Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.

OBJECTIVES/GOALS: The effect of immunosuppressive metabolites on anti-tumor immunity in human papillomavirus (HPV)-associated vs carcinogen-driven head and neck cancer is unknown. The objective of this study is to define the extent to which metabolites impair this response and identify novel metabolic targets for enhancing anti-tumor immunity. METHODS/STUDY POPULATION: HPV-associated and carcinogen-driven head and neck squamous cell carcinoma specimens were frozen following surgical excision, and tumor sections were cut onto glass slides. Slides were coated in alpha-cyano-4-hydroxy-cinnamic acid (CHCA) matrix and subjected to mass spectrometry imaging using matrix-assisted laser desorption ionization (MALDI) on a Bruker SolariX XR 12T Hybrid QqFT-ICR mass spectrometer run in positive mode. Slides were then stained for immunohistochemistry (IHC) using markers of CD8 T cells, macrophages (CD163), B cells (CD20), and tumor cells (panCK). Mass spectrometry imaging and IHC spatially resolved data will be co-registered and metabolite intensity in regions of interest (cell types) quantified. RESULTS/ANTICIPATED RESULTS: A total of seven HPV-associated (three metastatic lymph nodes and four primary tumors) and six carcinogen-driven (primary tumors) HNSC specimens were subjected to MALDI and IHC. Metabolites significantly enriched in HPV-associated HNSC relative to carcinogen-driven HNSC include 2,3-diphosphoglyceric acid, xanthine, 2,3,5-Trichloromaleylacetate, and indole-3-carboxyaldehyde. Metabolites significantly enriched in carcinogen-driven HNSC relative to HPV-associated HNSC include hesperetin 3'-O-sulfate, hypoxanthine, phosphorylcholine, and L-homocysteine sulfonic acid. In ongoing analyses, we anticipate identifying a relationship between CD8+ T cell enriched vs depleted regions and immunosuppressive metabolites (e.g., kynurenine, adenosine monophosphate). DISCUSSION/SIGNIFICANCE: Defining the extent to which CD8+ T cells interact with the metabolic milieu of the microenvironment will provide a foundation for metabolic Precision Medicine. Strategically targeting metabolic pathways to enhance the anti-tumor immune response will be leveraged for the design and implementation of immune modulatory metabolic therapy.

OBJECTIVES/GOALS: Glioblastoma (GBM) is the most common and aggressive adult primary brain malignancy. Clinically, GBM is refractory to T cell immune checkpoint blockade (ICB), in part due to its dense immune suppressive myeloid stroma. Here we show that myeloid-targeting STING agonists can repolarize the GBM microenvironment to cure ICB-refractory GBM models. METHODS/STUDY POPULATION: Using the synthetic cyclic di-nucleotide STING agonist IACS-8803 (8803) we treated orthotopic ICB-refractory QPP8 orthotopic murine GBM tumors intratumorally. We then analyzed survival and performed high parameter flow cytometry profiling of the tumor immune microenvironment following STING agonist treatment. To assess the contribution of adaptive immunity to STING agonist therapeutic efficacy, we treated orthotopic QPP8 tumors implanted in RAG1 KO mice and monitored survival. RESULTS/ANTICIPATED RESULTS: We found that STING agonist therapy cured murine orthotopic QPP8 tumors, in contrast to ICB that showed no survival benefit. In RAG1-/- mice bearing QPP8 tumors STING agonist therapy extended survival, however, the curative effect observed in wild-type mice was lost in the absence of adaptive immunity. STING agonist-treated QPP8 tumors displayed increased counts of CD8 T cells and NK cells, and decreased CD8 T cell PD1 expression. Infiltration of STING-treated gliomas by Ly6C+ F4/80+ Mono-MDSC substantially increased; however, these cells expressed reduced CD206 and CD163, suggestive of reduced immuno-suppression. Finally, in the cervical LN of QPP8-treated mice the frequency and CD80/CD86 expression of cDC1 cells increased.​ DISCUSSION/SIGNIFICANCE: ICB has failed in GBM, and the suppressive myeloid stroma remains a major barrier to generating anti-GBM T cell responses. Our work shows that STING activation, which primarily targets innate immunity myeloid cells 'upstream' of T cells in the antitumor immunity cycle, can cure ICB-refractory GBM tumors in an adaptive immunity-dependent manner.

A theoretical and experimental framework for novel metamaterial with programmable damping properties is presented. This material system is able to switch between elastic-dominated and damping-dominated regimes with different overall stiffness under dynamic loading depending on the external stimulus. The unit cell combines an auxetic and a bellow-like layer separated by an interface through which the amount of media flow can be tuned depending on the lateral strain. A simplified analytical model is derived to analyse the programmable damping effect. The model is further extended with a fluid-dynamics approach to link the effective damping properties with geometrical parameters to aid with the practical design of the metamaterial. Afterward, experiments are conducted on a macroscopic level using laser-sintered unit cells to validate the functionality of the concept both with air and water as media within the unit cells. To conclude the work, initial results on microscopic-level unit cells fabricated by two-photon lithography are introduced to showcase the scalability of the concept. This work provides an experimentally validated theoretical framework for future investigations to design unit cells with programmable damping on different length scales for applications requiring tailored dynamic energy dissipation.

Few prospective studies have documented the seropositivity among those children infected with severe acute respiratory syndrome coronavirus 2. From 2 April 2021 to 24 June 2021, we prospectively enrolled children between the ages of 2 and 17 years at three North Carolina healthcare systems. Participants received at least four at-home serological tests detecting the presence of antibodies against, but not differentiating between, the nucleocapsid or spike antigen. A total of 1,058 participants were enrolled in the study, completing 2,709 tests between 1 May 2021 and 31 October 2021. Using multilevel regression with poststratification techniques and considering our assay sensitivity and sensitivity, we estimated that the seroprevalence of infection-induced antibodies among unvaccinated children and adolescents aged 2–17 years in North Carolina increased from 15.2% (95% credible interval, CrI 9.0–22.0) in May 2021 to 54.1% (95% CrI 46.7–61.1) by October 2021, indicating an average infection-to-reported-case ratio of 5. A rapid rise in seropositivity was most pronounced in those unvaccinated children aged 12–17 years, based on our estimates. This study underlines the utility of serial, serological testing to inform a broader understanding of the regional immune landscape and spread of infection.

We studied 83 cardiac-surgery patients with nasal S. aureus carriage who received 4 intranasal administrations of XF-73 nasal gel or placebo <24 hours before surgery. One hour before surgery, patients exhibited a S. aureus nasal carriage reduction of 2.5 log10 with XF-73 compared to 0.4 log10 CFU/mL for those who received placebo (95% CI, −2.7 to −1.5; P < .0001).

Illicit substance use is dangerous in both acute and chronic forms, frequently resulting in lethal poisoning, addiction, and other negative consequences. Similar to research in other psychiatric conditions, whose ultimate goal is to enable effective prevention and treatment, studies in substance use are focused on factors elevating the risk for the disorder. The rapid growth of the substance use problem despite the effort invested in fighting it, however, suggests the need in changing the research approach. Instead of attempting to identify risk factors, whose neutralization is often infeasible if not impossible, it may be more promising to systematically reverse the perspective to the factors enhancing the aspect of liability to disorder that shares the same dimension but is opposite to risk, that is, resistance to substance use. Resistance factors, which enable the majority of the population to remain unaffected despite the ubiquity of psychoactive substances, may be more amenable to translation. While the resistance aspect of liability is symmetric to risk, the resistance approach requires substantial changes in sampling (high-resistance rather than high-risk) and using quantitative indices of liability. This article provides an overview and a practical approach to research in resistance to substance use/addiction, currently implemented in a NIH-funded project. The project benefits from unique opportunities afforded by the data originating from two longitudinal twin studies, the Virginia Twin Study of Adolescent and Behavioral Development and the Minnesota Twin Family Study. The methodology described is also applicable to other psychiatric disorders.

There is limited documentation of cross-tenure collaborative weed management programs, and no consistent set of metrics for evaluating their performance. In this study, 12 weed management practitioners in southeast Australia participated in a qualitative social research project to discuss and document examples of cross-tenure collaborative weed management and critically reflect on whether existing metrics are suitable for evaluating the performance of their programs. Analysis of focus group discussions, project documentation, subsequent reflections, and review of the literature reveal that weed management practitioners, in Australia and elsewhere, mostly rely on metrics that measure weed management inputs, such as herbicides, labor, and costs. Metrics used to evaluate social outcomes focus on benefits for individuals rather than social relationships or achievement of equitable outcomes. Social research on collaborative governance and social science methods more broadly, such as social network analysis and collective narratives, could be used by weed management practitioners to better evaluate and explain social–ecological outcomes over time.

It is argued that New Zealand’s privatisation programme is unlikely to meet its main overt objective of easing fiscal problems. In the case of sales of major public utilities, neither allocative, internal nor social efficiency are likely to be enhanced either. A brief history, and calendar, of the asset sales programme is provided.

Academics rarely raise the need to consider persons with disabilities when preventing, investigating and prosecuting international humanitarian law (IHL) violations. Worse still, no actual attempts have been made to include a disability perspective into practical guidance and monitoring mechanisms. This article addresses that void by laying out how existing yet unutilized IHL obligations can be leveraged to repress and suppress disability-based IHL violations. In doing so, the article will detail how fact-finding approaches, criminal investigative processes and reporting methods for IHL violations can be inclusive of persons with disabilities and thus more appropriately address the endemic under-representation of a disability perspective in the planning and execution of military operations during armed conflict and the specific crimes they thereby suffer. Additionally, this article will articulate concrete changes that should be made to international criminal law procedures for prosecuting war crimes to provide recognition and accountability for disability-based IHL violations, as has been done for violations against women and children. Finally, this article will diagnose the state of the law to address any legal challenges or hurdles that may hamper the inclusion of a disability perspective in fulfilling the IHL obligation to reduce and address violations of humanitarian law.

Inspired by the recent realization of a two-dimensional (2-D) chiral fluid as an active monolayer droplet moving atop a 3-D Stokesian fluid, we formulate mathematically its free-boundary dynamics. The surface droplet is described as a general 2-D linear, incompressible and isotropic fluid, having a viscous shear stress, an active chiral driving stress and a Hall stress allowed by the lack of time-reversal symmetry. The droplet interacts with itself through its driven internal mechanics and by driving flows in the underlying 3-D Stokes phase. We pose the dynamics as the solution to a singular integral–differential equation, over the droplet surface, using the mapping from surface stress to surface velocity for the 3-D Stokes equations. Specializing to the case of axisymmetric droplets, exact representations for the chiral surface flow are given in terms of solutions to a singular integral equation, solved using both analytical and numerical techniques. For a disc-shaped monolayer, we additionally employ a semi-analytical solution that hinges on an orthogonal basis of Bessel functions and allows for efficient computation of the monolayer velocity field, which ranges from a nearly solid-body rotation to a unidirectional edge current, depending on the subphase depth and the Saffman–Delbrück length. Except in the near-wall limit, these solutions have divergent surface shear stresses at droplet boundaries, a signature of systems with codimension-one domains embedded in a 3-D medium. We further investigate the effect of a Hall viscosity, which couples radial and transverse surface velocity components, on the dynamics of a closing cavity. Hall stresses are seen to drive inward radial motion, even in the absence of edge tension.

Survivors of childhood trauma are at increased risk of complex post-traumatic stress disorder (CPTSD). The Recovering from Child Abuse Programme (RCAP) is a cognitive behavioural therapy (CBT) group promoting adaptive coping strategies which may help overcome CPTSD symptoms in adult survivors of childhood trauma. We sought to explore patient experiences of factors influencing treatment acceptability and potential mechanisms of therapeutic change in a sample of participants in the RCAP programme. As the group was delivered during the COVID-19 pandemic, necessitating a transition to remote therapy, we further aimed to capture experiences of the transition to telehealth delivery of the programme. A naturalistic sample of 10 women with CPTSD attending a specialist out-patient psychological trauma service participated in the study. Therapy sessions were recorded, transcribed verbatim and group members completed written feedback forms following each session. Reflexive thematic analysis was used to analyse the written feedback and transcripts. The RCAP was acceptable to group members and several themes were identified related to the experience of change in the group. Key themes centred on group solidarity; safety in the psychotherapeutic process; schema changes related to the self, others and future catalysed by the shifting of self-blame; increased emotional regulation to feel safer in the present; and increased future optimism. Therapeutic progress continued following the transition to telehealth, although face-to-face delivery was generally preferred. The programme was acceptable and led to cognitive change, enabling increased emotional regulation in the present and improved self-concept, thereby addressing key symptoms of CPTSD.

This report provides the first confirmed identifications of wahoo (Acanthocybium solandri) and striped marlin (Kajikia audax) in the Red Sea, expanding the known ranges of these species into the basin. Potential mechanisms responsible for the lack of regional documentation of the two species are further discussed. These findings illustrate the need for systematic biodiversity surveys of pelagic fish assemblages in the Red Sea.