Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny.

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

Assessment of immunosuppression induction with basiliximab compared to antithymocyte-globulin in adult heart transplant patients.

BACKGROUND: Patients undergoing heart transplants are at risk of rejection which can have significant morbidity and mortality. Induction immunosuppression at the time of transplant reduces the early risk and has additional benefits. The induction agent of choice within our program was changed from rabbit antithymocyte-globulin (rATG) to basiliximab, so it was necessary to evaluate whether this had any impact on patient outcomes. OBJECTIVES: Our primary objective was to describe rejection, infection, and other outcomes in adult heart transplant patients at the University of Alberta Hospital in Edmonton, Canada. METHODS: This study was a nonrandomized, retrospective cohort study. RESULTS: Sixty-three patients were included with median ages 50 years versus 54 years. More female patients received rATG (20% vs. 42.4%). The most common indication for transplant in both cohorts was ICM (63.3% vs. 57.6%). Patients who received rATG had significantly higher PRA (0% vs. 43%, p < .001). Acute rejection episodes were similar between basiliximab and rATG at 3 months (16.7% vs. 15.1%; p = 1.0) and 6-months (30.0% vs. 18.1%; p = .376). Infections were not statistically different with basiliximab compared to rATG at 3-months, 43.3% vs. 63.6% and at 6-months 60.0% vs. 66.7%). There were no fatalities in either group. CONCLUSIONS: Our study did not demonstrate differences in rejection with basiliximab compared to rATG. Mortality did not differ, but basiliximab-treated patients had fewer infections and infection-related hospitalizations than those treated with rATG. Larger studies with longer durations are needed to more completely describe the differences in rejection and infectious outcomes.

Safety and Effectiveness of Track Cauterization for Lung Cryoablation.

PURPOSE: To evaluate the safety and effectiveness of track cauterization for lung cryoablation through comparison of postprocedural adverse event (AE) rates. MATERIALS AND METHODS: Fifty-nine patients who underwent 164 percutaneous lung cryoablation procedures between 2013 and 2018 were included in this retrospective study. The study cohort was subdivided by whether track cauterization was conducted or not at the end of the procedure. The study cohort was also subdivided by the number of probes (1-2 probes vs 3-4 probes). Postablation AE rates were assessed by immediate and delayed (at 1 month or later) AEs, pneumothorax, hemothorax, pleural effusion, and whether intervention was required. Univariate and multivariate logistic regression analyses were used to compare differences in AE rates. RESULTS: Patients who underwent procedures with track cautery were 2.6 times less likely to exhibit pleural effusion (P = .017). Patients who underwent procedures conducted with a higher number of probes were 3.8 times more likely to receive interventions (P < .001), 1.6 times more likely to experience pneumothorax (P = .037), and 2.1 times more likely to experience pleural effusion (P = .003). History of lung surgery, increased number of probes, size of the probe, and absence of track cautery were noted to be significant predictors of AEs and need for interventions (all P < .05). CONCLUSIONS: Track cauterization in lung cryoablation was proven to reduce pleural effusion, but no difference in pneumothorax or delayed AEs was noted. The use of fewer probes was associated with a lower rate of AEs.

LncRNA Biomarkers of Inflammation and Cancer.

Long noncoding RNAs (lncRNAs) are promising candidates as biomarkers of inflammation and cancer. LncRNAs have several properties that make them well-suited as molecular markers of disease: (1) many lncRNAs are expressed in a tissue-specific manner, (2) distinct lncRNAs are upregulated based on different inflammatory or oncogenic stimuli, (3) lncRNAs released from cells are packaged and protected in extracellular vesicles, and (4) circulating lncRNAs in the blood are detectable using various RNA sequencing approaches. Here we focus on the potential for lncRNA biomarkers to detect inflammation and cancer, highlighting key biological, technological, and analytical considerations that will help advance the development of lncRNA-based liquid biopsies.

Neural Network Detection of Pacemakers for MRI Safety.

Flagging the presence of cardiac devices such as pacemakers before an MRI scan is essential to allow appropriate safety checks. We assess the accuracy with which a machine learning model can classify the presence or absence of a pacemaker on pre-existing chest radiographs. A total of 7973 chest radiographs were collected, 3996 with pacemakers visible and 3977 without. Images were identified from information available on the radiology information system (RIS) and correlated with report text. Manual review of images by two board certified radiologists was performed to ensure correct labeling. The data set was divided into training, validation, and a hold-back test set. The data were used to retrain a pre-trained image classification neural network. Final model performance was assessed on the test set. Accuracy of 99.67% on the test set was achieved. Re-testing the final model on the full training and validation data revealed a few additional misclassified examples which are further analyzed. Neural network image classification could be used to screen for the presence of cardiac devices, in addition to current safety processes, providing notification of device presence in advance of safety questionnaires. Computational power to run the model is low. Further work on misclassified examples could improve accuracy on edge cases. The focus of many healthcare applications of computer vision techniques has been for diagnosis and guiding management. This work illustrates an application of computer vision image classification to enhance current processes and improve patient safety.

Cadaveric Costal Cartilage Grafts in Rhinoplasty and Septorhinoplasty: A Systematic Review and Meta-Analysis of Patient-Reported Functional Outcomes and Complications.

ABSTRACT: Irradiated cadaveric costal cartilage (CC) has been utilized as an alternative to autologous cartilage (AC) in functional and aesthetic nasal surgery. The impact of graft choice between AC and CC on functional outcomes in rhinoplasty has yet to be studied. A systematic review was performed in PubMed, Embase, and Cochrane databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify comparative studies evaluating the efficacy and safety of CC in nasal surgery. Functional and aesthetic outcomes and complications were reviewed and compared between AC and CC. Meta-analytic comparisons were performed when appropriate using data from comparative studies using a random-effects model. Four studies met inclusion criteria. The indication for surgery was functional in the majority of cases, and 34.6% of cases were revision rhino- or septorhinoplasties. Disparate data across studies prevented meta-analysis on functional outcomes; however, qualitative review of function outcomes demonstrated comparable outcomes between the CC and AC groups. No differences in graft infection, warping, and resorption rates were detected. Analysis of all graft-related complications was higher in the CC group (P = 0.02); however, when AC donor site-related complications were included, no significance between the two groups was observed. In conclusion, limited, high quality data was available for analysis. Of the available studies, this systematic review suggest that the use of AC or CC may lead to comparable results in terms of functional outcomes. More long-term studies directly comparing AC and CC functional outcomes would be welcomed.

Istradefylline reduces memory deficits in aging mice with amyloid pathology.

Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aß, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.

Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.

Amyloid-ß oligomers may cause cognitive deficits in Alzheimer's disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-ß oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer's disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-ß-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer's disease.

Safety of an i.v. ß-adrenergic blockade protocol for heart rate optimization before coronary CT angiography.

OBJECTIVE: The purpose of this study was to assess the safety of heart rate optimization by use of ß-adrenergic blockade solely by the i.v. route before coronary CT angiography. MATERIALS AND METHODS: The records of 679 patients undergoing CT coronary angiography after receiving i.v. ß-adrenergic blockade were retrospectively analyzed. Health screening was completed before scanning, and heart rate was optimized by administration of i.v. metoprolol titrated to a maximum of 70 mg to achieve a heart rate less than 65 beats/min. RESULTS: The median i.v. dose was 20 mg (range, 5-70 mg). The 679 patients analyzed had a total of 10 complications (1.47%). Major complications, defined as not resolving with observation and analgesia alone, occurred in only three patients (0.44%). These complications included a second-degree atrioventricular block. A total of 299 patients (44.0%) needed more than 20 mg of i.v. metoprolol to achieve target heart rate. Only three patients needed the maximum i.v. dose of 70 mg metoprolol. Target heart rate was reached successfully in 666 patients (98.1%) with doses of less than 70 mg. This study did not show a statistically significant association between increasing complication frequency and increasing dose. CONCLUSION: This study showed that high doses of i.v. metoprolol can be used effectively and with a low rate of major complications to control heart rate before coronary CT angiography in correctly screened patients.

The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study.

BACKGROUND: Nationally, symptomatic heart failure affects 1.5-2% of Canadians, incurs $3 billion in hospital costs annually and the global burden is expected to double in the next 1-2 decades. The current one-year mortality rate after diagnosis of heart failure remains high at >25%. Consequently, new therapeutic strategies need to be developed for this debilitating condition. METHODS/DESIGN: The objective of the Alberta HEART program (http://albertaheartresearch.ca) is to develop novel diagnostic, therapeutic and prognostic approaches to patients with heart failure with preserved ejection fraction. We hypothesize that novel imaging techniques and biomarkers will aid in describing heart failure with preserved ejection fraction. Furthermore, the development of new diagnostic criteria will allow us to: 1) better define risk factors associated with heart failure with preserved ejection fraction; 2) elucidate clinical, cellular and molecular mechanisms involved with the development and progression of heart failure with preserved ejection fraction; 3) design and test new therapeutic strategies for patients with heart failure with preserved ejection fraction. Additionally, Alberta HEART provides training and education for enhancing translational medicine, knowledge translation and clinical practice in heart failure. This is a prospective observational cohort study of patients with, or at risk for, heart failure. Patients will have sequential testing including quality of life and clinical outcomes over 12 months. After that time, study participants will be passively followed via linkage to external administrative databases. Clinical outcomes of interest include death, hospitalization, emergency department visits, physician resource use and/or heart transplant. Patients will be followed for a total of 5 years. DISCUSSION: Alberta HEART has the primary objective to define new diagnostic criteria for patients with heart failure with preserved ejection fraction. New criteria will allow for targeted therapies, diagnostic tests and further understanding of the patients, both at-risk for and with heart failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT02052804.

Lessons Learned From TranslateCovid, a Multilingual Online Resource Hub for Asian American and Pacific Islander Communities and Beyond.

The COVID-19 pandemic exacerbated health disparities among immigrant communities. Delivering accurate information and addressing misinformation on protective measures and vaccination to linguistically disadvantaged groups was critical for mitigating the effects of the pandemic. One group that was especially vulnerable to miscommunication about COVID-19 was non-native English-speaking immigrants. To address these disparities, the Asian American Studies Center and the Fielding School of Public Health at the University of California, Los Angeles, partnered to create a multilingual resource hub, TranslateCovid.org, to disseminate credible and reliable information about COVID-19 safety measures, the science behind the vaccines, and vaccine safety. We identified >1300 verified resources in 60 languages from government, academic, and nonprofit organizations and reposted them on the TranslateCovid website. We also developed public service announcement videos on handwashing, use of face masks, and social distancing in 10 languages and a fact sheet for frequently asked questions in 20 languages. We used a participatory approach to develop strategies for disseminating these resources. We discuss lessons learned, including strategies for forming government, community, and academic partnerships to support the timely development and dissemination of information. We conclude with a discussion on the unique role of universities in promoting equitable access to public health resources among immigrant communities in times of crisis.

Multiparametric Radiogenomic Model to Predict Survival in Patients with Glioblastoma.

BACKGROUND: Clinical, histopathological, and imaging variables have been associated with prognosis in patients with glioblastoma (GBM). We aimed to develop a multiparametric radiogenomic model incorporating MRI texture features, demographic data, and histopathological tumor biomarkers to predict prognosis in patients with GBM. METHODS: In this retrospective study, patients were included if they had confirmed diagnosis of GBM with histopathological biomarkers and pre-operative MRI. Tumor segmentation was performed, and texture features were extracted to develop a predictive radiomic model of survival (<18 months vs. ≥18 months) using multivariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regularization to reduce the risk of overfitting. This radiomic model in combination with clinical and histopathological data was inserted into a backward stepwise logistic regression model to assess survival. The diagnostic performance of this model was reported for the training and external validation sets. RESULTS: A total of 116 patients were included for model development and 40 patients for external testing validation. The diagnostic performance (AUC/sensitivity/specificity) of the radiomic model generated from seven texture features in determination of ≥18 months survival was 0.71/69.0/70.3. Three variables remained as independent predictors of survival, including radiomics (p = 0.004), age (p = 0.039), and MGMT status (p = 0.025). This model yielded diagnostic performance (AUC/sensitivity/specificity) of 0.77/81.0/66.0 (training) and 0.89/100/78.6 (testing) in determination of survival ≥ 18 months. CONCLUSIONS: Results show that our radiogenomic model generated from radiomic features at baseline MRI, age, and MGMT status can predict survival ≥ 18 months in patients with GBM.

Molecular states associated with dysfunction and graft loss in heart transplants.

BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.

X-chromosome epigenetic reprogramming in pluripotent stem cells via noncoding genes.

Acquisition of the pluripotent state coincides with epigenetic reprogramming of the X-chromosome. Female embryonic stem cells are characterized by the presence of two active X-chromosomes, cell differentiation by inactivation of one of the two Xs, and induced pluripotent stem cells by reactivation of the inactivated X-chromosome in the originating somatic cell. The tight linkage between X- and stem cell reprogramming occurs through pluripotency factors acting on noncoding genes of the X-inactivation center. This review article will discuss the latest advances in our understanding at the molecular level. Mouse embryonic stem cells provide a standard for defining the pluripotent ground state, which is characterized by low levels of the noncoding Xist RNA and the absence of heterochromatin marks on the X-chromosome. Human pluripotent stem cells, however, exhibit X-chromosome epigenetic instability that may have implications for their use in regenerative medicine. XIST RNA and heterochromatin marks on the X-chromosome indicate whether human pluripotent stem cells are developmentally 'naïve', with characteristics of the pluripotent ground state. X-chromosome status and determination thereof via noncoding RNA expression thus provide valuable benchmarks of the epigenetic quality of pluripotent stem cells, an important consideration given their enormous potential for stem cell therapy.

Clinical outcomes of patients treated with a second course of stereotactic radiosurgery for locally or regionally recurrent brain metastases after prior stereotactic radiosurgery.

Patients with metastatic disease are living longer and may be confronted with locally or regionally recurrent brain metastases (BM) after prior stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). This study analyzes outcomes in patients without prior whole brain radiotherapy (WBRT) who were treated with a second course of SRS/FSRT for locally or regionally recurrent BM. We identified 32 patients at our institution who were treated with a second course of SRS/FSRT after initial SRS/FSRT for newly diagnosed BM. We report clinical outcomes including local control, survival, and toxicities. Control rates and survival were calculated using Kaplan-Meier analysis and the multivariate proportional hazards model. The Kaplan-Meier estimate of local control at 6 months was 77 % for targets treated by a second course of SRS/FSRT with 11/71 (15 %) targets experiencing local failure. Multivariate analysis shows that upon re-treatment, local recurrences were more likely to fail than regional recurrences (OR 8.8, p = 0.02). Median survival for all patients from first SRS/FSRT was 14.6 months (5.3-72.2 months) and 7.9 months (0.7-61.1 months) from second SRS/FSRT. Thirty-eight percent of patients ultimately received WBRT as salvage therapy after the second SRS/FSRT. Seventy-one percent of patients died without active neurologic symptoms. The present study demonstrates that the majority of patients who progress after SRS/FSRT for newly diagnosed BM are candidates for salvage SRS/FSRT. By reserving WBRT for later salvage, we believe that a significant proportion of patients can avoid WBRT all together, thus putting fewer patients at risk for neurocognitive toxicity.

Asymptomatic thoracic Pantopaque cyst mimicking an intradural extramedullary lipoma on MR images.

OBJECTIVE: Oil-based contrast media such as Pantopaque have not used for imaging for several decades, but because these contrast media have an extremely low clearance rate, the remnant contrast media or residual sequelae of these materials may be encountered in the clinical field. CLINICAL PRESENTATION: A 63-year-old woman presented to our hospital complaining of increasing lower back pain and lower extremity paresthesia with incontinence for 2 years. A plain X-ray film revealed single droplet-like mass at the lower thoracic T9-T10. A magnetic resonance image (MRI) study revealed a dorsally placed extramedullary intradural lesion, compressing the thoracic cord and minimally displacing it anteriorly. Spinal stenosis was also noted at the L4-5 level. INTERVENTION: The patient was performed for two consecutive surgeries. Total laminectomy was performed at T9-T10 to remove mass. A 0.5 × 0.5 × 4 cm yellowish intradural extramedullary cystic mass was removed without any leakage of cystic contents. Partial hemi-laminectomy and foraminotomy was then done at L4-5 levels for radiculopathy symptom relief. The fluid from the cyst was composed mainly of iodide. CONCLUSION: Intraspinal masses showing metal-like density in X-ray or computed tomography but in MRI showing only lipoma or cystic lesions, not metallic characteristics, the differential diagnosis should include iophendylate (Pantopaque) cyst. Oil-based contrast medium is believed to have the potential to make a syrinx formation via arachnoiditis, which can lead to severe neurologic deteriorations, so even if the patients do not represent with an acute neurologic deficit, surgical total removal of remnant material without leaking should be considered.

Special Considerations and Techniques of Interventions in Lung Transplant Recipients.

Lung transplant remains an important treatment option for patients with end-stage lung diseases providing improvement in survival rates and quality of life. Specialized considerations should be applied with interventions of lung transplant recipients as they host specific anatomic variations and high risk towards certain complications. In this article, we highlight the role of interventional radiology for lung transplant recipients along with discussion of interventional techniques. Specific emphasis is placed on describing and explaining the techniques pertained to the points of anastomosis, diagnosis and treatment of malignancies, and management of complications in lung transplant recipients.

Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids.

Mutant KRAS regulates transposable element (TE) RNA and interferon-stimulated gene (ISG) expression, but it remains unclear whether diverse mutations in KRAS affect different TE RNAs throughout the genome. We analyzed the transcriptomes of 3D human lung cancer spheroids that harbor KRAS(G12C) mutations to determine the landscape of TE RNAs regulated by mutant KRAS(G12C). We found that KRAS(G12C) signaling is required for the expression of LINE- and LTR-derived TE RNAs that are distinct from TE RNAs previously shown to be regulated by mutant KRAS(G12D) or KRAS(G12V). Moreover, KRAS(G12C) inhibition specifically upregulates SINE-derived TE RNAs from the youngest Alu subfamily AluY. Our results reveal that TE RNA dysregulation in KRAS-driven lung cancer cells is mutation-dependent, while also highlighting a subset of young, Alu-derived TE RNAs that are coordinately activated with innate immunity genes upon KRAS(G12C) inhibition.

Parental Refusals of Blood Transfusions from COVID-19 Vaccinated Donors for Children Needing Cardiac Surgery.

There is a growing trend of refusal of blood transfusions from COVID-19 vaccinated donors. We highlight three cases where parents have refused blood transfusions from COVID-19 vaccinated donors on behalf of their children in the setting of congenital cardiac surgery. These families have also requested accommodations such as explicit identification of blood from COVID-19 vaccinated donors, directed donation from a COVID-19 unvaccinated family member, or use of a non-standard blood supplier. We address the ethical challenges posed by these issues. We describe the current screening and safety processes for standard blood donation and explore the importance of donor anonymity and challenges with directed donation and non-standard blood suppliers. We present an ethical framework using the Best Interest Standard, the Zone of Parental Discretion, and the Harm Principle when considering these refusals. Finally, we provide recommendations for how to approach these requests as they potentially become more commonplace in pediatrics.