization.

Objective: To assess efficacy, safety and pharmacokinetics (PK) of oral lenacapavir (LEN) when used as oral bridging (OB) between delayed subcutaneous (SC) LEN injections., Design: Posthoc analysis of participants in two clinical trials of SC LEN for HIV-1 treatment who required OB when LEN SC dosing was interrupted., Methods: Oral LEN [300 mg once weekly (QW)] was initiated within 2 weeks of the next scheduled injection (dosing interval: 26 weeks). Efficacy, safety, and PK were assessed every 10-12 weeks., Results: Overall, 139 participants received ≥1 dose of oral 300 mg QW LEN plus other antiretrovirals. Median duration of OB was 19 weeks in both clinical trials. By missing = excluded analysis, over 95% of participants maintained virologic suppression (HIV-1 RNA <50 copies/ml) at Weeks 10, 20, and 30. Treatment-emergent AEs (TEAEs) were similar to those with SC LEN (excluding injection site reactions). No Grade ≥3 or serious TEAEs were considered related to oral LEN. Throughout OB, mean LEN plasma concentrations and lower bound 90% confidence intervals (CIs) were consistently above inhibitory quotient 4 (4-fold in-vitro protein binding-adjusted 95% effective concentration). OB adherence (by pill count) was ≥95% in the majority of participants in both clinical trials., Conclusions: High rates of virological suppression were maintained during OB. Oral 300 mg QW LEN was well tolerated and provided adequate plasma concentrations to bridge SC LEN dosing. This analysis supports using 300 mg QW LEN for OB when SC LEN treatment is interrupted., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Little is known about how to sustain evidence-based interventions with fidelity in community mental health settings. Phase 1 of the Working to Implement and Sustain Digital Outcome Measures (WISDOM) trial showed that an organizational strategy improved the implementation of measurement-based care (MBC) in mental health services for youths 1-12 months after clinician MBC training. The authors report results from phase 2 of the trial, in which the strategy's effects on MBC sustainment 13-26 months after clinician MBC training were examined., Methods: Twenty-one outpatient mental health clinics were randomly assigned to MBC training and technical assistance plus the Leadership and Organizational Change for Implementation (LOCI) strategy (11 clinics) or to training and technical assistance only (10 clinics). In phase 2, the primary outcomes of MBC completion rate, youth symptom improvement, and MBC fidelity were examined for 452 youths who entered treatment 13-26 months after clinician MBC training., Results: No differences were found in MBC completion rate or symptom improvement between the two conditions; however, among the 81 youths who received MBC, fidelity was significantly higher at LOCI sites relative to control sites (24%, SE=11.1 vs. 1%, SE=1.0, respectively; p=0.003)., Conclusions: During phase 2, LOCI sites (vs. control sites) sustained superior MBC fidelity when MBC was used; however, superior MBC completion rates and clinical outcomes were not sustained. Sustainment of MBC may require strategies that improve its fit with regulatory and reimbursement environments in addition to strategies that develop clinic infrastructure., Competing Interests: Dr. Marcus reports having received consulting fees from Janssen Global Services. The other authors report no financial relationships with commercial interests.

The selective amination of aromatic C-H bonds is a powerful strategy to access aryl amines, functionalities found in many pharmaceuticals and agrochemicals. Despite advances in the field, a platform for the direct, selective C-H amination of electronically diverse (hetero)arenes, particularly electron-deficient (hetero)arenes, remains an unaddressed fundamental challenge. 1-10 In addition, many (hetero)arenes present difficulty in common selective pre-functionalization reactions, such as halogenation 11 , or metal-catalyzed borylation 12 and silylation 13 . Here, we report a general solution to these limitations that enables selective C-H amination across a comprehensive scope of (hetero)arenes. Key to this strategy's success is the oxidative generation of highly electrophilic N -radical dications from bicyclic tertiary amines (DABCO) that reacts across a wide range of arenes with high selectivity. Notably, this platform constitutes the first anodically generated N -radical cations that engage in aromatic C-H amination over well-reported hydrogen atom transfer (HAT) with weak C-H bonds. 14-16 This C-H amination reaction that allows selective functionalization of both electron-rich and deficient arenes, as well as pyridines, is a rarity in the general area of non-directed aromatic C-H functionalization. 1-4 This sustainable electrochemical DABCOylation reaction provides access to many complex drug-like aryl- and pyridinylpiperazines with high functionality tolerance, chemoselectivity, and site-selectivity. 17 ., Competing Interests: Declarations Competing Interests The authors do not claim any competing interests.

Background: Neuropsychiatric adverse events (NPAEs) are associated with several antiretrovirals. Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor indicated for HIV-1 treatment, does not interact significantly with known neurotransmitter receptors in vitro. First-line therapy with DOR-based regimens resulted in significantly fewer NPAEs than efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) and similar rates to those of ritonavir-boosted darunavir (DRV/r) with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) through Week 96 of the phase 3 DRIVE-AHEAD and DRIVE-FORWARD studies, respectively., Methods: In DRIVE-AHEAD (NCT02403674) and DRIVE-FORWARD (NCT02275780), treatment-naive adults randomly received DOR/lamivudine/TDF or EFV/FTC/TDF and DOR + 2 NRTIs or DRV/r + 2 NRTIs, respectively, for a 96-week double-blind phase; afterward, participants could continue or switch to a DOR-based regimen for a 96-week open-label extension., Results: Overall, 269 and 233 participants in DRIVE-AHEAD and DRIVE-FORWARD, respectively, switched to a DOR-based regimen. At Week 96, 26 and 15 participants randomized to EFV/FTC/TDF and DRV/r + 2 NRTIs, respectively, had ongoing NPAEs, resolving by Week 192 in 73% (19/26) and 40% (6/15) of participants switching to a DOR-based regimen. New-onset NPAEs were reported by 9% (25/269) and 8% (18/233) of participants; by Week 192, new-onset NPAEs were resolved and/or resolving in 60% (15/25) and 61% (11/18) of participants., Conclusions: In both trial extensions, NPAEs persisted in 3-4% of participants 96 weeks after switching to a DOR-based regimen, possibly representing the background rate for these events. This suggests DOR-based therapy may be a good option for adults with baseline neuropsychiatric symptoms or those experiencing NPAEs with other antiretrovirals., Competing Interests: Conflicts of Interest and Source of Funding: FM, HW, PS, RMP, and RL are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or options in Merck & Co., Inc., Rahway, NJ, USA. GM has no conflicts to report., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

As ecosystems face unprecedented change and habitat loss, pursuing comprehensive and resilient habitat restoration will be integral to protecting and maintaining natural areas and the services they provide. Microbiomes offer an important avenue for improving restoration efforts as they are integral to ecosystem health and functioning. Despite microbiomes' importance, unresolved knowledge gaps hinder their inclusion in restoration efforts. Here, we address two critical gaps in understanding microbial roles in restoration-fungal microbiomes' importance in "reconstructive" restoration efforts and how management and restoration decisions interactively impact fungal communities and their cascading effects on trees. We combined field surveys, microbiome sequencing, and greenhouse experiments to determine how reconstructing an iconic landscape feature-tree islands-in the highly imperiled Everglades impacts fungal microbiomes and fungal effects on native tree species compared with their natural counterparts under different proposed hydrological management regimes. Constructed islands used in this research were built from peat soil and limestone collected from deep sloughs and levees nearby the restoration sites in 2003, providing 18 years for microbiome assembly on constructed islands. We found that while fungal microbiomes from natural and constructed tree islands exhibited similar diversity and richness, they differed significantly in community composition. These compositional differences arose mainly from changes to which fungal taxa were present on the islands rather than changes in relative abundances. Surprisingly, ~50% of fungal hub taxa (putative keystone fungi) from natural islands were missing on constructed islands, suggesting that differences in community composition of constructed island could be important for microbiome stability and function. The differences in fungal composition between natural and constructed islands had important consequences for tree growth. Specifically, these compositional differences interacted with hydrological regime (treatments simulating management strategies) to affect woody growth across the four tree species in our experiment. Taken together, our results demonstrate that reconstructing a landscape feature without consideration of microbiomes can result in diverging fungal communities that are likely to interact with management decisions leading to meaningful consequences for foundational primary producers. Our results recommend cooperation between restoration practitioners and ecologists to evaluate opportunities for active management and restoration of microbiomes during future reconstructive restoration., (© 2025 The Author(s). Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.g. genotypes and gene expression levels) on a phenotype, particularly while accommodating routine issues, such as having related subjects' data in analyses. In this paper, we extend an existing composite kernel machine regression model to integrate two multi-omics data types, while accommodating for general correlation structures amongst outcomes. Due to the kernel machine regression framework, our methods allow for the integration of high-dimensional omics data with small, nonlinear, and interactive effects, and accommodation of general study designs. Here, we focus on scientific questions that aim to assess the association between a functional grouping (such as a gene or a pathway) and a quantitative trait of interest. We use a kernel machine regression to integrate the two multi-omics data types, as they may relate to the trait, and perform a global test of association. We demonstrate the advantage of this approach over single data type association tests via simulation. Finally, we apply this method to a large, multi-ethnic data set to investigate how predicted gene expression and rare genetic variation may be related to two platelet traits., (© 2025 Wiley Periodicals LLC.)