Six Months of Remote Patient Monitoring Is Associated with Blood Pressure Reduction in Hypertensive Patients: An Uncontrolled Observational Study.

Background: Remote physiological monitoring (RPM) is a form of telehealth that measures vital signs at home and automatically reports the results to providers, thereby possibly improving chronic disease management. Medicare payment for RPM began in 2019. Two potential obstacles to RPM growth are the paucity of published clinical outcomes data and the Medicare requirement that monitoring be done at least 16 days per month to bill for the service. To help address these issues, we report the following uncontrolled observational study. Methods: A total of 1,102 consecutive patients enrolled in RPM were divided into four groups based on initial average mean arterial pressure (MAP) and into six groups based on the number of days per month MAP was measured. We report changes in MAP after 6 months of RPM as a function of initial MAP, and number of days per month MAP was monitored. Results: After 6 months of RPM, average MAP dropped from 97 to 93 (p < 0.01). This drop was greatest in the 50% of patients initially hypertensive. These patients saw average MAP reductions from 106 to 97 (p < 0.001) and became normotensive. Although MAP reduction was greatest the more frequently patients measured, significant reduction occurred in the hypertensive patients whether they measured more or less than 16 days per month (p < 0.001). No minimum threshold of measurements was found that predicted failure of RPM to lower MAP. Conclusions: RPM is associated with clinically and statistically significant reductions in average MAP in patients who were initially hypertensive. This benefit occurred irrespective of the number of days per month patients measured MAP.

CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.

In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-beta triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.

CD47 blockade reduces ischemia/reperfusion injury and improves survival in a rat liver transplantation model.

Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant. Serum transaminases, histological changes of the liver, and animal survival were assessed. Oxidative stress, inflammatory responses, and hepatocellular damage were also quantified. A significant survival benefit was not achieved when CD47mAb400 was administered to the donor alone. However, CD47mAb400 administration to both the donor and the recipient increased animal survival afterward. The CD47mAb400-treated group showed lower serum transaminases, bilirubin, oxidative stress, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, caspase-3 activity, and proinflammatory cytokine expression of tumor necrosis factor α, interleukin-1ß, and interleukin-6. Thus, CD47 blockade with CD47mAb400 administered both to the donor and the recipient reduced liver graft IRI in a rat liver transplantation model. This may translate to decreased liver dysfunction and increased survival of liver transplant recipients.

Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand.

Although extensive homology exists between their extracellular domains, NK cell inhibitory receptors killer Ig-like receptor (KIR) 2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-γ production by the human KHYG-1 NK cell line compared with KIR2DL3*001, a low-affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 were critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 toward that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations.

Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis.

Tissue macrophages comprise a heterogeneous group of cell types differing in location, surface markers and function. Red pulp macrophages are a distinct splenic subset involved in removing senescent red blood cells. Transcription factors such as PU.1 (also known as Sfpi1) and C/EBPalpha (Cebpa) have general roles in myelomonocytic development, but the transcriptional basis for producing tissue macrophage subsets remains unknown. Here we show that Spi-C (encoded by Spic), a PU.1-related transcription factor, selectively controls the development of red pulp macrophages. Spi-C is highly expressed in red pulp macrophages, but not monocytes, dendritic cells or other tissue macrophages. Spic(-/-) mice have a cell-autonomous defect in the development of red pulp macrophages that is corrected by retroviral Spi-C expression in bone marrow cells, but have normal monocyte and other macrophage subsets. Red pulp macrophages highly express genes involved in capturing circulating haemoglobin and in iron regulation. Spic(-/-) mice show normal trapping of red blood cells in the spleen, but fail to phagocytose these red blood cells efficiently, and develop an iron overload localized selectively to splenic red pulp. Thus, Spi-C controls development of red pulp macrophages required for red blood cell recycling and iron homeostasis.

Acoustic detection, tracking, and characterization of three tornadoes.

Acoustic data recorded at 1000 samples per second by two sensor arrays located at ranges of 1-113 km from three tornadoes that occurred on 24 May 2011 in Oklahoma are analyzed. Accurate bearings to the tornadoes have been obtained using beamforming methods applied to the data at infrasonic frequencies. Beamforming was not viable at audio frequencies, but the data demonstrate the ability to detect significant changes in the shape of the estimated power spectral density in the band encompassing 10 Hz to approximately 100 Hz at distances of practical value from the sensors. This suggests that arrays of more closely spaced sensors might provide better bearing accuracy at practically useful distances from a tornado. Additionally, a mathematical model, based on established relationships of aeroacoustic turbulence, is demonstrated to provide good agreement to the estimated power spectra produced by the tornadoes at different times and distances from the sensors. The results of this analysis indicate that, qualitatively, an inverse relationship appears to exist between the frequency of an observed peak of the power spectral density and the reported tornado intensity.

Imaging of CD47 expression in xenograft and allograft tumor models.

CD47 functions as a marker of "self" by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET) in both human xenograft and murine allograft tumor models. Anti-CD47 antibodies were conjugated with p-isothiocyanatobenzyldesferrioxamine (Df-Bz-NCS) and labeled with 89Zr. We employed xenograft and allograft small-animal models of cancer in biodistribution and PET imaging studies to investigate the specificity and PET imaging robustness of CD47. Ab-Df-Bz-NCS conjugates were labeled with 89Zr with specific activity of 0.9 to 1.6 µCi/µg. Biodistribution studies in the xenograft and allograft model showed similar specific tumor uptake of the antihuman and antimouse CD47 antibodies. However, the tracer retention in the liver, spleen, and kidneys was significantly higher in the allograft-bearing animals, suggesting uptake mediated by the CD47 normally expressed throughout the reticular endothelial system. CD47, a marker of "self," was evaluated as a diagnostic PET biomarker in xenograft and allograft cancer animal models. CD47 imaging is feasible, warranting further studies and immunoPET tracer development.

Early Initiation of non-invasive ventilation at home improves survival and reduces healthcare costs in COPD patients with chronic hypercapnic respiratory failure: A retrospective cohort study.

BACKGROUND: While non-invasive ventilation at home (NIVH) is gaining wider acceptance as a treatment option for chronic obstructive pulmonary disease with chronic respiratory failure (COPD-CRF), uncertainty remains about the optimal time to begin NIVH, whether a specific phenotype of COPD-CRF predicts improved outcomes, and how NIVH affects healthcare costs. MATERIALS AND METHODS: Using 100% research identifiable fee-for-service Medicare claims from 2016 through 2020, we designed an observational, retrospective, cohort study to determine how NIVH use in COPD-CRF patients stratified by CRF phenotype and by timing of initiation affected mortality, healthcare utilization, and total healthcare costs compared to a matched control group. RESULTS: In hypercapnic COPD-CRF patients starting NIVH within the first week following diagnosis, risk of death was reduced by 43% (HR, 0.57; 95% CI 0.51-0.63, p < .0001), those starting 8-15 days following diagnosis had mortality reduction of 31% (HR, 0.69; 95% CI 0.62-0.77, p < .0001), and those starting 16-30 days following diagnosis showed mortality reduction of 16% (HR 0.84, CI 0.073-0.096, p < .01) compared to controls. Medicare spending was also associated with timing of NIVH initiation in hypercapnic COPD-CRF. Those beginning treatment 0-7 days and 0-15 days following diagnosis had a $5484 and a $3412 reduction in Medicare expenditures respectively the next year. NIVH was not associated with improved clinical outcomes or decreased Medicare spending in COPD-CRF patients who were not hypercapnic. CONCLUSION: In this study, early initiation of NIVH for hypercapnic COPD-CRF patients was associated with reductions in the risk of death and in total Medicare spending.

Prediction of grain structure after thermomechanical processing of U-10Mo alloy using sensitivity analysis and machine learning surrogate model.

Hot rolling and annealing are critical intermediate steps for controlling microstructures and thickness variations when fabricating uranium alloyed with 10% molybdenum (U-10Mo), which is highly relevant to worldwide nuclear non-proliferation efforts. This work proposes a machine-learning surrogate model combined with sensitivity analysis to identify and predict U-10Mo microstructure development during thermomechanical processing. Over 200 simulations were collected using physics-based microstructure models covering a wide range of thermomechanical processing routes and initial alloy grain features. Based on the sensitivity analysis, we determined that an increase in rolling reduction percentage at each processing pass has the strongest effect in reducing the grain size. Multi-pass rolling and annealing can significantly improve recrystallization regardless of the reduction percentage. With a volume fraction below 2%, uranium carbide particles were found to have marginal effects on the average grain size and distribution. The proposed stratified stacking ensemble surrogate predicts the U-10Mo grain size with a mean square error four times smaller than a standard single deep neural network. At the same time, with a significant speedup (1000×) compared to the physics-based model, the machine learning surrogate shows good potential for U-10Mo fabrication process optimization.

Non-invasive ventilation at home improves survival and decreases healthcare utilization in medicare beneficiaries with Chronic Obstructive Pulmonary Disease with chronic respiratory failure.

BACKGROUND: Patients with Chronic Obstructive Pulmonary Disease with chronic respiratory failure (COPD-CRF) experience high mortality and healthcare utilization. Non-invasive home ventilation (NIVH) is increasingly used in such patients. We examined the associations between NIVH and survival, hospitalizations, and emergency room (ER) use in COPD-CRF Medicare beneficiaries. MATERIALS AND METHODS: Retrospective cohort study using the Medicare Limited Data Set (2012-2018). Patients receiving NIVH within two months of CRF diagnosis (treatment group) were matched on demographic and clinical characteristics to patients never receiving NIVH (control group). CRF diagnosis was identified using ICD-9-CM/ICD-10-CM codes. Time to death, first hospitalization, and first ER visit were estimated using Cox regressions. RESULTS: After matching, 517 patients receiving NIVH and 511 controls (mean age: 70.6 years, 44% male) were compared. NIVH significantly reduced risk of death (aHR: 0.50; 95%CI: 0.36-0.65), hospitalization (aHR: 0.72; 95%CI: 0.52-0.93), and ER visit (aHR: 0.48; 95%CI: 0.38-0.58) at diagnosis. The NIVH risk reduction became smaller over time for mortality and ER visits, but continued to accrue for hospitalizations. One-year post-diagnosis, 28% of treated patients died versus 46% controls. For hospitalizations and ER visits, 55% and 72% treated patients experienced an event, respectively, versus 67% and 92% controls. The relative risk reduction was 39% for mortality, 17% for hospitalizations, and 22% for ER visits. Number needed to treat were 5.5, 9, and 5 to prevent a death, hospitalization, or ER visit one-year post-diagnosis, respectively. CONCLUSION: NIVH treatment is associated with reduced risk of death, hospitalizations, and ER visits among COPD-CRF Medicare beneficiaries.

Noninvasive ventilation at home reduces mortality in COPD with CRF.

OBJECTIVES: Patients with chronic respiratory failure resulting from chronic obstructive pulmonary disease (COPD-CRF) have limited treatment options and poor health outcomes. We examined the effect of noninvasive ventilation at home (NIVH) treatment on all-cause mortality, hospitalizations, and emergency department (ED) visits. STUDY DESIGN: Retrospective cohort study. METHODS: Using Medicare claims data between 2012 and 2017, we divided patients with COPD-CRF into a treatment group, defined by NIVH receipt within 2 months of CRF diagnosis, and a control group without NIVH receipt in the entire follow-up period. We modeled time to death, first hospitalization, and first ED visit. Cox regressions were performed, mitigating selection bias using stabilized inverse probability of treatment weights with regression controls. Sensitivity analyses with time-varying exposure to NIVH were conducted on the full sample irrespective of treatment timing. RESULTS: We identified 410 patients treated with NIVH and 36,247 controls. We observed a reduced risk of hospitalizations (HR, 0.790; 95% CI, 0.592-0.988), ED visits (HR, 0.571; 95% CI, 0.457-0.686), and mortality (HR, 0.617; 95% CI, 0.462-0.772). The benefit of NIVH diminished over time for mortality and ED visits but remained constant for hospitalizations. However, no survival benefit was observed in the sensitivity analyses that accounted for immortal-time bias; further exploration suggests that earlier NIVH treatment following CRF diagnosis may be an important factor in improving survival outcomes. CONCLUSIONS: Patients with COPD-CRF who received NIVH had statistically significant reductions in hospitalizations and ED visits compared with patients not treated with NIVH. Further research is needed to examine the effect of NIVH on mortality.

Development of AO-176, a Next-Generation Humanized Anti-CD47 Antibody with Novel Anticancer Properties and Negligible Red Blood Cell Binding.

Inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. CD47 is an innate immune checkpoint receptor broadly expressed on normal tissues and overexpressed on many tumors. Binding of tumor CD47 to signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggers a "don't eat me" signal that inhibits phagocytosis enabling escape of innate immune surveillance. Blocking CD47/SIRPα interaction promotes phagocytosis reducing tumor burden in numerous xenograft and syngeneic animal models. We have developed a next-generation humanized anti-CD47 antibody, AO-176, that not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also induces tumor cytotoxicity in hematologic and solid human tumor cell lines, but not normal noncancerous cells, by a cell autonomous mechanism (not ADCC). AO-176 also binds preferentially to tumor versus many normal cell types. In particular, AO-176 binds negligibly to RBCs in contrast to tumor cells, even at high concentrations up to 200 µg/mL and does not agglutinate RBCs up to 1 mg/mL in vitro These properties are expected not only to decrease the antigen sink, but also to minimize on-target clinical adverse effects observed following treatment with other reported RBC-binding anti-CD47 antibodies. When tested in cynomolgus monkeys, AO-176 was well tolerated with no adverse effects. Finally, we show that AO-176 demonstrates dose-dependent antitumor activity in tumor xenograft models. Taken together, the unique properties and antitumor activity of our next-generation anti-CD47 antibody, AO-176, distinguishes it from other CD47/SIRPα axis targeting agents in clinical development.

Increasing survival of ischemic tissue by targeting CD47.

Thrombospondin-1 (TSP1) limits the angiogenic and vasodilator activities of NO. This activity of TSP1 can be beneficial in some disease states, but endogenous TSP1 limits recovery of tissue perfusion following fixed ischemic injury in dorsal skin flaps in mice. Using mice lacking the TSP1 receptors CD36 or CD47, we now show that CD47 is the necessary receptor for limiting NO-mediated vascular smooth muscle relaxation and tissue survival following ischemic injury in skin flaps and hindlimbs. We further show that blocking CD47 or TSP1 using monoclonal antibodies and decreasing CD47 expression using an antisense morpholino oligonucleotide are effective therapeutic approaches to dramatically increase survival of soft tissue subjected to fixed ischemia. These treatments facilitate rapid vascular remodeling to restore tissue perfusion and increase skin and muscle viability. Thus, limiting CD47-dependent antagonism of NO-mediated vasodilation and vascular remodeling is a promising therapeutic modality to preserve tissues subject to ischemic stress.

CD47: a new target in cardiovascular therapy.

CD47, originally named integrin-associated protein, is a receptor for thrombospondin-1. A number of important roles for CD47 have been defined in regulating the migration, proliferation, and survival of vascular cells, and in regulation of innate and adaptive immunity. The recent discovery that thrombospondin-1 acts via CD47 to inhibit nitric oxide signaling throughout the vascular system has given new importance and perhaps a unifying mechanism of action to these enigmatic proteins. Here we trace the development of this exciting new paradigm for CD47 function in vascular physiology.

Modeling Ertapenem: the impact of body mass index on distribution of the antibiotic in the body.

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation.

Control of alphaIIb beta3 and alphav beta3 integrin activation is critical for cardiovascular homeostasis. Mutations that perturb association of integrin alpha and beta subunits in their transmembrane and cytoplasmic regions activate the integrin heterodimer, suggesting that a low-affinity or "off" conformation is the default state, likely corresponding to the bent conformation seen in the crystal structure of alphav beta3. In this bent structure, a segment of alphav (301-308) and beta3 (560-567) are juxtaposed. Here we provide evidence that these regions of alphav/alphaIIb and beta3 function as a novel extracellular clasp to restrain activation. Synthetic peptides representing the alphaIIb and beta3 clasp regions promote integrin activation as judged by cell adhesion, cell spreading, and exposure of epitopes for three beta3 LIBS antibodies. Mutation of the clasp region of alphav or beta3 results in a constitutively activated integrin, confirming the role of the extracellular clasp in restraining integrin activation. Molecular dynamics simulations of the alphav beta3 structure yield a refined model for the alphav beta3 clasp and provide plausible explanations for the effects of the activating mutations.

Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease.

BACKGROUND: Insufficient tissue perfusion underlies many acute and chronic diseases. Tissue perfusion in turn requires adequate blood flow, determined in large part by the relative state of relaxation or constriction of arterial vessels. Nitric oxide (NO) produced by vascular cells modulates blood flow and tissue perfusion by relaxing and dilating arteries. Recently, we reported that the secreted protein thrombospondin-1 (TSP1), through its cell surface receptor CD47, limits the ability of NO to relax and dilate blood vessels and thus decreases tissue perfusion. In the present study, we tested the hypothesis that blocking TSP1-CD47 signaling increases ischemic tissue survival in random cutaneous porcine flaps. METHODS: Random cutaneous flaps 2 x 10 cm2 were raised in white hairless Yucatan miniature pigs and were treated with a monoclonal antibody to TSP1, an antisense morpholino oligonucleotide to CD47 or control agents and tissue survival assessed. Primary vascular smooth muscle cell cultured from Yucatan pigs were also treated with the same agents +/- and an NO donor (DEA/NO) and cGMP quantified. RESULTS: Antibody blockade of TSP1 or morpholino suppression of CD47 dramatically enhanced survival of random tissue flaps. These responses correlated with increased blood vessel patency and tissue blood flow on vessel injection studies. NO-stimulated cGMP flux in Yucatan vascular smooth muscle cell was abrogated after antibody or morpholino treatment. CONCLUSION: Antibody ligation of TSP1 or antisense morpholino knock down of CD47 greatly increased tissue survival to ischemia. Given the similarity between porcine and human soft tissues these results suggest significant therapeutic potential for people.

Blocking thrombospondin-1/CD47 signaling alleviates deleterious effects of aging on tissue responses to ischemia.

OBJECTIVE: Decreased blood flow secondary to peripheral vascular disease underlies a significant number of chronic diseases that account for the majority of morbidity and mortality among the elderly. Blood vessel diameter and blood flow are limited by the matricellular protein thrombospondin-1 (TSP1) through its ability to block responses to the endogenous vasodilator nitric oxide (NO). In this study we investigate the role TSP1 plays in regulating blood flow in the presence of advanced age and atherosclerotic vascular disease. METHODS AND RESULTS: Mice lacking TSP1 or CD47 show minimal loss of their resistance to ischemic injury with age and increased preservation of tissue perfusion immediately after injury. Treatment of WT and apolipoprotein E-null mice using therapeutic agents that decrease CD47 or enhance NO levels reverses the deleterious effects of age- and diet-induced vasculopathy and results in significantly increased tissue survival in models of ischemia. CONCLUSIONS: With increasing age and diet-induced atherosclerotic vascular disease, TSP1 and its receptor CD47 become more limiting for blood flow and tissue survival after ischemic injury. Drugs that limit TSP1/CD47 regulation of blood flow could improve outcomes from surgical interventions in the elderly and ameliorate vascular complications attendant to aging.

Office-based laryngeal laser surgery: a review of 443 cases using three wavelengths.

BACKGROUND: Unsedated office-based laser surgery (UOLS) of the larynx and trachea has significantly improved the treatment options for patients with laryngotracheal pathology including recurrent respiratory papillomas, granulomas, leukoplakia, and polypoid degeneration. UOLS delivered by flexible endoscopes has dramatically impacted office-based surgery by reducing the time, costs, and morbidity of surgery. OBJECTIVES: To review our experience with 443 laryngotracheal cases treated by UOLS. METHODS: The laser logbooks at the Center for Voice and Swallowing Disorders were reviewed for UOLS, and the medical and laryngological histories were detailed, as were the treatment modalities, frequencies, and complications. RESULTS: Of the 443 cases, 406 were performed with the pulsed-dye laser, 10 with the carbon-dioxide laser, and 27 with the thulium: yttrium-aluminum-garnet laser. There were no significant complications in this series. A review of indications and wavelength selection criteria is presented. CONCLUSION: Unsedated, office-based, upper aerodigestive tract laser surgery appears to be a safe and effective treatment option for many patients with laryngotracheal pathology.