Risk Factors and Outcomes Associated with Gaps in Care in Children with Congenital Heart Disease.

Adults with congenital heart disease (CHD) benefit from cardiology follow-up at recommended intervals of ≤ 2 years. However, benefit for children is less clear given limited studies and unclear current guidelines. We hypothesize there are identifiable risks for gaps in cardiology follow-up in children with CHD and that gaps in follow-up are associated with differences in healthcare utilization. Our cohort included children < 10 years old with CHD and a healthcare encounter from 2008 to 2013 at one of four North Carolina (NC) hospitals. We assessed associations between cardiology follow-up and demographics, lesion severity, healthcare access, and educational isolation (EI). We compared healthcare utilization based on follow-up. Overall, 60.4% of 6,969 children received cardiology follow-up within 2 years of initial encounter, including 53.1%, 58.1%, and 79.0% of those with valve, shunt, and severe lesions, respectively. Factors associated with gaps in care included increased drive time to a cardiology clinic (Hazard Ratio (HR) 0.92/15-min increase), EI (HR 0.94/0.2-unit increase), lesion severity (HR 0.48 for shunt/valve vs severe), and older age (HR 0.95/month if < 1 year old and 0.94/year if > 1 year old; p < 0.05). Children with a care gap subsequently had more emergency department (ED) visits (Rate Ratio (RR) 1.59) and fewer inpatient encounters and procedures (RR 0.51, 0.35; p < 0.05). We found novel factors associated with gaps in care for cardiology follow-up in children with CHD and altered health care utilization with a gap. Our findings demonstrate a need to mitigate healthcare barriers and generate clear cardiology follow-up guidelines for children with CHD.

Metacognitive accuracy predicts self-reported quality of life following traumatic brain injury.

OBJECTIVE: Metacognition and quality of life (QoL) are both adversely affected by traumatic brain injury (TBI), but the relation between them is not fully understood. As such, the purpose of this study was to determine the degree to which metacognitive accuracy predicts QoL in individuals with TBI. METHODS: Eighteen participants with moderate-to-severe TBI completed a stimulus-response task requiring the discrimination of emotions depicted in pictures of faces and then provided a retrospective confidence judgment after each response. Metacognitive accuracy was calculated using participants' response accuracy and confidence judgment accuracy. Participants also completed the Quality of Life After Brain Injury (QOLIBRI) questionnaire to assess QoL in various areas of functioning. RESULTS: Performance of a linear regression analysis revealed that higher metacognitive accuracy significantly predicted lower overall QoL. Additionally, higher metacognitive accuracy significantly predicted lower QoL related to cognition and physical limitations. CONCLUSION: The study results provide evidence of an inverse relation between metacognitive performance and QoL following TBI. Metacognitive changes associated with TBI and their relation to QoL have several clinical implications for TBI rehabilitation.

DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity.

Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1high and TRP1low), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1high and TRP1low CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1high- and TRP1low-mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-γ, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.

Single-cell RNA sequencing of murine ankle joints over time reveals distinct transcriptional changes following Borrelia burgdorferi infection.

Lyme disease is caused by the bacterial pathogen Borrelia burgdorferi, which can be readily modeled in laboratory mice. In order to understand the cellular and transcriptional changes that occur during B. burgdorferi infection, we conducted single-cell RNA sequencing (scRNA-seq) of ankle joints of infected C57BL/6 mice over time. We found that macrophages/monocytes, T cells, synoviocytes and fibroblasts all showed significant differences in gene expression of both inflammatory and non-inflammatory genes that peaked early and returned to baseline before the typical resolution of arthritis. Predictions of cellular interactions showed that macrophages appear to communicate extensively between different clusters of macrophages as well as with fibroblasts and synoviocytes. Our data give unique insights into the interactions between B. burgdorferi and the murine immune system over time and allow for a better understanding of mechanisms by which the dysregulation of the immune response may lead to prolonged symptoms in some patients.

Blockade of innate inflammatory cytokines TNFα, IL-1ß, or IL-6 overcomes virotherapy-induced cancer equilibrium to promote tumor regression.

Cancer therapeutics can lead to immune equilibrium in which the immune response controls tumor cell expansion without fully eliminating the cancer. The factors involved in this equilibrium remain incompletely understood, especially those that would antagonize the anti-tumor immune response and lead to tumor outgrowth. We previously demonstrated that continuous treatment with a non-replicating herpes simplex virus 1 expressing interleukin (IL)-12 induces a state of cancer immune equilibrium highly dependent on interferon-γ. We profiled the IL-12 virotherapy-induced immune equilibrium in murine melanoma, identifying blockade of innate inflammatory cytokines, tumor necrosis factor alpha (TNFα), IL-1ß, or IL-6 as possible synergistic interventions. Antibody depletions of each of these cytokines enhanced survival in mice treated with IL-12 virotherapy and helped to overcome equilibrium in some tumors. Single-cell RNA-sequencing demonstrated that blockade of inflammatory cytokines resulted in downregulation of overlapping inflammatory pathways in macrophages, shifting immune equilibrium towards tumor clearance, and raising the possibility that TNFα blockade could synergize with existing cancer immunotherapies.

Impact of Prenatal Diagnosis of Critical Congenital Heart Disease on Preoperative and Postoperative Outcomes.

The objective of this study was to assess the relationship of prenatal diagnosis of critical congenital heart disease (CHD) to preoperative and postoperative patient findings. Retrospective analysis of neonates with critical CHD who underwent cardiothoracic surgery at one of four centers in North Carolina between 2008 and 2013. Surgical data collected by sites for submission to the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) and the North Carolina CHD Lifespan Database were queried. There were 715 patients with STS records; 558 linked to the NC-CHD database. Patients with prenatal diagnosis had a lower incidence of preoperative risk factors, including need for mechanical ventilation and presence of shock. However, prenatally diagnosed patients had worse short-term outcomes, including higher operative mortality, higher incidence of select postoperative complications, and longer LOS. There was no difference in one-year mortality. Our findings are consistent with current literature which suggests that prenatal diagnosis of critical CHD is associated with a more optimized preoperative clinical status. However, we found that patients with prenatal diagnoses had less favorable postoperative outcomes. This needs to be investigated further, but may be secondary to patient-specific factors, such as CHD disease severity.

IFNγ is a central node of cancer immune equilibrium.

Tumors in immune equilibrium are held in balance between outgrowth and destruction by the immune system. The equilibrium phase defines the duration of clinical remission and stable disease, and escape from equilibrium remains a major clinical problem. Using a non-replicating HSV-1 vector expressing interleukin-12 (d106S-IL12), we developed a mouse model of therapy-induced immune equilibrium, a phenomenon previously seen only in humans. This immune equilibrium was centrally reliant on interferon-γ (IFNγ). CD8+ T cell direct recognition of MHC class I, perforin/granzyme-mediated cytotoxicity, and extrinsic death receptor signaling such as Fas/FasL were all individually dispensable for equilibrium. IFNγ was critically important and played redundant roles in host and tumor cells such that IFNγ sensing in either compartment was sufficient for immune equilibrium. We propose that these redundant mechanisms of action are integrated by IFNγ to protect from oncogenic or chronic viral threats and establish IFNγ as a central node in therapy-induced immune equilibrium.

Third-Grade Academic Performance and Episodes of Cardiac Care Among Children with Congenital Heart Defects.

Children with congenital heart defects (CHDs) are at risk for poor academic performance. The degree to which receipt of health care services is associated with adverse academic outcomes is not known. We examined the association between episodes of cardiac care and third-grade performance in children with CHD. We identified subjects between 1/1/2008 and 4/30/2012 among 5 centers in North Carolina. We classified children by CHD type and linked subjects to the state educational records. Any inpatient or outpatient cardiac encounter on a date of service was considered an encounter. We calculated the number of encounters by adding the number of inpatient or outpatient cardiac visits prior to the date of the end-of-grade (EOG) tests. We estimated the odds of failing third-grade reading or math EOG tests by episodes of care stratified at the 50th percentile, controlling for CHD type, maternal education, sex, race/ethnicity, birth weight, and gestational age. A total of 184 children had third-grade EOG scores linked to health care records. The median number of episodes of care was 4 (range: 1-60). Those with visits ˃ 50th percentile (> 4 encounters/year over the 4.3 year observation period) had 2.09 (95% CI 1.04, 4.21) greater odds of failing the math EOG compared to those ≤ 50th percentile (1-4 encounters). The third-grade math score declined by 1.5 points (P < 0.008) for every 10 episodes of care. There was no association of episodes of care on third-grade reading performance. Children with CHD with > 4 episodes of cardiac care/year may be at risk for delays in third-grade academic performance. Strategies to minimize school absenteeism may improve academic success in this population.

Disparities in Loss to Follow-Up Among Adults With Congenital Heart Disease in North Carolina.

BACKGROUND: The AHA/ACC Adult Congenital Heart Disease guidelines recommend that most adults with congenital heart disease (CHD) follow-up with CHD cardiologists every 1 to 2 years because longer gaps in care are associated with adverse outcomes. This study aimed to determine the proportion of patients in North Carolina who did not have recommended follow-up and to explore predictors of loss to follow-up. METHODS: Patients ages ≥18 years with a healthcare encounter from 2008 to 2013 in a statewide North Carolina database with an ICD-9 code for CHD were assessed. The proportion with cardiology follow-up within 24 months following index encounter was assessed with Kaplan-Meier estimates. Cox regression was utilized to identify demographic factors associated with differences in follow-up. RESULTS: 2822 patients were identified. Median age was 35 years; 55% were female. 70% were white, 22% black, and 3% Hispanic; 36% had severe CHD. The proportion with 2-year cardiology follow-up was 61%. Those with severe CHD were more likely to have timely follow-up than those with less severe CHD (72% vs 55%, P < .01). Black patients had a lower likelihood of follow-up than white patients (56% vs 64%, P = .01). Multivariable Cox regression identified younger age, non-severe CHD, and non-white race as risk factors for a lower likelihood of follow-up by 2 years. CONCLUSION: 39% of adults with CHD in North Carolina are not meeting AHA/ACC recommendations for follow-up. Younger and minority patients and those with non-severe CHD were particularly vulnerable to inadequate follow-up; targeted efforts to retain these patients in care may be helpful.

Dose rate versus gantry speed performance evaluation for slow gantry speeds using DICOM RT plans.

PURPOSE: Varian provides a DICOM RT Plan file that users can deliver to the electronic portal imaging device (EPID) panel to confirm the linear accelerator delivers consistent dose output across several regions of interest for varying dose rates and gantry speeds (DRGS). This work investigates if (a) the vendor-provided DRGS DICOM RT Plan is valid within the gantry speed range of stereotactic body radiation therapy (SBRT) treatments, and (b) if output constancy is maintained at those gantry speeds on a TrueBeam. METHODS: Python code was written to iterate through all control points in the DICOM RT Plan files for 21 SBRT patients and the MU per degree values were calculated for each control point. A histogram was generated to illustrate how MU per degree was distributed among the control points from the patient plans. Then, the total number of MUs was increased in the vendor-provided DRGS DICOM file to make a "modified DRGS DICOM RT Plan," which surpasses the maximum MU per degree value found in the patient plans, forcing the gantry to travel at slow speeds and deliver more MU per degree over the same arc length (representative of those during SBRT treatment delivery). The modified DRGS DICOM RT Plan file was then delivered on a TrueBeam to acquire EPID images of the dose distribution. The EPID images were analyzed with Pylinac, a Python library that analyzes DICOM RT images acquired during routine linac QA. RESULTS: Over 83% of patient DICOM RT Plan control points had MU per degree values greater than the MU per degree values in the vendor-provided DRGS DICOM file. The Pylinac analysis of the EPID-acquired images found a maximum deviation of 0.4% from machine baselines. CONCLUSIONS: The modified DRGS DICOM file can be used to determine if a TrueBeam linac is operating within specifications even when very low gantry speeds are reached.

Implementation and Evaluation of a TG-275 Key Recommendation: An Additional Early Physics Check.

PURPOSE: We report our experience of performing an extra, earlier physics plan check as recommended by the American Association of Physicists in Medicine Task Group 100 and Task Group 275 reports. We assessed utilization and timing of the extra check as well as the time required in a medium-sized clinic. METHODS AND MATERIALS: We retrospectively extracted and analyzed timestamp data from the record and verify system for the quality checklist (QCL) items related to treatment planning and physics "prechecks" for 3487 patients treated at our institution from February 2017 to February 2021. The dosimetry staff was interviewed for their perception of the value and efficacy of the practice. RESULTS: Physics prechecks were requested for 19.0% of plans. The number of requests declined from 43.9% of cases in 2017 to 18.4% in 2018. The introduction of automated plan-check tools and a dosimetrist checklist further contributed to a drop in number of precheck requests to 3.5% in 2019. For patients who received a physics precheck, the treatment planning process was a median 3.6 hours longer compared with those without (P < .001). A total of 12.9% of the precheck requests were canceled by the dosimetrist after waiting a median time of 5.3 hours. There was a strong positive correlation (0.899) between a precheck being requested and the time remaining until treatment start. Higher complexity plans and plans with a specific concern (eg, possible collision) were more likely to have a precheck requested. CONCLUSIONS: Physics prechecks have become standard practice for certain cases in our clinic. However, the perception in the department was that, as a universal practice, waiting for a precheck was not worth the time saved redoing work on the few cases in which an error was caught. Dosimetrist access to automated checking tools and checklists, which were motivated by the precheck process, contributed to this perception.

The Role of Neuroinflammation in Neuropsychiatric Disorders Following Traumatic Brain Injury: A Systematic Review.

BACKGROUND: Neuropsychiatric symptoms are common following traumatic brain injury (TBI), but their etiological onset remains unclear. Mental health research implicates neuroinflammation in the development of psychiatric disorders. The presence of neuroinflammatory responses after TBI thus prompts an investigation of their involvement in the emergence of neuropsychiatric disorders postinjury. OBJECTIVE: Review the literature surrounding the role of neuroinflammation and immune response post-TBI in the development of neuropsychiatric disorders. METHODS: A search of scientific databases was conducted for original, empirical studies in human subjects. Key words such as "neuroinflammation," "TBI," and "depression" were used to identify psychopathology as an outcome TBI and the relation to neuroinflammatory response. RESULTS: Study results provide evidence of neuroinflammation mediated post-TBI neuropsychiatric disorders including anxiety, trauma/stress, and depression. Inflammatory processes and stress response dysregulation can lead to secondary cell damage, which promote the development and maintenance of neuropsychiatric disorders postinjury. CONCLUSION: This review identifies both theoretical and empirical support for neuroinflammatory response as feasible mechanisms underlying neuropsychiatric disorders after TBI. Further understanding of these processes in this context has significant clinical implications for guiding the development of novel treatments to reduce psychiatric symptoms postinjury. Future directions to address current limitations in the literature are discussed.

Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.

Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

Simultaneous Characterization of Implant Wear and Tribocorrosion Debris within Its Corresponding Tissue Response Using Infrared Chemical Imaging.

Biotribology is one of the key branches in the field of artificial joint development. Wear and corrosion are among fundamental processes which cause material loss in a joint biotribological system; the characteristics of wear and corrosion debris are central to determining the in vivo bioreactivity. Much effort has been made elucidating the debris-induced tissue responses. However, due to the complexity of the biological environment of the artificial joint, as well as a lack of effective imaging tools, there is still very little understanding of the size, composition, and concentration of the particles needed to trigger adverse local tissue reactions, including periprosthetic osteolysis. Fourier transform infrared spectroscopic imaging (FTIR-I) provides fast biochemical composition analysis in the direct context of underlying physiological conditions with micron-level spatial resolution, and minimal additional sample preparation in conjunction with the standard histopathological analysis workflow. In this study, we have demonstrated that FTIR-I can be utilized to accurately identify fine polyethylene debris accumulation in macrophages that is not achievable using conventional or polarized light microscope with histological staining. Further, a major tribocorrosion product, chromium phosphate, can be characterized within its histological milieu, while simultaneously identifying the involved immune cell such as macrophages and lymphocytes. In addition, we have shown the different spectral features of particle-laden macrophages through image clustering analysis. The presence of particle composition variance inside macrophages could shed light on debris evolution after detachment from the implant surface. The success of applying FTIR-I in the characterization of prosthetic debris within their biological context may very well open a new avenue of research in the orthopedics community.

Causes of Death in Infants and Children with Congenital Heart Disease.

With improved surgical outcomes, infants and children with congenital heart disease (CHD) may die from other causes of death (COD) other than CHD. We sought to describe the COD in youth with CHD in North Carolina (NC). Patients from birth to 20 years of age with a healthcare encounter between 2008 and 2013 in NC were identified by ICD-9 code. Patients who could be linked to a NC death certificate between 2008 and 2016 were included. Patients were divided by CHD subtypes (severe, shunt, valve, other). COD was compared between groups. Records of 35,542 patients < 20 years old were evaluated. There were 15,277 infants with an annual mortality rate of 3.5 deaths per 100 live births. The most frequent COD in infants (age < 1 year) were CHD (31.7%), lung disease (16.1%), and infection (11.4%). In 20,265 children (age 1 to < 20 years), there was annual mortality rate of 9.7 deaths per 1000 at risk. The most frequent COD in children were CHD (34.2%), neurologic disease (10.2%), and infection (9.5%). In the severe subtype, CHD was the most common COD. In infants with shunt-type CHD disease, lung disease (19.5%) was the most common COD. The mortality rate in infants was three times higher when compared to children. CHD is the most common underlying COD, but in those with shunt-type lesions, extra-cardiac COD is more common. A multidisciplinary approach in CHD patients, where development of best practice models regarding comorbid conditions such as lung disease and neurologic disease could improve outcomes in this patient population.

Evaluating emissions reductions from zero waste strategies under dynamic conditions: A case study from Boston.

In 2018 and 2019 the City of Boston (Massachusetts, USA) conducted zero waste and carbon neutral planning efforts. Here we present the results of an accompanying analysis of the impacts of zero waste strategies on greenhouse gases (GHG) emissions associated with waste treatment. Emissions analysis in the waste sector is complicated by the contribution of significant indirect impacts that can exhibit temporal and spatial heterogeneity. For example, lifecycle GHG analysis of waste-to-energy combustion grants credits for the emissions avoided due to electricity generated from organic waste (biogenic carbon) that displaces electricity generation that could be carbon-emitting. As electricity grids decarbonize, this credit approaches zero. Long-term emissions planning needs to account for such dynamics to realistically assess the GHG mitigation potential associated with alternative waste management strategies. Here, we seek to capture these dynamics in a forward-looking analysis of waste sector emissions under a zero-waste strategy for the City of Boston. Using publicly available data sets such as EPA's Waste Reduction Model (WARM), we show that the implementation of zero waste strategies reduces the combustion of plastics and biomass in waste-to-energy (WtE) combustion facilities and associated GHG emissions. While WtE has been considered less-carbon intensive than other forms of waste treatment and fossil-based electricity generation, our analysis shows that more renewables will eventually eliminate the perceived GHG benefits associated with waste-to-energy combustion. While our approach provides policymakers with an understanding of the impacts of decisions in a dynamic context, we also identify common knowledge gaps in conducting forward-looking waste-GHG assessments.

Increasing the value and efficiency of herbicide resistance surveys.

The scale of herbicide resistance within a cropping region can be estimated and monitored using surveys of weed populations. The current approach to herbicide resistance surveys is time-consuming, logistically challenging and costly. Here we review past and current approaches used in herbicide resistance surveys with the aims of (i) defining effective survey methodologies, (ii) highlighting opportunities for improving efficiencies through the use of new technologies and (iii) identifying the value of repeated region-wide herbicide resistance surveys. One of the most extensively surveyed areas of the world's cropping regions is the Australian grain production region, with >2900 fields randomly surveyed in each of three surveys conducted over the past 15 years. Consequently, recommended methodologies are based on what has been learned from the Australian experience. Traditional seedling-based herbicide screening assays remain the most reliable and widely applicable method for characterizing resistance in weed populations. The use of satellite or aerial imagery to plan collections and image analysis to rapidly quantify screening results could complement traditional resistance assays by increasing survey efficiency and sampling accuracy. Global management of herbicide-resistant weeds would benefit from repeated and standardized surveys that track herbicide resistance evolution within and across cropping regions. © 2021 Society of Chemical Industry.

Checkpoint blockade toxicities: Insights into autoimmunity and treatment.

Checkpoint blockade has transformed not only the way cancers are treated, but also highlighted the importance of mounting a proper immune response against tumors. Despite advances in the field of immunotherapy, many patients develop a range of inflammatory toxicities that limit the efficacy of these therapies. These toxicities range from barrier site injury, such as colitis, to endocrine organ dysfunction, such as diabetes. In order to properly treat patients with cancer and avoid checkpoint blockade induced toxicities, we must gain a deeper understanding of the underlying mechanisms generating these adverse events. Cytotoxic and tissue-resident T cells likely play an important role in mediating some toxicities, though high levels of cytokines and the generation of auto-antibodies in other toxicities demonstrates these mechanisms are not all shared. Certain risk factors for specific toxicities may be able to predict who might benefit most from alternative therapies given the risk-benefit associated with checkpoint blockade. As the targets of checkpoint inhibitors have important functions in the prevention of autoimmunity, insights into risk factors and causes of toxicities will further our knowledge of fundamental immunology and enable the development of novel therapeutics.

Infrared spectral microscopy as a tool to monitor lung fibrosis development in a model system.

Tissue fibrosis is a progressive and destructive disease process that can occur in many different organs including the liver, kidney, skin, and lungs. Fibrosis is typically initiated by inflammation as a result of chronic insults such as infection, chemicals and autoimmune diseases. Current approaches to examine organ fibrosis are limited to radiological and histological analyses. Infrared spectroscopic imaging offers a potential alternative approach to gain insight into biochemical changes associated with fibrosis progression. In this study, we demonstrate that IR imaging of a mouse model of pulmonary fibrosis can identify biochemical changes observed with fibrosis progression and the beginning of resolution using K-means analysis, spectral ratios and multivariate data analysis. This study demonstrates that IR imaging may be a useful approach to understand the biochemical events associated with fibrosis initiation, progression and resolution for both the clinical setting and for assessing novel anti-fibrotic drugs in a model system.