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Abstract Detecting shielded special nuclear material, such as nuclear explosives, is a difficult challenge pursued by non-proliferation, anti-terrorism, and nuclear security programs worldwide. Interrogation with intense fast-neutron pulses is a promising method to characterize concealed nuclear material rapidly but is limited by suitable source availability and proven instrumentation. In this study we have pioneered a demonstration of such an interrogation method using a high-intensity, short-pulse, laser-driven neutron source that offers potential benefits compared to conventional neutron sources. The measurement results reported here represent the first experimental demonstration of this interrogation approach on enriched uranium items and demonstrate the feasibility of a precise measurement using realistic nuclear materials, representative of field scenarios, even with just a single laser-driven neutron pulse. Bright pulsed sources can overcome the nuisance background of items with strong internal neutron sources, improving analytical power, while single-shot assay is attractive in high-throughput situations where time is at a premium. The science and technology of this type of neutron production is developing rapidly, and we anticipate that practical mobile interrogation systems will become available based on the detection concepts demonstrated here to meet the growing measurement needs.

Adolescence is a developmental period of significant change and increasing independence, during which parents and caregivers play a critical role guiding their teen toward adulthood. Parents of adolescents with disability face heightened challenges managing their teens’ growing independence and shift to adult-based services across health, recreation, and employment. Using a mixed-methods-treatment-group-only design, this study explored the implementation and outcomes of a program designed to build parenting capacity to support their adolescent with disability. Parents enrolled in one of ten groups were invited to attend three sessions covering content tailored to adolescent development including post-school opportunities, financial support, risk-taking and decision-making, future planning, relationships, and mental health. Surveys were administered pre-program, post-program, and six months after program participation (n = 160) to measure intervention outcomes including parenting self-efficacy, self-advocacy, adolescent self-advocacy, parent confidence to support their adolescent’s growing independence, confidence to support their adolescent through sensitive developmental stages, parental hopes and aspirations, and parental empowerment. A subset of parents (n = 11) also participated in semi-structured interviews about the program’s acceptability and usefulness, and their satisfaction with the program content and delivery. All outcome variables except parent hopes and aspirations increased significantly from pre- to post-program. Parent self-efficacy, self-advocacy, and parental empowerment remained higher 6 months after program completion. Thematic analysis identified program strengths as the co-facilitation model of program delivery, practical and actionable content, the use of narratives and the facilitator’s lived experience as parents of adolescents with disability, the use of visualizations (video, pictures, diagrams), and the service provider’s trusted reputation and credibility. In conclusion, an online co-facilitated group program for parents of adolescents with disability can contribute to positive change for families by improving parent confidence, self-advocacy, and parental empowerment.

Abstract Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.

Abstract Background Estimating program costs when planning community-based mental health programs can be burdensome. Our aim was to retrospectively document the cost for the first year of planning and implementing Healthy Minds Healthy Communities (HMHC), a mental health promotion and prevention multi-level intervention initiative. This Program is among the first to use the Community Initiated Care (CIC) model in the US and is aimed at building community resilience and the capacity for communities to provide mental health support, particularly among those disproportionately impacted by COVID-19. Our objective is to share our methods for costing a program targeting 10 zip codes that are ethnically and linguistically diverse and provide an example for estimating the cost of a mental health prevention and promotion programs consisting of multiple evidence-based interventions. Methods We used a semi-structured interview process to collect cost data through the first year of program planning, start-up and initial implementation from key staff. We calculated costs for each activity, grouped them by major project categories, and identified the cost drivers of each category. We further validated cost estimates through extensive literature review. The cost analysis was done from the provider’s perspective, which included the implementing agency and its community partners. We delineated costs that were in-kind contributions to the program by other agency, and community partners. Sensitivity analyses were conducted to estimate uncertainty around parameters. Results For the first year of the development and implementation of the program, (funded through program and in-kind) is estimated at $1,382,669 (2022 US$). The costs for the three main activity domains for this project are: project management $135,822, community engagement $364,216 and design and execution $756,934. Overall, the cost drivers for the first year of this intervention were: hiring and onboarding staff, in-person community building/learning sessions, communications and marketing, and intervention delivery. Conclusion Implementation of community-based mental health promotion and prevention programs, when utilizing a participatory approach, requires a significant amount of upfront investment in program planning and development. A large proportion of this investment tends to be human capital input. Developing partnerships is a successful strategy for defraying costs.

A novel flow process to produce low-molecular-weight (Mwt) methacrylate oligomer mixtures that have potential as vaccine adjuvants and chain transfer agents (CTAs) is reported. The chemistry and process were designed to significantly reduce the number of stages required to manufacture methyl methacrylate oligomer-in-monomer mixtures with an oligomer Mwt range of dimers to pentamers and >50% conversion. Combining rapid in-flow, in situ catalytic chain transfer polymerization catalyst synthesis and volumetric microwave heating of the reaction medium resulted in catalyst flow synthesis being completed in

Background & Aims: The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration. Methods: We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IGF2 messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization. Results: Epithelial Imp1 deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased colocalization. Conclusions: Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.

Background & Aims: Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. Methods: We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. Results: Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-IDHigh) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-IDLow). RNA sequencing suggested increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in basal cells localized beyond the outermost cell layer. Conclusions: Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity.

Background & Aims: Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is up-regulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown. Methods: We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air–liquid interface cultures stimulated with interleukin (IL)13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse-transcription polymerase chain reaction, Western blot, histology, and functional analyses of barrier integrity. Results: Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL13 in differentiated cells. LOX-overexpressing organoids showed suppressed basal and up-regulated differentiation markers. In addition, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified an enriched bone morphogenetic protein (BMP) signaling pathway compared with wild-type organoids. In particular, LOX overexpression increased BMP2 and decreased the BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells. Conclusions: Our data support a model whereby LOX exhibits noncanonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of the BMP pathway in the esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

IntroductionTranslation of cancer research into practice takes around 15 years. Programs informed by implementation science methods and frameworks offer potential to improve cancer outcomes by addressing the implementation gap.MethodsWe describe the development of a Test Evidence Transition (TET) program which provides funding and support to health system delivery teams and project design and evaluation partners working together to achieve three objectives: Test innovations to support optimal cancer pathways that transform clinical practice; Evidence the process, outcome, and impact of implementation; and work with strategic partners to ensure the Transition of best practice into effective and equitable adoption across UK health systems.ResultsPhase 1 launched in April 2023. Teams with the capability and motivation to implement evidence-based pathway innovations were identified and invited to submit expressions of interest. Following peer-review, teams were supported to develop full proposals with input from academics specializing in health services research, evaluation, and implementation science. Projects were selected for funding, providing an opportunity to implement and evaluate innovations with support from academic and health system partners.ConclusionsTET aims to improve cancer outcomes by identifying and addressing local-level barriers to evidence-based practice and translating findings into consistent and equitable adoption across health systems. Phase 1 projects focus on pathway innovations in diagnosis for breast and prostate cancer. We are now launching Phase 2, focusing on colorectal cancer.

PurposeThis study investigates the accuracy of either computerized tomography (CT) or magnetic resonance imaging (MRI) for the evaluation of various orbital diseases.MethodsWe collected 126 CT scans and 65 MRI scans from 144 subjects and asked two radiologists to interpret the images without clinical information. Images included 14 with a clinical diagnosis of orbital infection, 144 with orbital inflammation, and 33 with orbital neoplasm. The inflammatory diseases included thyroid eye disease (TED, n = 69), non-specific orbital inflammation (NSOI, n = 44), IgG4-related disease (IgG4-RD, n = 15), sarcoidosis (Sarcoid, n = 9), granulomatosis with polyangiitis (GPA, n = 5), and Erdheim-Chester disease (ECD, n = 2).ResultsThe balanced accuracy (BA) for the two radiologists ranged from 0.87 to 0.90 for cellulitis, 0.81 to 0.86 for inflammation, and 0.82 to 0.85 for neoplasm. Radiologists were excellent at recognizing GPA (BA = 0.98 to 0.99) and very good for TED (BA = 0.80 to 0.86). They also did well identifying IgG4-RD (BA = 0.75 to 0.77), but slightly less well for NSOI (BA = 0.69 to 0.75) and poorly for Sarcoid (BA = 0.48 to 0.50).ConclusionsCT or MRI scanning contributes to the evaluation of patients with orbital disease, but accuracy does varies based depending on the diagnosis. We could not evaluate issues such as determination of disease activity, variability based on the unit used for imaging or the skills beyond those of our two specialized neuroradiologists. Future studies should directly compare the two imaging modalities and assess the utility of imaging to determine disease activity.

AbstractBackground: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case’s onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Abstract Middle infrared spectral results obtained in‐situ by the Hayabusa2 MARA instrument are generally in‐line with previous results and a new comparison with sample C0137 returned from asteroid (162173) Ryugu, being similar to an aqueously altered CI1 chondrite. The mid‐IR spectrum of the boulder on Ryugu measured by MARA is shallower around 9 μm compared to the laboratory spectrum of C0137. Here we show that discontinuous, fine dust deposits can partially explain the differences in the spectral data and remain in agreement with the temperature observations of the boulder by MARA if an opaque dust layer covers less than 3% of the field of view. Such a presence of dust covering a low porosity boulder was discounted by previous analysis of the mid‐infrared MARA data which did not consider a highly porous boulder as we do here.

Central nervous system (CNS) glia, including astrocytes, microglia, and oligodendrocytes, play prominent roles in traumatic injury and degenerative disorders. Due to their importance, active pharmaceutical ingredients (APIs) are being developed to modulate CNS glia in order to improve outcomes in traumatic injury and disease. While many of these APIs show promise in vitro, the majority of APIs that are systemically delivered show little penetration through the blood–brain barrier (BBB) or blood-spinal cord barrier (BSCB) and into the CNS, rendering them ineffective. Novel nanomaterials are being developed to deliver APIs into the CNS to modulate glial responses and improve outcomes in injury and disease. Nanomaterials are attractive options as therapies for central nervous system protection and repair in degenerative disorders and traumatic injury due to their intrinsic capabilities in API delivery. Nanomaterials can improve API accumulation in the CNS by increasing permeation through the BBB of systemically delivered APIs, extending the timeline of API release, and interacting biophysically with CNS cell populations due to their mechanical properties and nanoscale architectures. In this review, we present the recent advances in the fields of both locally implanted nanomaterials and systemically administered nanoparticles developed for the delivery of APIs to the CNS that modulate glial activity as a strategy to improve outcomes in traumatic injury and disease. We identify current research gaps and discuss potential developments in the field that will continue to translate the use of glia-targeting nanomaterials to the clinic.

Nutraceutical immune support offers potential for designing blends with complementary mechanisms of action for robust support of innate immune alertness. We documented enhanced immune activation when bovine colostrum peptides (BC-Pep) were added to an immune blend (IB) containing β-glucans from yeast, shiitake, maitake, and botanical non-β-glucan polysaccharides. Human peripheral blood mononuclear cells (PBMCs) were cultured with IB, BC-Pep, and IB + BC-Pep for 20 h, whereafter expression of the activation marker CD69 was evaluated on NK cells, NKT cells, and T cells. Cytokine levels were tested in culture supernatants. PBMCs were co-cultured with K562 target cells to evaluate T cell-mediated cytotoxicity. IB + BC-Pep triggered highly significant increases in IL-1β, IL-6, and TNF-α, above that of cultures treated with matching doses of either IB or BC-Pep. NK cell and T cell activation was increased by IB + BC-Pep, reaching levels of CD69 expression several fold higher than either BC-Pep or IB alone. IB + BC-Pep significantly increased T cell-mediated cytotoxic killing of K562 target cells. This synergistic effect suggests unique amplification of signal transduction of NK cells and T cells due to modulation of IB-induced signaling pathways by BC-Pep and is of interest for further pre-clinical and clinical testing of immune defense activity against virally infected and transformed cells.

Bacterial biofilms are hardy, adaptable colonies, evading immune recognition while triggering and sustaining inflammation. The goals for this study were to present a method for testing the immunogenicity of secreted metabolites from pathogenic biofilm and to document whether biofilm treated with a nutraceutical enzyme and botanical blend (NEBB) showed evidence of reprogrammed bacterial metabolism, potentially becoming more recognizable to the immune system. We screened immune-modulating properties of metabolites from established biofilm from Pseudomonas aeruginosa (Pa), Stapholycoccus simulans (Ss), and Borrelia burgdorferi (Bb). Secreted metabolites significantly increased the cytokine production by human peripheral blood mononuclear cells, including Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), macrophage inflammatory protein-1-alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), and interleukin-10 (IL-10). Pa metabolites triggered the most robust increase in IL-1β, whereas Bb metabolites triggered the most robust increase in IL-10. NEBB-disrupted biofilm produced metabolites triggering altered immune modulation compared to metabolites from untreated biofilm. Metabolites from NEBB-disrupted biofilm triggered increased MIP-1α levels and reduced IL-10 levels, suggesting a reduced ability to suppress the recruitment of phagocytes compared to untreated biofilm. The results suggest that nutraceutical biofilm disruption offers strategies for inflammation management in chronic infectious illnesses. Further clinical studies are warranted to evaluate clinical correlations in infected human hosts.

The Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS-REx) mission recently returned a sample of rocks and dust collected from asteroid Bennu. We analyzed the highest-resolution thermal data obtained by the OSIRIS-REx Thermal Emission Spectrometer (OTES) to gain insight into the thermal and physical properties of the sampling site, including rocks that may have been sampled, and the immediately surrounding Hokioi Crater. After correcting the pointing of the OTES data sets, we find that OTES fortuitously observed two dark rocks moments before they were contacted by the spacecraft. We derived thermal inertias of 100–150 (±50) J m ^−2 K ^−1 s ^−1/2 for these two rocks—exceptionally low even compared with other previously analyzed dark rocks on Bennu (180–250 J m ^−2 K ^−1 s ^−1/2 ). Our simulations indicate that monolayer coatings of sand- to pebble-sized particles, as observed on one of these rocks, could significantly reduce the apparent thermal inertia and largely mask the properties of the substrate. However, the other low-thermal-inertia rock that was contacted is not obviously covered in particles. Moreover, this rock appears to have been partially crushed, and thus potentially sampled, by the spacecraft. We conclude that this rock may be highly fractured and that it should be sought in the returned sample to better understand its origin in Bennu’s parent body and the relationship between its thermal and physical properties.

Abstract 3D patient-derived organoids (PDOs) have been utilized to evaluate potential therapies for patients with different cancers. However, the use of PDOs created from treatment-naive patient biopsies for prediction of clinical outcomes in patients with esophageal cancer has not yet been reported. Herein we describe a pilot prospective observational study with the goal of determining whether esophageal cancer PDOs created from treatment naive patients can model or predict clinical outcomes. Endoscopic biopsies of treatment-naive patients at a single tertiary care center were used to generate esophageal cancer PDOs, which were treated with standard-of-care chemotherapy, gamma-irradiation, and newer non-standard approaches, such as proton beam therapy or two small molecule inhibitors. Clinical outcomes of patients following neoadjuvant treatment were compared to their in vitro PDO responses, demonstrating the PDO’s ability to mirror clinical response, suggesting the value of PDOs in prediction of clinical response to new therapeutic approaches. Future prospective clinical trials should test the use of pre-treatment PDOs to identify specific, targeted therapies for individual patients with esophageal adenocarcinoma.

Abstract Evidence suggests that mangroves protect economic activity in coastal areas. We estimate this protection from mangroves and coastal elevation globally, examining both “direct” and “indirect” exposure events (

Abstract Radiologic orbital imaging provides important information in the diagnosis and management of orbital inflammation. However, the diagnostic value of orbital imaging is not well elucidated. This study aimed to investigate the diagnostic accuracy of orbital imaging to diagnose orbital inflammatory diseases and its ability to detect active inflammation. We collected 75 scans of 52 patients (49 computed tomography (CT) scans; 26 magnetic resonance (MR) imaging scans). Clinical diagnoses included thyroid eye disease (TED) (41 scans, 31 patients), non-specific orbital inflammation (NSOI) (22 scans, 14 patients), sarcoidosis (4 scans, 3 patients), IgG4-related ophthalmic disease (IgG4-ROD) (5 scans, 3 patients), and granulomatosis with polyangiitis (GPA) (3 scans, 1 patient). Two experienced neuroradiologists interpreted the scans, offered a most likely diagnosis, and assessed the activity of inflammation, blinded to clinical findings. The accuracy rate of radiological diagnosis compared to each clinical diagnosis was evaluated. Sensitivity and specificity in detecting active inflammation were analyzed for TED and NSOI. The accuracy rate of radiologic diagnosis was 80.0% for IgG4-ROD, 77.3% for NSOI, and 73.2% for TED. Orbital imaging could not diagnose sarcoidosis. Orbital CT had a sensitivity of 50.0% and a specificity of 75.0% to predict active TED using clinical assessment as the gold standard. The sensitivity/specificity of orbital MR was 83.3/16.7% for the detection of active NSOI. In conclusion, orbital imaging is accurate for the diagnosis of IgG4, NSOI, and TED. Further studies with a large number of cases are needed to confirm this finding, especially with regard to uncommon diseases. Orbital CT showed moderate sensitivity and good specificity for identifying active TED.

Curcumin, a bioactive phenol derived from turmeric, is an antioxidant, anti-inflammatory, and antibacterial molecule. Although curcumin exhibits beneficial effects in its innate form, it is highly hydrophobic, which leads to poor water solubility and, consequently, low bioavailability. The lack of bioavailability limits curcumin’s effectiveness as a treatment and restricts its use in clinical applications. Furthermore, to achieve beneficial, clinically relevant results, high doses of curcumin are required for systemic administration. Many researchers have utilized biomaterial carriers, including electrospun fibers, nanoparticles, hydrogels, and composite scaffolds, to overcome curcumin’s principle therapeutic limitation of low bioavailability. By using biomaterials to deliver curcumin directly to injury sites, researchers have harnessed the beneficial natural properties of curcumin while providing scaffolding to support tissue regeneration. This review will provide an in-depth overview of the literature that utilizes biomaterial delivery of curcumin for tissue regeneration in injury and disease models.

The Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS-REx) spacecraft mission characterized and collected a sample from asteroid (101955) Bennu. After the OSIRIS-REx Sample Return Capsule released to Earth’s surface in 2023 September, the spacecraft diverted into a new orbit that encounters asteroid (99942) Apophis in 2029, enabling a second mission with the same unique capabilities: OSIRIS–Apophis Explorer (APEX). On 2029 April 13, the 340 m diameter Apophis will draw within ∼32,000 km of Earth’s surface, less than 1/10 the lunar distance. Apophis will be the largest object to approach Earth this closely in recorded history. This rare planetary encounter will alter Apophis’s orbit, will subject it to tidal forces that change its spin state, and may seismically disturb its surface. APEX will distantly observe Apophis during the Earth encounter and capture its evolution in real time, revealing the consequences of an asteroid undergoing tidal disturbance by a major planet. Beginning in 2029 July, the spacecraft’s instrument suite will begin providing high-resolution data of this “stony” asteroid—advancing knowledge of these objects and their connection to meteorites. Near the mission’s end, APEX will use its thrusters to excavate regolith, a technique demonstrated at Bennu. Observations before, during, and after excavation will provide insight into the subsurface and material properties of stony asteroids. Furthermore, Apophis’s material and structure have critical implications for planetary defense.

Summary: Here, we outline detailed protocols to isolate and profile murine splenic dendritic cells (DCs) through advanced flow cytometry of the myeloid compartment and single-cell transcriptomic profiling with integrated cell surface protein expression through CITE-seq. This protocol provides a general transferrable road map for different tissues and species.For complete details on the use and execution of this protocol, please refer to Lukowski et al. (2021).

Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.Setting Prospective, international, multicentre, observational cohort study.Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration number NCT04323644

High-need, high-cost patients include those with diagnosed serious mental illnesses (e.g., schizophrenia; SMI). They often delay or fail to seek treatment. If they receive treatment, care is often sought from generalist settings (e.g., primary care or emergency medicine) or is suboptimal due to the provision of limited, non-evidence-based intervention and lack of communication, integration, and coordination among providers. This results in high aggregate costs and poor outcomes. Value-based health care requires care coordination to address the medical and social needs of this population. We describe a unique early intervention program for SMI that emanates from an inpatient setting: The Early Onset Treatment Program (EOTP) at the University of Texas Health Science Center at Houston–Harris County Psychiatric Center. The EOTP offers free, phase-specific, multidisciplinary treatment to young adults without health insurance with the aim of improving their long-term outcomes and reducing the rate of rehospitalization. An evaluation of the EOTP indicates program participants were significantly less likely to be rehospitalized at six months (4.73 times less likely) and at 12 months (3.5 times less likely) than a comparison group ( p

The influence of contaminants is one of the factors hindering self-sustained thermonuclear burn in inertial confinement fusion. Here, the authors present evidence, through simulations and experiments, that contaminants do not fully reach thermal equilibrium, and thus their amount is usually underestimated.

Abstract Natural killer (NK) cells are important innate effector cells that are well described in their ability to kill virally-infected cells and tumors. However, there is increasing appreciation for the role of NK cells in the control of other pathogens, including intracellular parasites such as Plasmodium, the cause of malaria. NK cells may be beneficial during the early phase of Plasmodium infection—prior to the activation and expansion of antigen-specific T cells—through cooperation with myeloid cells to produce inflammatory cytokines like IFNγ. Recent work has defined how Plasmodium can activate NK cells to respond with natural cytotoxicity, and inhibit the growth of parasites via antibody-dependent cellular cytotoxicity mechanisms (ADCC). A specialized subset of adaptive NK cells that are negative for the Fc receptor γ chain have enhanced ADCC function and correlate with protection from malaria. Additionally, production of the regulatory cytokine IL-10 by NK cells prevents overt pathology and death during experimental cerebral malaria. Now that conditional NK cell mouse models have been developed, previous studies need to be reevaluated in the context of what is now known about other immune populations with similarity to NK cells (i.e., NKT cells and type I innate lymphoid cells). This brief review summarizes recent findings which support the potentially beneficial roles of NK cells during Plasmodium infection in mice and humans. Also highlighted are how the actions of NK cells can be explored using new experimental strategies, and the potential to harness NK cell function in vaccination regimens.

In this study, we describe the complete mitochondrial genome of Diopatra cuprea (Bosc, 1802). The mitogenome was found to contain 14,990 base pairs (67.53% A + T content), with a total of 37 genes (13 protein coding, 22 transfer RNAs, and 2 ribosomal RNAs). This study also examined mitogenome phylogenetics relationships of closely related species and recovered that D. cuprea is closely related to eunicids. This work has added to the genetic resources for furthering evolutionary studies of Annelida.

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

The development of tolerizing therapies aiming to inactivate autoreactive effector T-cells is a promising therapeutic approach to control undesired autoimmune responses in human diseases such as Type 1 Diabetes (T1D). A critical issue is a lack of sensitive and reproducible methods to analyze antigen-specific T-cell responses, despite various attempts. We refined a proliferation assay using the fluorescent dye 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) to detect responding T-cells, highlighting the fundamental issues to be taken into consideration to monitor antigen-specific responses in patients with T1D. The critical elements that maximize detection of antigen-specific responses in T1D are reduction of blood storage time, standardization of gating parameters, titration of CFSE concentration, selecting the optimal CFSE staining duration and the duration of T-cell stimulation, and freezing in medium containing human serum. Optimization of these elements enables robust, reproducible application to longitudinal cohort studies or clinical trial samples in which antigen-specific T-cell responses are relevant, and adaptation to other autoimmune diseases.

This paper presents the ggtern package for R, which has been developed for the rendering of ternary diagrams. Based on the well-established ggplot2 package (Wickham 2009), the present package adopts the familiar and convenient programming syntax of its parent. We demonstrate that ggplot2 can be used as the basis for producing specialized plotting packages and, in the present case, a package has been developed specifically for the production of high quality ternary diagrams. In order to produce ggtern, it was necessary to overcome a number of design issues, such as finding a means to modify existing geometries designed for a 2D Cartesian coordinate system and permitting them to function in an environment that requires an additional spatial aesthetic mapping. In the present paper, we provide examples of this package in its most basic form followed by a demonstration of its ease of use, particularly if one is familiar with, and has a predilection towards using ggplot2 on a regular basis.

Abstract Background Waterborne diseases are one of the leading causes of mortality in developing countries, and diarrhea alone is responsible for over 1.5 million deaths annually. Such waterborne illnesses most often affect those in impoverished rural communities who rely on rivers for their supply of drinking water. Deaths are most common among infants and the elderly. Without knowledge of which communities are upstream of a community, upstream sanitary and bathing behaviors can never be directly linked to downstream health outcomes including disease outbreaks. Although current GIS technologies can answer the upstream question for a limited number of downstream communities, no systematic way existed of labeling each downstream village with all its upstream contributing villages along river networks or within basins at the large national scale, such as in Indonesia. This limitation prohibits macro analyses of waterborne illness across developing world communities globally. Results This novel method approach combines parallel computing, big data, community data, and open source GIS to create a database of upstream communities for 50,000–70,0000 villages in Indonesia across four differing periods. The resultant village database provides information that can be tied to the Indonesian PODES health and behavior surveys in each village to connect upstream sanitary behaviors to downstream health outcomes. We find that the approximately 250,000 communities analyzed across the four periods in Indonesia have a combined total of 13.7 million upstream villages. The average number of upstream villages per village was almost 55, the maximum number of upstream villages for any single village was over 5300. Conclusions Advances in big-data availability, particularly high-resolution elevation data, the lowering of the cost of parallel computing options, mass survey data, and open source GIS algorithms that can utilize parallel processing and big-data, open new opportunities for the study of human health at micro granularities but across entire nations. The database generated has already been used by health researchers to compute the influence of upstream behaviors on downstream diarrhea outbreaks and to monitor avoidance behaviors to upstream water behaviors across all downstream 250,000 Indonesian villages over 4 years, and further waterborne health analyses are underway.

Introduction: Gastro-jejunostomy tubes (GJT) are commonly used for enteral nutrition in patients with gastric feeding intolerance, gastroesophageal reflux, and those at high risk of aspiration. Complications are generally minor, however highly morbid complications exist, specifically in younger and smaller infants. Case presentation: A 12 month old male with a history of long gap esophageal atresia presented for management of refractory esophageal stricture and intolerance of enteral feeds. To improve his nutritional status and enteral tolerance, he underwent conversion of his gastrostomy tube to a GJT with fluoroscopic guidance. Eight days later, a computed tomography scan of the chest obtained for preoperative planning incidentally noted a splenic abscess containing the tip of the GJT. The patient was taken to the operating room where diagnostic laparoscopy revealed a small bowel perforation at the ligament of Treitz (LOT), with the tip of the GJT embedded within the spleen. The tube was removed, the abscess was debrided, and the small bowel repaired. He completed a post-operative course of intravenous antibiotics and recovered without further complications. Conclusion: While complications from GJTs are well described, this case uniquely highlights the risk of intestinal perforation from GJT, with a delayed and subtle presentation. We suggest that patients, specifically those under 12 months of age and weighing under 10 kg, be monitored closely for complications post-operatively, and the use of modified GJTs with jejunal limbs employing smaller/thinner feeding tubes that are placed well beyond LOT be strongly considered.