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Understanding the conditionally-dependent clinical variables that drive cardiovascular health outcomes is a major challenge for precision medicine. Here, we deploy a recently developed massively scalable comorbidity discovery method called Poisson Binomial based Comorbidity discovery (PBC), to analyze Electronic Health Records (EHRs) from the University of Utah and Primary Children's Hospital (over 1.6 million patients and 77 million visits) for comorbid diagnoses, procedures, and medications. Using explainable Artificial Intelligence (AI) methodologies, we then tease apart the intertwined, conditionally-dependent impacts of comorbid conditions and demography upon cardiovascular health, focusing on the key areas of heart transplant, sinoatrial node dysfunction and various forms of congenital heart disease. The resulting multimorbidity networks make possible wide-ranging explorations of the comorbid and demographic landscapes surrounding these cardiovascular outcomes, and can be distributed as web-based tools for further community-based outcomes research. The ability to transform enormous collections of EHRs into compact, portable tools devoid of Protected Health Information solves many of the legal, technological, and data-scientific challenges associated with large-scale EHR analyses.

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

The segregation of glycosylphosphatidylinositol-anchored proteins (GPI-APs) to distinct domains on the plasma membrane of eukaryotic cells is important for their correct cellular function, but the mechanisms by which GPI-APs are sorted are yet to be fully resolved. An extreme example of this is in African trypanosomes, where the major surface glycoprotein floods the whole cell surface while most GPI-APs are retained in a specialised domain at the base of the flagellum. One possibility is that anchor attachment signals direct differential sorting of proteins. To investigate this, we fused a monomeric reporter to the GPI-anchor insertion signals of trypanosome proteins that are differentially sorted on the plasma membrane. Fusions were correctly anchored by GPI, post-translationally modified, and routed to the plasma membrane, but this delivery was independent of retained signals upstream of the ω site. Instead, ω−minus signal strength appears key to efficacy of GPI addition and to GPI-AP cellular level. Thus, at least in this system, sorting is not encoded at the time of GPI anchor addition or in the insertion sequence retained in processed proteins. We discuss these findings in the context of previously proposed models for sorting mechanisms in trypanosomes.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Abstract Objective Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single‐ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. Methods We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Results Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single‐ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. Interpretation We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

The sterile insect technique (SIT) is an environmentally friendly method of pest control in which insects are mass-produced, irradiated and released to mate with wild counterparts. SIT has been used to control major pest insects including the pink bollworm (Pectinophora gossypiella Saunders), a global pest of cotton. Transgenic technology has the potential to overcome disadvantages associated with the SIT, such as the damaging effects of radiation on released insects. A method called RIDL (Release of Insects carrying a Dominant Lethal) is designed to circumvent the need to irradiate insects before release. Premature death of insects' progeny can be engineered to provide an equivalent to sterilisation. Moreover, this trait can be suppressed by the provision of a dietary antidote. In the pink bollworm, we generated transformed strains using different DNA constructs, which showed moderate-to-100% engineered mortality. In permissive conditions, this effect was largely suppressed. Survival data on cotton in field cages indicated that field conditions increase the lethal effect. One strain, called OX3402C, showed highly penetrant and highly repressible lethality, and was tested on host plants where its larvae caused minimal damage before death. These results highlight a potentially valuable insecticide-free tool against pink bollworm, and indicate its potential for development in other lepidopteran pests.

Abstract The balance of processes affecting electron density drives the dynamics of upper‐atmospheric electrical events, such as sprites. We examine the detachment of electrons from negatively charged atomic oxygen (O−) via collisions with neutral molecular nitrogen (N2) leading to the formation of nitrous oxide (N2O). Past research posited that this process, even without significant vibrational excitation of N2, strongly impacts the dynamics of sprites. We introduce updated rate coefficients derived from recent experimental measurements which suggest a negligible influence of this reaction on sprite dynamics. Given that previous rates were incompatible with the observed decay of the light emissions from sprite glows, our findings support that glows actually result from electron depletion in sprite columns.

Abstract Neuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at the systems level are lacking. We describe a translational drug discovery platform based on organotypic culture of murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, the brain slices assume a chronic neuroinflammatory state marked by transcriptomic profiles indicative of activation of microglia and astrocytes and loss of neuronal function. Microglia are necessary for manifestation of this neuroinflammation, as depletion of microglia prior to isolation of the brain slices prevents both activation of astrocytes and robust loss of synaptic function genes. The transcriptomic pattern of neuroinflammation in the mouse platform is present in published datasets derived from patients with amyotrophic lateral sclerosis, Huntington’s disease, and frontotemporal dementia. Pharmacological utility of the platform was validated by demonstrating reversal of microglial activation and the overall transcriptomic signature with transforming growth factor-β. Additional anti-inflammatory targets were screened and inhibitors of glucocorticoid receptors, COX-2, dihydrofolate reductase, and NLRP3 inflammasome all failed to reverse the neuroinflammatory signature. Bioinformatics analysis of the neuroinflammatory signature identified protein tyrosine phosphatase non-receptor type 11 (PTPN11/SHP2) as a potential target. Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery.

Abstract Background Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables. Methods Bayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD. Results As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold. Conclusions Our analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

Purpose: This study was undertaken to evaluate our 16-year experience with fistulas between the rectum and urethra or urinary bladder, collectively called recto-urinary fistulas (RUFs), and their devastating consequences in patients treated with radiation for prostate cancer. Methods: We downloaded the records of all patients with radiation-related RUFS from 2004 to 2020 at our institution using the electronic medical record system. Details concerning patient demographics, clinical presentation, diagnostic approaches and surgical management were obtained and assessed. Results: We identified a total of seven patients with radiation-induced RUFS: all were male and had an average age of 66 at diagnosis. Each had a history of prostate cancer that was treated with external, internal (i.e.brachytherapy), or combination radiation therapy. No fistulas were noted in patients treated with radiation for another malignancy. Radiation proctitis with rectal ulcer formation occurred in 6 of 7 patients. Common symptoms included fecaluria, pneumaturia, urine leakage via rectum, rectal pain and urinary tract infection. CT scanning was the most useful diagnostic tool. Once confirmed, fistula management included both urinary and fecal diversion in all patients. Only one patient received definitive repair of the fistula. Five others either died before repair could be attempted or had prohibitive co-morbid diseases. One patient declined repair. Conclusions: Although rare, the development of a recto-urinary fistula is a dreaded complication. Our results indicate that radiation proctitis with rectal ulcer formation precedes fistula formation in most patients and must be aggressively managed. While fecal and urinary diversion can manage fistula symptoms in the majority of patients, definitive fistula repair is only possible in selected individuals.

Peripheral nerve injuries are common and can have a devastating effect on physical, psychological, and socioeconomic wellbeing. Peripheral nerve transfers have become the standard of care for many types of peripheral nerve injury due to their superior outcomes relative to conventional techniques. As the indications for, and use of, nerve transfers expand, the importance of pre-operative assessment and post-operative optimization increases. There are two principal advantages of nerve transfers: (1) their ability to shorten the time to reinnervation of muscles undergoing denervation because of peripheral nerve injury; and (2) their specificity in ensuring proximal motor and sensory axons are directed towards appropriate motor and sensory targets. Compared to conventional nerve grafting, nerve transfers offer opportunities to reinnervate muscles affected by cervical spinal cord injury and to augment natural reinnervation potential for very proximal injuries. This article provides a narrative review of the current scientific knowledge and clinical understanding of nerve transfers including peripheral nerve injury assessment and pre- and post-operative electrodiagnostic testing, adjuvant therapies, and post-operative rehabilitation for optimizing nerve transfer outcomes.

Severe traumatic brain injury (TBI), such as that suffered by patients with cerebral contusion, is a major cause of death and disability in young persons. Effective therapeutics to treat or mitigate the effects of severe TBI are lacking, in part because drug delivery to the injured brain remains a challenge. Promising therapeutics targeting secondary injury mechanisms may have poor pharmacokinetics/pharmacodynamics, unwanted side effects, or high hydrophobicity. To address these challenges, we have developed a multi-lamellar vesicle nanoparticle (MLV-NP) formulation with a narrow size distribution (243?nm in diameter, 0.09 polydispersity index) and the capability of encapsulating hydrophobic small molecule drugs for delivery to the injured brain. To demonstrate the utility of these particles, we produced dual-fluorescent labeled nanoparticles containing the organic dyes, coumarin 153 and rhodamine B, that were delivered intravenously to Sprague-Dawley rats and C57Bl6/J mice at 1, 1 and 4, 24, or 48?h after controlled cortical impact injury. Distribution of particles was measured at 5, 25, 48, or 49?h post-injury by fluorescence microscopy of coronal brain sections. In all cases of MLV administration, a 1.2- to 1.9-fold enhancement of ipsilateral fluorescence signal was observed compared to the contralateral cortex. Enhanced fluorescence was also observed in the injured hippocampal tissue in these animals. MLV-NPs administered at 1?h were observed intracellularly in the injured hemisphere at 48?h, suggesting the possibility of concentrated drug delivery to injured cells. These results suggest that MLV-NP delivery of therapeutic agents may be a viable strategy for treating cerebral contusion TBI.

Developmental disorders, disabilities, and delays are a common outcome for individuals with complex congenital heart disease, yet targeting early factors influencing these conditions after birth and during the neonatal hospitalization for cardiac surgery remains a critical need. The purpose of this science advisory is to (1) describe the burden of developmental disorders, disabilities, and delays for infants with complex congenital heart disease, (2) define the potential health and neurodevelopmental benefits of developmental care for infants with complex congenital heart disease, and (3) identify critical gaps in research aimed at evaluating developmental care interventions to improve neurodevelopmental outcomes in complex congenital heart disease. This call to action targets research scientists, clinicians, policymakers, government agencies, advocacy groups, and health care organization leadership to support funding and hospital‐based infrastructure for developmental care in the complex congenital heart disease population. Prioritization of research on and implementation of developmental care interventions in this population should be a major focus in the next decade.

Anthropogenic emissions of ammonia to the atmosphere, particularly those from agricultural sources, can be damaging to the environment and human health and can drive a need for sensor technologies that can be used to detect and quantify the emissions. Mobile sensing approaches that can be deployed on ground-based or aerial vehicles can provide scalable solutions for high throughput measurements but require relatively compact and low-power sensor systems. This contribution presents an ammonia sensor based on wavelength modulation spectroscopy (WMS) integrated with a Herriott multi-pass cell and a quantum cascade laser (QCL) at 10.33 µm oriented to mobile use. An open-path configuration is used to mitigate sticky-gas effects and achieve high time-response. The final sensor package is relatively small (~20 L), lightweight (~3.5 kg), battery-powered (

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.