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OBJECTIVES:. Studies evaluating telemedicine critical care (TCC) have shown mixed results. We prospectively evaluated the impact of TCC implementation on risk-adjusted mortality among patients stratified by pre-TCC performance. DESIGN:. Prospective, observational, before and after study. SETTING:. Three adult ICUs at an academic medical center. PATIENTS:. A total of 2,429 patients in the pre-TCC (January to June 2016) and 12,479 patients in the post-TCC (January 2017 to June 2019) periods. INTERVENTIONS:. TCC implementation which included an acuity-driven workflow targeting an identified “lower-performing” patient group, defined by ICU admission in an Acute Physiology and Chronic Health Evaluation diagnoses category with a pre-TCC standardized mortality ratio (SMR) of greater than 1.5. MEASUREMENTS AND MAIN RESULTS:. The primary outcome was risk-adjusted hospital mortality. Risk-adjusted hospital length of stay (HLOS) was also studied. The SMR for the overall ICU population was 0.83 pre-TCC and 0.75 post-TCC, with risk-adjusted mortalities of 10.7% and 9.5% (p = 0.09). In the identified lower-performing patient group, which accounted for 12.6% (n = 307) of pre-TCC and 13.3% (n = 1671) of post-TCC ICU patients, SMR decreased from 1.61 (95% CI, 1.21–2.01) pre-TCC to 1.03 (95% CI, 0.91–1.15) post-TCC, and risk-adjusted mortality decreased from 26.4% to 16.9% (p < 0.001). In the remaining (“higher-performing”) patient group, there was no change in pre- versus post-TCC SMR (0.70 [0.59–0.81] vs 0.69 [0.64–0.73]) or risk-adjusted mortality (8.5% vs 8.4%, p = 0.86). There were no pre- to post-TCC differences in standardized HLOS ratio or risk-adjusted HLOS in the overall cohort or either performance group. CONCLUSIONS:. In well-staffed and overall higher-performing ICUs in an academic medical center, Acute Physiology and Chronic Health Evaluation granularity allowed identification of a historically lower-performing patient group that experienced a striking TCC-associated reduction in SMR and risk-adjusted mortality. This study provides additional evidence for the relationship between pre-TCC performance and post-TCC improvement.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging 1-4 . Given the unique effector functions of macrophages and their capacity to penetrate tumors 5 , we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.

The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The fish bulbus arteriosus (BA) smooths cardiac output by expanding during cardiac systole and rebounding during diastole, thereby providing constant perfusion of the gills downstream. Published data have demonstrated innervation of the teleost BA and shown that the tension and compliance of the BA responded to vasoactive agonists, such as epinephrine and acetylcholine, suggesting that the BA was more than a mere "windkessel." To examine vasoactivity in the BA more directly, we measured the responses of isolated tissue rings from the BA of the eel, Anguilla rostrata to a suite of putative vasoactive agonists, which had been shown to affect vascular smooth muscle in a variety of teleosts. The BA of the eel was insensitive to acetylcholine but constricted when endothelin (ET-1) was applied. Nitric oxide, sodium nitroprusside (SNP; NO donor), natriuretic peptides (NP), and prostaglandin E1 (but not the prostacyclin agonist carbaprostacyclin) produced significant dilation in the BA. Since both ET-1 and sarafotoxin S6c produced concentration-dependent constriction, it appears that endothelin receptor B-type (ETB) receptors (and possibly ETA receptors) are present. The dilation produced by SNP was also concentration dependent, as were the dilations produced by porcine C-type natriuretic peptide, eel atrial natriuretic peptide (NP receptor agonists), Sulprostone and Butaprost (PGE receptor agonists). Our data demonstrate that the BA of eel is responsive to a variety of vasoactive agonists, suggesting that the BA is under neurohumoral control. The role of agonist-induced changes in BA tension in fish cardiovascular physiology remains to be determined, as do the specific receptor types involved.