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OBJECTIVE The American Spine Registry (ASR) is a collaborative effort between the American Academy of Orthopaedic Surgeons and the American Association of Neurological Surgeons. The goal of this study was to evaluate how representative the ASR is of the national practice with spinal procedures, as recorded in the National Inpatient Sample (NIS). METHODS The authors queried the NIS and the ASR for cervical and lumbar arthrodesis cases performed during 2017–2019. International Classification of Diseases, 10th Revision and Current Procedural Terminology codes were used to identify patients undergoing cervical and lumbar procedures. The two groups were compared for the overall proportion of cervical and lumbar procedures, age distribution, sex, surgical approach features, race, and hospital volume. Outcomes available in the ASR, such as patient-reported outcomes and reoperations, were not analyzed due to nonavailability in the NIS. The representativeness of the ASR compared to the NIS was assessed via Cohen’s d effect sizes, and absolute standardized mean differences (SMDs) of < 0.2 were considered trivial, whereas > 0.5 were considered moderately large. RESULTS A total of 24,800 arthrodesis procedures were identified in the ASR for the period between January 1, 2017, and December 31, 2019. During the same time period, 1,305,360 cases were recorded in the NIS. Cervical fusions comprised 35.9% of the ASR cohort (8911 cases) and 36.0% of the NIS cohort (469,287 cases). The two databases presented trivial differences in terms of patient age and sex for all years of interest across both cervical and lumbar arthrodeses (SMD < 0.2). Trivial differences were also noted in the distribution of open versus percutaneous procedures of the cervical and lumbar spine (SMD < 0.2). Among lumbar cases, anterior approaches were more common in the ASR than in the NIS (32.1% vs 22.3%, SMD = 0.22), but the discrepancy among cervical cases in the two databases was trivial (SMD = 0.03). Small differences were illustrated in terms of race, with SMDs < 0.5, and a more significant discrepancy was identified in the geographic distribution of participating sites (SMDs of 0.7 and 0.74 for cervical and lumbar cases, respectively). For both of these measures, SMDs in 2019 were smaller than those in 2018 and 2017. CONCLUSIONS The ASR and NIS databases presented a very high similarity in proportions of cervical and lumbar spine surgeries, as well as similar distributions of age and sex, and distribution of open versus endoscopic approach. Slight discrepancies in anterior versus posterior approach among lumbar cases and patient race, and more significant discrepancies in geographic representation were also identified, yet decreasing trends in differences suggested the improving representativeness of the ASR over the course of time and its progressive growth. These conclusions are important to underline the external validity of quality investigations and research conclusions to be drawn from analyses in which the ASR is used.

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Age is among the main risk factors for cancer and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches.

The development of persistent cellular reservoirs of latent human immunodeficiency virus (HIV) is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Previous studies show that HIV persists in myeloid cells (monocytes and macrophages) in blood and tissues in virologically suppressed people with HIV (vsPWH). However, how myeloid cells contribute to the size of the HIV reservoir and what impact they have on rebound after treatment interruption remain unclear. Here we report the development of a human monocyte-derived macrophage quantitative viral outgrowth assay (MDM-QVOA) and highly sensitive T cell detection assays to confirm purity. We assess the frequency of latent HIV in monocytes using this assay in a longitudinal cohort of vsPWH (n = 10, 100% male, ART duration 5–14 yr) and find half of the participants showed latent HIV in monocytes. In some participants, these reservoirs could be detected over several years. Additionally, we assessed HIV genomes in monocytes from 30 vsPWH (27% male, ART duration 5–22 yr) utilizing a myeloid-adapted intact proviral DNA assay (IPDA) and demonstrate that intact genomes were present in 40% of the participants and higher total HIV DNA correlated with reactivatable latent reservoirs. The virus produced in the MDM-QVOA was capable of infecting bystander cells resulting in viral spread. These findings provide further evidence that myeloid cells meet the definition of a clinically relevant HIV reservoir and emphasize that myeloid reservoirs should be included in efforts towards an HIV cure.

It is shown that a local Nullstellensatz holds over an arbitrary commutative ring A (with identity 1 ≠ 0); specifically, if B = A[x1, . . . , xn] is a finitely generated extension ring of A and N is a maximal ideal in B, then NBN = (N ∩ A, x1 − c1, . . . , xn − cn)BN for some c1, . . . , cn ∈ BN .

Current guidelines recommend extubation only if a patient is not receiving vasopressor therapy or is receiving minimal doses of vasopressors. However, recent data indicate that extubation of patients receiving higher vasopressor doses may be safe. This study was undertaken to examine practices regarding extubation of patients receiving vasopressor therapy reported by clinician respondents to a survey by the Michigan Health and Hospital Association Keystone Center. One-third of respondents indicated that they would extubate a patient receiving vasopressors, and one-quarter indicated that it depended on the agent used, but more than half reported that their unit did not have a vasopressor use protocol or they did not know whether it did. Practices regarding extubation of patients receiving vasopressor therapy differed significantly by unit type and by role as a direct care provider. These data indicate that patient and clinician factors may drive practice patterns. Additional research to inform guidelines and local protocols is warranted.

A high-leverage strategy first discussed more than 50 years ago, wait time has many benefits for both teachers and students yet is not used to its full potential. See how it can enhance your students’ mathematical discourse.

Newly generated immature B cells that bind self-antigen with high avidity arrest in differentiation and undergo central tolerance via receptor editing and clonal deletion. These autoreactive immature B cells also express low surface levels of the coreceptor CD19, a key activator of the PI3K pathway. Signals emanating from both CD19 and PI3K are known to be critical for attenuating receptor editing and selecting immature B cells into the periphery. However, the mechanisms that modulate CD19 expression at this stage of B cell development have not yet been resolved. Using in vivo and in vitro models, we demonstrate that Cd19 de novo gene transcription and translation do not significantly contribute to the differences in CD19 surface expression in mouse autoreactive and nonautoreactive immature B cells. Instead, CD19 downregulation is induced by BCR stimulation in proportion to BCR engagement, and the remaining surface IgM and CD19 molecules promote intracellular PI3K-AKT activity in proportion to their level of expression. The internalized CD19 is degraded with IgM by the lysosome, but inhibiting lysosome-mediated protein degradation only slightly improves surface CD19. In fact, CD19 is restored only upon Ag removal. Our data also reveal that the PI3K-AKT pathway positively modulates CD19 surface expression in immature B cells via a mechanism that is independent of inhibition of FOXO1 and its role on Cd19 gene transcription while is dependent on mTORC1.

Antecedentes: La investigación es necesaria en el ámbito médico, debido a que asegura una buena calidad de la atención médica y avances en la prevención y tratamiento de enfermedades. Objetivo: Describir la producción científica de la Asociación Científica de Estudiantes de Medicina de la Universidad Católica de Honduras - Campus San Pedro y San Pablo (ASOCEM UNICAH - SPSP). Métodos: Estudio bibliométrico. La población fueron los trabajos publicados por miembros de la ASOCEM UNICAH SPSP, obtenidos de la base de datos institucional y revistas indizadas. Las variables fueron analizadas mediante estadística descriptiva. Resultados: La producción científica fue, 45 trabajos publicados por la asociación científica desde 2014 hasta marzo del 2022, 31 trabajos originales, 14 reportes de casos con un promedio de 6 autores. Treinta y siete trabajos se publicaron en revistas con indexación a PubMed/MEDLINE y Scopus, en los idiomas inglés y español. Conclusión: Aun siendo una asociación científica compuesta de jóvenes se ha logrado crear ciencia, se necesitan mejores herramientas educativas, mayor apoyo institucional, comités de ética y entidades en cada unidad de salud que facilite e impulse la investigación, los centros que sirven como hospitales escuelas deberían contar con departamentos de registro e investigación, personal capacitado y proactivo que estimulen a sus estudiantes a la investigación.

Owing to ease of access and high yield, most murine myeloid-derived suppressor cell (MDSC) knowledge comes from the study of spleen-derived MDSCs rather than those isolated from the tumor. Although several studies have identified subtle differences in suppressive function between these MDSCs, a recent report demonstrated that the whole peripheral myeloid compartment poorly reflects myeloid populations found at the tumor. We confirm and extend these observations by presenting data that indicate extensive differences exist between peripheral and tumor MDSCs, suggesting that it may be inappropriate to use spleen MDSCs as surrogates for studying tumor MDSCs. Using cytospins, we observed that tumor MDSCs have undergone a morphologic shift from immature myeloid cell forms commonly seen in bone marrow (BM) and spleen MDSCs and acquired mature myeloid cell characteristics. Spleen and BM monocyte-like MDSCs (M-MDSCs) readily responded to differentiation signals for multiple myeloid cell types whereas tumor M-MDSCs had remarkably reduced cellular plasticity. At the time of isolation, M-MDSCs from BM or spleen have little to no T cell suppressive activity whereas those from the tumor possess immediate and efficient T cell suppressive function. Finally, microarray analysis revealed that the transcriptomes of tumor and spleen M-MDSCs possessed >4500 differentially expressed transcripts. We conclude that tumor M-MDSCs are more differentiated and mature, and that they are morphologically, genetically, and functionally distinct from spleen and BM M-MDSCs. These observations have important implications for the design of anti-MDSC therapies and suggest that preclinical studies using nontumor MDSCs could lead to results not applicable to tumor MDSCs.

SH2 containing protein tyrosine phosphatase-2 (SHP2) is recognized as a druggable oncogenic phosphatase that is expressed in both tumor cells and immune cells. How tumor cell–autonomous SHP2 contributes to an immunosuppressive tumor microenvironment (TME) and therapeutic failure of immune checkpoint blockades in metastatic breast cancer (MBC) is not fully understood. Herein, we utilized systemic SHP2 inhibition and inducible genetic depletion of SHP2 to investigate immune reprogramming during SHP2 targeting. Pharmacologic inhibition of SHP2 sensitized MBC cells growing in the lung to α-programmed death ligand 1 (α-PD-L1) antibody treatment via relieving T-cell exhaustion induced by checkpoint blockade. Tumor cell–specific depletion of SHP2 similarly reduced pulmonary metastasis and also relieved exhaustion markers on CD8+ and CD4+ cells. Both systemic SHP2 inhibition and tumor cell–autonomous SHP2 depletion reduced tumor-infiltrated CD4+ T cells and M2-polarized tumor-associated macrophages. Analysis of TCGA datasets revealed that phosphorylation of SHP2 is important for immune-cell infiltration, T-cell activation and antigen presentation. To investigate this mechanistically, we conducted in vitro T-cell killing assays, which demonstrated that pretreatment of tumor cells with FGF2 and PDGF reduced the cytotoxicity of CD8+ T cells in a SHP2-dependent manner. Both growth factor receptor signaling and three-dimensional culture conditions transcriptionally induced PD-L1 via SHP2. Finally, SHP2 inhibition reduced MAPK signaling and enhanced STAT1 signaling, preventing growth factor–mediated suppression of MHC class I. Overall, our findings support the conclusion that tumor cell–autonomous SHP2 is a key signaling node utilized by MBC cells to engage immune-suppressive mechanisms in response to diverse signaling inputs from TME. Significance: Findings present inhibition of SHP2 as a therapeutic option to limit breast cancer metastasis by promoting antitumor immunity.

This study aims to examine the duration and rate of delayed diagnosis in Charcot foot. We systematically reviewed articles published in Medline, SCOPUS, and Cumulative Index of Nursing and Allied Health Literature to identify articles discussing delayed or misdiagnosis of Charcot foot. Random-effects models were generated to determine the average time from symptom onset to correct diagnosis (diagnostic delay duration) and proportion of patients misdiagnosed prior to being correctly diagnosed (delayed diagnosis rate). Our search identified 142 articles, 7 of which are included in this review. The review found that 53.2% of cases of Charcot osteoarthropathy experienced a delay in diagnosis (95% CI: 28.9%-77.4%). Overall, the duration of diagnostic delay was determined to be 86.9 days (95% CI: 10.5-162.1). We found that patients with Charcot foot experienced prolonged delays from symptom onset to correct diagnosis, and a majority of patients are misdiagnosed. These delays in diagnosis contribute to worse patient outcomes.

In this article, we ask what it means to think of infrastructure discursively through situational analysis. First, we consider how policymakers have historically used writing and rhetoric to redefine, reframe, and resituate what infrastructure can be in technical documents. Second, we address the impact of policymakers' discursive practices on the spaces and material realities of communities. We view the infrastructural function of writing "as a conceptual foundation for revealing structures and foundations of organizations that affect people" (Read, 2019, p. 237). We use three texts as the space of our discourse mapping: President Franklin Roosevelt's "Fireside Chat on the Recovery Program," the Green New Deal, and President Joseph Biden's recently proposed American Jobs Plan. Through these three cases, we argue that infrastructure has always been defined in relation to environment. Any definition of infrastructure is rooted in environment or seeks to change environment. These shifts in definition have been used strategically to bring more visibility to marginalized communities and make their concerns central to the concerns of the United States' socio-economic agenda. We close with implications for both communities and policymakers.

Community planning around housing needs of older adults is, at present, very understudied. This study stemmed from a practical need to determine the housing preferences of residents as part of an Age Friendly Community initiative. Data presented in this paper focus on the quantitative component of a sequential mixed methods study examining attitudes and preferences about housing. This first phase of this project involved data collected from 1,514 residents aged 30+ using a researcher-devised survey of 43 items. There was little difference in housing preferences between older and younger respondents or among those with varying financial means. Analysis revealed the most important housing considerations were safety in home, affordability, privacy, proximity to services frequently used, and accessibility. An unexpected finding was that almost half of older respondents expressed a willingness to share a home with a roommate. There were also differences in preferences on home environment based on current marital status. Data suggests that city planners and property developers should prioritize these preferences when planning for the housing-related needs of older residents. Future research should examine the interpretation of housing preferences, such as qualitative exploration of what it means for housing to be "safe" or 'affordable.'

Objectives: The Coronavirus-2019 (COVID-19) pandemic presents a unique burden specifically for workers in service industries. However, limited research on service worker’s experience during the onset of COVID-19 exists. We aimed to describe the experiences and concerns of service industry workers during the pandemic’s onset. Methods: This is a mixed-method study. Participants were recruited through social media and completed either a survey or a phone interview during May and June 2020. The survey and transcribed interview data were analyzed using the SPSS software and content analysis, respectively. Results: Twenty-seven individuals completed audio-recorded phone interviews and 28 completed the survey. Participants were mostly women between 19 and 65 years old. Participants worked in food retail ( n = 23), restaurant ( n = 25), and hospitality ( n = 7) industries. There was discordance in perceived threat level of COVID-19. Most participants reported that their workplace complied with their state’s mandates for protection measures, while others reported lacking basic supplies such as soap, hand sanitizer, and masks. Job insecurity, change of job tasks, and work hours were the most common ways that COVID-19 affected the workers. Worker’s assertiveness to self-protect while at work was influenced by their perceived severity of the pandemic. Conclusion/Application to Practice: This study highlights the vulnerability of service workers relating to job security and job tasks during the pandemic. Organizational processes are needed to promote safe work environments and facilitate access to resources for these workers. In addition, occupational health practitioners need to be aware of and address the emerging health risks and worker needs.

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D(3) would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D(3) (2000 IU per day), n–3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D(3), as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D(3) supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.)

Scholars interested in understanding if and to what extent social environments influence individual political behavior are plagued by the reality that individuals construct their social environments. Though there is acknowledgement that this construction is determined by homophily – likes associating with likes – the extent to which political beliefs drive environment selection is yet untested. This paper seeks to understand the extent to which political beliefs inform individuals’ decisions on which social environments to select into. To do so, I follow individuals as they select into social environments across their first year in a university setting – first contacting them before they are embedded in a new social environment, tracking their selections into friendships and groups, and observing how their attitudes change over a year and a half period. Results demonstrate that political beliefs can be significant predictors of selection into non-political social contexts, especially for those with the strongest beliefs about politics.

The Wound, Ostomy and Continence Nurses (WOCN) Society charged a task force with updating the venous leg ulcer (VLU) algorithm to include the addition of lymphedema with the new title of "Compression for Lower Extremity Venous Disease and Lymphedema (CLEVDAL)." As part of the process, the task force was charged to develop consensus-based statements to serve as clinical guidance related to CLEVDAL. The 3-member task force assisted by a moderator completed a scoping literature review to identify recommendations supported by research to qualify as evidence-based and to identify areas where guidance is needed to provide CLEVDAL. Based on the findings of the scoping review, the WOCN Society convened a panel of experts to develop consensus statements to direct care for those with lower extremity venous disease and lymphedema. These consensus statements underwent a second round of content validation with a different panel of clinicians with expertise in venous disease and lymphedema management. This article reports on the scoping review and subsequent evidence-based statements, along with the generation and validation of consensus-based statements to assist clinical decision-making in the CLEVDAL algorithm.

The hierarchical interaction between the actor and critic in actor-critic based reinforcement learning algorithms naturally lends itself to a game-theoretic interpretation. We adopt this viewpoint and model the actor and critic interaction as a two-player general-sum game with a leader-follower structure known as a Stackelberg game. Given this abstraction, we propose a meta-framework for Stackelberg actor-critic algorithms where the leader player follows the total derivative of its objective instead of the usual individual gradient. From a theoretical standpoint, we develop a policy gradient theorem for the refined update and provide a local convergence guarantee for the Stackelberg actor-critic algorithms to a local Stackelberg equilibrium. From an empirical standpoint, we demonstrate via simple examples that the learning dynamics we study mitigate cycling and accelerate convergence compared to the usual gradient dynamics given cost structures induced by actor-critic formulations. Finally, extensive experiments on OpenAI gym environments show that Stackelberg actor-critic algorithms always perform at least as well and often significantly outperform the standard actor-critic algorithm counterparts.

The outer membranes (OM) of Gram-negative bacteria contain a class of proteins (TBDTs) that require energy for the import of nutrients and to serve as receptors for phages and protein toxins. Energy is derived from the proton motif force (pmf) of the cytoplasmic membrane (CM) through the action of three proteins, namely, TonB, ExbB, and ExbD, which are located in the CM and extend into the periplasm.

Background Depres sion is reported in up to 90% of cancer patients but to this date, a standardized screening tool for depression specifically modified for patients diagnosed with brain tumors is lacking. Thus, this study aims to develop an adapted screening tool and identify a suitable time slot for screening. Methods Sixty-one patients with brain lesions were interviewed prior to neurosurgical resection. For screening purposes, established depression scores were used. A study-specific questionnaire (SSQ) was developed based on patient interviews prior to the trial. Two subgroups were analyzed: patients with benign and patients with malignant tumors (including brain metastases). As a subgroup within malignant lesions, patients with glioblastoma (GBM) were also analyzed separately. Results Of patients, 87.5% with GBM presented with results > 16 points on the Center for Epidemiologic Studies Depression Scale (CES-D) after surgery. A decline in patients with benign brain tumors (p = 0.0058) and an increase in patients with malignant tumors (p = 0.0491) could be shown over time for CES-D scores. In this study, we established a new prototype screening tool for depression. In patients diagnosed with GBM, the number of patients needed to screen for identification of symptoms of depression was 1.59. Best time for screening was 35 days after surgery. Conclusions Considering the high prevalence and low number needed to screen of depression in patients diagnosed with GBM, we strongly encourage their routine screening during follow-up appointments (35 days after surgery). We encourage a plan to further establish the questionnaire developed in this pilot study.

Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild–moderate Alzheimer’s disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.

Earth’s radiation belts are a hazardous environment containing trapped charged particles. Radial diffusion is one of the major processes driving radiation belt physics, accounting for energisation, transport and loss of electrons in the outer belt. The outer radiation belt is highly variable in energy and location, resulting in behaviour which is difficult to model accurately. Ensemble modelling is needed to characterise this variability. Ensembles can be constructed by varying physical parameters (capturing the uncertainty in our knowledge across many scales) and considering the spread of the final model outputs. However, it is unclear what proportion of the subsequent variability comes from physics versus the numerical methods used. We investigate the effect of varying initial conditions for typical radial diffusion coefficients. We present two methods of establishing the timescale over which initial conditions affect the subsequent radial diffusion; time to monotonicity (the time taken for the particle distribution to reach a state where radial diffusion effects become uninteresting) and dimensional analysis. Both are needed to capture the processes we are interested in as well as the inherent timescales from diffusion. Our measures are often domain dependent, indicating that the choice of where we perform our radial diffusion simulations is significant.

Whistler-Mode Chorus (WMC) waves are an important contributor to the dynamics of the magnetosphere, not only for their prevalence in measured observations of near-Earth space but also for their dominant role in transporting energy and particles throughout it. It is therefore of key importance to space weather modelling that we understand how WMC waves are generated, how they subsequently evolve and how they interact with the particle populations that they transport. There are also fundamental physics question to answer as WMC waves display nonlinear phenomena rarely seen in other fields, including their ability to raise and lower their frequency repeatedly and rapidly leading to rising and falling tone waves respectively. Are the interactions between the wave and the particles driving such phenomena, and if so to what degree are they doing so? In this talk, we revisit the nonlinear evolution of WMC waves from a theoretical perspective. Wave-particle interactions are shown to be a key driver of the modulational instabilities that lead to element and subelement formation which are well represented by an extension of the well-known Nonlinear Schrodinger equation. Simulations of this yields power spectrum reminiscent of the rising and falling tone emissions observed in mission data from the Van Allen probes, THEMIS, MMS and Cluster and determines that that wave-particle interactions are the primary cause of this effect. As a result, this nonlinear theory indicates regimes in which these frequency sweeps can be enhanced or dampened, and suggests why the WMC band gap at half the gyrofrequency exists.

BACKGROUND Digital personal health records (PHR) integrated with electronic health records via Fast Healthcare Interoperability Resources (FHIR) are promising digital health tools to support care coordination for children and youth with special healthcare needs (CYSHCN) but have not yet been widely adopted. As adoption of digital health tools grows, mixed method and implementation research methods can help inform needed real-world implementation and evaluation. OBJECTIVE This study’s objectives are to: (1) evaluate the feasibility of a FHIR-enabled digital PHR mobile application to coordinate care for CYSHCN; (2) characterize determinants of implementation; and (3) explore associations between adoption and patient/family-reported outcomes. METHODS This non-randomized, single arm, prospective feasibility trial will test use of a FHIR-enabled digital PHR mobile app by families of CYSHCN in primary care settings. Key features of the mobile app are FHIR-enabled access to structured data from the child’s medical record, ability of families to longitudinally track patient/family-centered care goals, and sharing progress towards care goals with the child’s PCP via a clinician dashboard. We aim to enroll 40 parents/caregivers of CYSHCN to use the app for a six-month period. Eligibility criteria for CYSHCN to be included in the study are: age 0-16 years; receive primary care at a participating site; have complex needs that benefit from care coordination; at high-risk for hospitalization in the next six months; English-speaking; have requisite technology at home (internet access, Apple iOS© mobile device); and have an active online electronic health record patient portal account to which a parent/caregiver has full proxy access. Digital prescriptions will be used to disseminate study recruitment materials directly to eligible participants via their existing electronic health record patient portal accounts. We will apply an intervention mixed methods research study design to link quantitative and qualitative (semi-structured interviews and family engagement panels with parents of CYSHCN) data and characterize implementation determinants. Two care coordination frameworks (Pediatric Care Coordination Framework; Patient-Centered Medical Home) and two evaluation frameworks (Consolidated Framework for Implementation Research; Technology Acceptance Model) provide theoretical foundations for this study. RESULTS Participant recruitment began in Fall 2022. Over 300 potentially eligible patients were identified in electronic health record data before recruitment began. A family engagement panel in Fall 2021 generated formative feedback from family partners. Integrated analysis of pre-trial quantitative and qualitative data informed changes aimed at enhancing the family-centeredness of study and recruitment procedures. CONCLUSIONS Findings of this study will inform how to integrate a FHIR-enabled digital PHR mobile app for CYSHCN into clinical care. Use of mixed method and implementation research methods is anticipated to strengthen implementation in diverse clinical settings. The study is positioned to advance knowledge of how to use digital health innovations for improving care and outcomes for CYSHCN and their families. CLINICALTRIAL ClinicalTrials.gov: NCT05513235

Corresponding representative dot plots for the quantification in figure 2D-F and additional myeloid composition analysis in the study of D2.A1 model.

T cell composition analysis in mice bearing SHP2 manipulated 4T1 metastases and representative dot plots for data shown in figure 4A.