Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.

Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

Development and Evaluation of Conformal Prediction Methods for Quantitative Structure-Activity Relationship.

The quantitative structure-activity relationship (QSAR) regression model is a commonly used technique for predicting the biological activities of compounds using their molecular descriptors. Besides accurate activity estimation, obtaining a prediction uncertainty metric like a prediction interval is highly desirable. Quantifying prediction uncertainty is an active research area in statistical and machine learning (ML), but the implementation for QSAR remains challenging. However, most ML algorithms with high predictive performance require add-on companions for estimating the uncertainty of their prediction. Conformal prediction (CP) is a promising approach as its main components are agnostic to the prediction modes, and it produces valid prediction intervals under weak assumptions on the data distribution. We proposed computationally efficient CP algorithms tailored to the most widely used ML models, including random forests, deep neural networks, and gradient boosting. The algorithms use a novel approach to the derivation of nonconformity scores from the estimates of prediction uncertainty generated by the ensembles of point predictions. The validity and efficiency of proposed algorithms are demonstrated on a diverse collection of QSAR data sets as well as simulation studies. The provided software implementing our algorithms can be used as stand-alone or easily incorporated into other ML software packages for QSAR modeling.

NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.

CTL recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells but also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM-1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes (TIL) and long-term survival of melanoma patients. Using MART-1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM-1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior costimulatory effects of DNAM-1 over CD28 involved enhanced TCR signaling, CTL killer function and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in the antigen specificity and selectivity of killer function. In addition, the elevation of NKR-Ligand expression on cancer cells by chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAA. Our data help to explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.

mRNA COVID-19 vaccination during pregnancy was not linked to increased adverse neonatal outcomes.

SOURCE CITATION: Norman M, Magnus MC, Söderling J, et al. Neonatal outcomes after COVID-19 vaccination in pregnancy. JAMA. 2024;331:396-407. 38319332.

Hepatitis C Virus Care Cascade by Race/Ethnicity in a Statewide Correctional Population, 2019-2023.

IMPORTANCE: Hepatitis C virus (HCV) care cascade data by race/ethnicity for US correctional populations are sparse. OBJECTIVE: To evaluate the HCV care cascade by race/ethnicity for a state correctional population. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used Connecticut Department of Correction data for incarcerated individuals tested, diagnosed, and treated for chronic HCV infection with direct-acting antivirals (DAAs) from 2019 to 2023. MAIN OUTCOMES AND MEASURES: HCV care cascade outcomes, including testing, treatment, and cure rates, were compared by race/ethnicity. Poisson regression was used to estimate prevalence ratios (PRs), with adjustment for demographic and legal status factors. RESULTS: A total of 24,867 patients tested for HCV (88.9% men, mean (SD) age 35.6 (11.8), 32.7% White, 37.9% Black, 28.4% Hispanic, 0.6% Asian, 0.4% American Indian/Alaska Native (AIAN), 34.7% sentenced ≥ 1 year). Both HCV exposure and chronic HCV were highest for White (27.1% and 15.2%) and lowest for Black individuals (4.6% and 2.6%) (P < 0.01, for both outcomes). While incarcerated, 63.2% of chronic HCV patients started DAAs, and treatment rates did not significantly differ by race/ethnicity (P > 0.05). For those treated and having post-treatment lab data available, cure rates were 98.8% or better for all racial/ethnic groups (P > 0.05). In the adjusted regression analyses, HCV treatment initiation was lower for those sentenced < 1 year (PR, 0.76; 95% CI, 0.67-0.87) and unsentenced (PR, 0.85; 95% CI, 0.80-0.91) than those sentenced ≥ 1 year. The adjusted prevalence of advanced fibrosis stage/activity grade was not significantly associated with race/ethnicity. CONCLUSIONS: In this cohort study, less than two-thirds of chronic HCV patients initiated DAA treatment during their incarceration, and for those with available data, nearly all were cured. While there were disparities in HCV exposure and chronic HCV infection, significant racial/ethnic differences were not observed for treatment initiation or cure rates. Further efforts are needed to increase HCV treatment, especially for patients with shorter incarceration periods.

The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

Handling and Tagging Techniques for Implanting Juvenile American Shad with a New Acoustic Microtransmitter.

The use of telemetry techniques to better understand the behavior and survival of juvenile American shad (Alosa sapidissima), as they migrate through hydropower systems, has been challenging because shad are widely known to be particularly sensitive to handling. The goal of this study was to develop a tagging protocol using a new, acoustic micro transmitter that minimizes the detrimental effects of the tagging process and maximizes post-tagging survival of juvenile American shad. Limiting out-of-water handling and the use of brackish saltwater (7.5 parts per thousand) before and after tagging improved survival for shad tagged using a simple pectoral implantation method. This protocol provides a detailed, step-by-step procedure for tagging juvenile shad with acoustic transmitters. Fish tagged using this procedure and held in the laboratory for 60 days had an 81.5% survival rate, compared to 70% for their untagged counterparts. The successful tagging and handling practices developed in this study could be applied to field telemetry studies of juvenile shad and other sensitive species.

Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications.

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial.

Importance: In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. Objective: To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. Design, Setting, and Participants: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Interventions: Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Main Outcomes and Measures: Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. Results: The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. Conclusions and Relevance: In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT00781391.

Study on Bottom Distributed Bragg Reflector Radius and Electric Aperture Radius on Performance Characteristics of GaN-Based Vertical-Cavity Surface-Emitting Laser.

This article presents the results of a numerical analysis of a nitride-based vertical-cavity surface-emitting laser (VCSEL). The analyzed laser features an upper mirror composed of a monolithic high-contrast grating (MHCG) and a dielectric bottom mirror made of SiO2 and Ta2O5 materials. The emitter was designed for light emission at a wavelength of 403 nm. We analyze the influence of the size of the dielectric bottom mirrors on the operation of the laser, including its power-current-voltage (LIV) characteristics. We also study the effect of changing the electrical aperture radius (active area dimensions). We demonstrate that the appropriate selection of these two parameters enables the temperature inside the laser to be reduced, lowering the laser threshold current and increasing its optical power output significantly.

Synthesis and characterisation of copper(I) complexes with relevance to intramolecular Ullmann O,S-arylation.

Copper-catalysed intramolecular Ullman arylation has been frequently used to synthesise benzoxazoles and benzothiazoles. Despite widespread use, investigations into the mechanism and speciation of copper-containing complexes relevant to the catalytic pathway have remained relatively limited. Accordingly, this study aims to elucidate the structural details of potential copper(I) intermediates through the analysis of their solid-state structures using X-ray crystallography, while also investigating the reactivities of these complexes. Five novel copper complexes are reported which are formed prior to the aryl halide activation step and feature distinct aggregation modes based on either Cu4N4O4C4 or Cu4N4S4C4 clusters.

[What importance does outpatient care have for mobility in rural areas? Results from a GPS study among persons aged 75 and older]. / Außerhäusliche Mobilität von Personen ab 75 Jahren im ländlichen Raum. Ergebnisse aus einer GPS-Studie.

BACKGROUND: Out-of-home mobility, defined as active and passive movement through external environments, is a resource for autonomy, quality of life, and self-realization in older age. Various factors influence out-of-home mobility, primarily studied in urban settings. The study aims to examine associated factors in a study population aged 75 and above in rural areas. METHODS: Baseline data from the MOBILE trial involving 212 participants aged 75 and above and collected between June 2021 and October 2022 were analyzed. Out-of-home mobility was measured temporally as time out of home (TOH) and spatially as convex hull (CHull) using GPS over seven days. Mixed models considered outpatient care parameters as well as personal, social, and environmental factors along with covariates such as age and gender. RESULTS: Participants in the MOBILE study (average age 81.5; SD: 4.1; 56.1% female) exhibited average out-of-home mobility of TOH: 319.3 min (SD: 196.3) and CHull: 41.3 (SD: 132.8). Significant associations were found for age (TOH: ß = -0.039, p < 0.001), social network (TOH: ß = 0.123, p < 0.001), living arrangement (CHull: ß = 0.689, p = 0.035), health literacy (CHull: ß = 0.077, p = 0.008), sidewalk quality (ß = 0.366, p = 0.003), green space ratio (TOH: ß = 0.005, p = 0.047), outpatient care utilization (TOH: ß = -0.637, p < 0.001, CHull: ß = 1.532; p = 0.025), and active driving (TOH: ß = -0.361, p = 0.004). DISCUSSION: Previously known multifactorial associations related to objectively measured out-of-home mobility in old age could be confirmed in rural areas. Novel and relevant for research and practice is the significant correlation between out-of-home mobility and outpatient care utilization.

Cilofexor in Patients with Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: an Open-label Phase 1B Study.

OBJECTIVES: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis (PSC). METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers, and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7, -7.4) for alanine transaminase, -13.0% (-21.9, -8.6) for alkaline phosphatase, -43.5% (-52.1, -30.8) for gamma-glutamyl transferase, -12.7% (-25.0, 0.0) for total bilirubin, and -21.2% (-40.0, 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8, -31.6) for C4 and -60.5% (-81.8, -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. CONCLUSIONS: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to PSC (NCT04060147).

Reduction in Balloon Pump Size Reduces Axillary Intraaortic Balloon Pump Failure Risk.

Axillary artery intra-aortic balloon pump (axIABP) placement has been implemented as a bridging solution before heart transplantation. This study evaluates complications associated with axIABP support and describes an approach to minimize adverse events. We previously described a percutaneous approach for axIABP placement. However, patients receiving axIABP between September 1, 2017, and September 26, 2019 (n = 32) demonstrated a high rate of balloon pump malfunction (8/32; 25%) and other complications (totaling 15/32; 47%). Sixty-four patients were sequentially treated under a revised protocol. Compared to the initial cohort, no significant differences in demographics were noted. A significant reduction in rate of balloon malfunction (8/32, 25% vs. 1/64, 2%; p < 0.001) and total complications (15/32, 47% vs. 10/64, 16%; p = 0.0025) during the period of support were noted after intervention. Subsequent analysis of total complications per device size (40 vs. ≤ 34 ml balloon) revealed significantly reduced complications in patients with smaller devices (40% vs. 13%, respectively; p = 0.0022). This study provides guidelines to limit complications in patients supported with axIABP, facilitating a protracted period of bridging support.

Two-dimensional Perovskitoids Enhance Stability in Perovskite Solar Cells.

Two-dimensional (2D)/three-dimensional (3D) perovskite heterostructures have played a key role in advancing the performance of perovskite solar cells (PSCs)1,2. However, the migration of cations between 2D and 3D layers results in the disruption of octahedral networks that leads to degradation in performance over time3,4. We hypothesized that perovskitoids, with robust organic-inorganic networks enabled by edge- and face-sharing, could impede ion migration. We explored a set of perovskitoids of varying dimensionality, and found that cation migration within perovskitoid/perovskite heterostructures was suppressed compared to the 2D/3D perovskite case. Increasing the dimensionality of perovskitoids improves charge transport when they are interfaced with 3D perovskite surfaces - this the result of enhanced octahedral connectivity and out-of-plane orientation. The 2D perovskitoid (A6BfP)8Pb7I22 (A6BfP: N-aminohexyl-benz[f]-phthalimide) provides efficient passivation of perovskite surfaces and enables uniform large-area perovskite films. Devices based on perovskitoid/perovskite heterostructures achieve a certified quasi-steady-state power conversion efficiency of 24.6% for centimeter-area PSCs. We removed the fragile hole transport layers and showed stable operation of the underlying perovskitoid/perovskite heterostructure at 85°C for 1,250 hours for encapsulated large-area devices in an air ambient.

Species richness and evenness of European bird communities show differentiated responses to measures of productivity.

Understanding patterns of species diversity is crucial for ecological research and conservation, and this understanding may be improved by studying patterns in the two components of species diversity, species richness and evenness of abundance of species. Variation in species richness and evenness has previously been linked to variation in total abundance of communities as well as productivity gradients. Exploring both components of species diversity is essential because these components could be unrelated or driven by different mechanisms. The aim of this study was to investigate the relationship between species richness and evenness in European bird communities along an extensive latitudinal gradient. We examined their relationships with latitude and Net Primary Productivity, which determines energy and matter availability for heterotrophs, as well as their responses to territory densities (i.e. the number of territories per area) and community biomass (i.e. the bird biomass per area). We applied a multivariate Poisson log-normal distribution to unique long-term, high-quality time-series data, allowing us to estimate species richness of the community as well as the variance of this distribution, which acts as an inverse measure of evenness. Evenness in the distribution of abundance of species in the community was independent of species richness. Species richness increased with increasing community biomass, as well as with increasing density. Since both measures of abundance were explained by NPP, species richness was partially explained by energy-diversity theory (i.e. the more energy, the more species sustained by the ecosystem). However, species richness did not increase linearly with NPP but rather showed a unimodal relationship. Evenness was not explained either by productivity nor by any of the aspects of community abundance. This study highlights the importance of considering both richness and evenness to gain a better understanding of variation in species diversity. We encourage the study of both components of species diversity in future studies, as well as use of simulation studies to verify observed patterns between richness and evenness.

A theoretical explanation of naloxone provision among primary care physicians and community pharmacists in Tennessee.

BACKGROUND: Increasing access to naloxone reduces opioid-related morbidity and mortality. Primary care and community pharmacy settings are critical access points, yet limited theoretical research has examined naloxone prescribing and dispensing behaviors. OBJECTIVES: To determine if the theory of planned behavior (TPB) combined with theoretical constructs from communication science explains intentions to co-prescribe and discuss co-dispensing naloxone among primary care physicians and community pharmacists, respectively. METHODS: This cross-sectional study surveyed cohorts of licensed primary care physicians and community pharmacists in Tennessee in 2017. Intentions were measured using profession-specific case vignettes, whereby they were asked given 10 similar patients, how many times (0-10) would they co-prescribe or discuss co-dispensing naloxone. Bivariate and multivariable analyses were used. RESULTS: The analytic sample included 295 physicians (response rate = 15.6 %) and 423 pharmacists (response rate = 19.4 %). Approximately 65 % of physicians reported never intending to co-prescribe naloxone (0 out of 10 patients), while 47 % of pharmacists reported never intending to discuss co-dispensing. All TPB constructs-attitudes (AOR = 1.32, CI = 1.16-1.50), subjective norms (AOR = 1.17, CI = 1.06-1.30), and perceived behavioral control (AOR 1.16, CI = 1.02-1.33)-were associated with an increased likelihood of pharmacists always (versus never) discussing co-dispensing. Similarly, two TPB constructs-attitudes (AOR = 1.41, CI = 1.19-1.68) and subjective norms (AOR = 1.22, CI = 1.08-1.39)-were associated with an increased likelihood of physicians always co-prescribing. Among physicians only, one communication construct-self-perceived communication competence (AOR = 1.19, CI = 1.01-1.41)-was associated with an increased likelihood of always co-prescribing. CONCLUSION: Findings support the value of theory, particularly TPB, in explaining primary care physician intentions to co-prescribe and community pharmacist intentions to discuss co-dispensing naloxone.

Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

The Plumber Versus Electrician Dilemma: To Bypass or to Defibrillate?

We present a unique case of an 80-year-old male who presented to our emergency department following cardiac defibrillation when he was found to be in polymorphic ventricular tachycardia (VT) after a syncopal event while at cardiac rehabilitation. He had known coronary artery disease and had a four-vessel coronary artery bypass graft (CABG) 20 years prior to presentation. He underwent left heart catheterization (LHC) two months prior to the syncopal event for worsening shortness of breath and the decision at that time was to proceed with medical management and intervene with redo-CABG if shortness of breath did not improve or progressively worsened. While admitted under our care after the polymorphic VT event, we faced the dilemma of whether to proceed with redo-CABG first since cardiac ischemia is a common cause of polymorphic VT or whether to insert an implantable cardioverter-defibrillator (ICD) before proceeding with redo-CABG. We present the current literature that addresses ICD implantation for secondary prevention and our approach to this complicated case.