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1.
R I Med J (2013) ; 104(1): 61-64, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33517603

RESUMO

OBJECTIVE: To assess the impact of the COVID-19 pandemic and associated lockdowns on public interest in ophthalmology. METHODS: Search interest data for ophthalmic services and conditions were collected from January 1, 2019 to June 21, 2020. Temporal statistical analysis was used to identify significant trends. Weekly data on ophthalmic services and conditions search interest obtained from Google Trends were analyzed with analysis of variance testing and the generalized linear model based on dates. RESULTS: Ophthalmic services searches decreased after the first COVID-19 case in the country (p<0.001); ophthalmic services and conditions search interest also declined after the first COVID-19 case and lockdown orders in each state (p<0.001). Following the first in-state COVID-19 case, search interest in ophthalmic services fell more than for ophthalmic conditions (p=0.0088). Lockdown and COVID-19 had similar effects on ophthalmic services search interest (p=0.2246), but interest in ophthalmic conditions decreased more after lockdown than after the first in-state case (p<0.0001). CONCLUSIONS: Most of the decrease in search interest in ophthalmic services was associated with COVID-19 rather than lockdown orders, suggesting that public interest in ophthalmic care may be more sensitive to changes in the COVID-19 pandemic than lockdown orders.


Assuntos
/epidemiologia , Oftalmopatias/epidemiologia , Comportamento de Busca de Informação , Oftalmologia , /prevenção & controle , Oftalmopatias/terapia , Humanos , Sistemas On-Line , Oftalmologia/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Quarentena
2.
Environ Sci Technol ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33274635

RESUMO

Urban environments are characterized by pronounced spatiotemporal heterogeneity, which can present sampling challenges when utilizing conventional greenhouse gas (GHG) measurement systems. In Salt Lake City, Utah, a GHG instrument was deployed on a light rail train car that continuously traverses the Salt Lake Valley (SLV) through a range of urban typologies. CO2 measurements from a light rail train car were used within a Bayesian inverse modeling framework to constrain urban emissions across the SLV during the fall of 2015. The primary objectives of this study were to (1) evaluate whether ground-based mobile measurements could be used to constrain urban emissions using an inverse modeling framework and (2) quantify the information that mobile observations provided relative to conventional GHG monitoring networks. Preliminary results suggest that ingesting mobile measurements into an inverse modeling framework generated a posterior emission estimate that more closely aligned with observations, reduced posterior emission uncertainties, and extends the geographical extent of emission adjustments.

3.
J Am Chem Soc ; 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33382947

RESUMO

The electrochemical CO2 reduction reaction (CO2RR) using Cu-based catalysts holds great potential for producing valuable multi-carbon products from renewable energy. However, the chemical and structural state of Cu catalyst surfaces during the CO2RR remains a matter of debate. Here, we show the structural evolution of the near-surface region of polycrystalline Cu electrodes under in situ conditions through a combination of grazing incidence X-ray absorption spectroscopy (GIXAS) and X-ray diffraction (GIXRD). The in situ GIXAS reveals that the surface oxide layer is fully reduced to metallic Cu before the onset potential for CO2RR, and the catalyst maintains the metallic state across the potentials relevant to the CO2RR. We also find a preferential surface reconstruction of the polycrystalline Cu surface toward (100) facets in the presence of CO2. Quantitative analysis of the reconstruction profiles reveals that the degree of reconstruction increases with increasingly negative applied potentials, and it persists when the applied potential returns to more positive values. These findings show that the surface of Cu electrocatalysts is dynamic during the CO2RR, and emphasize the importance of in situ characterization to understand the surface structure and its role in electrocatalysis.

4.
J Child Neurol ; : 883073820966917, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112194

RESUMO

OBJECTIVE: Determine seizure frequency and association with neurologic outcomes in infants undergoing extracorporeal membrane oxygenation. Identify patient or clinical factors associated with seizures or brain injury on imaging. METHODS: Retrospective, single-center study including infants less than 1 year of age, who underwent extracorporeal membrane oxygenation between 2012 and 2017. RESULTS: A total of 104 infants met study criteria including 45 patients with continuous electroencephalographic (EEG) monitoring during their extracorporeal membrane oxygenation run and 59 infants without EEG. Seizures (electrographic-only or electro-clinical) were identified in 18 of the 45 (40%). Among the 18 infants with seizures, 14 (78%) had moderate to severe brain injury, whereas only 44% of those without seizures (12 of 27) on EEG had moderate to severe brain injury (P = .03). Cardiopulmonary resuscitation prior to extracorporeal membrane oxygenation (ECPR), mode of extracorporeal membrane oxygenation, length of stay, survival to discharge, and congenital heart disease were not associated with seizures. One of 10 patients with cyanotic congenital heart disease due to hypoplastic left heart syndrome had seizures compared with 7 of 10 patients with non-hypoplastic left heart syndrome lesions (P = .02). Seizures were associated with moderate to severe brain injury, after adjusting for ECPR and congenital heart disease (P = .04). CONCLUSIONS: Electrographic seizures were common in patients undergoing extracorporeal membrane oxygenation and higher than previously reported. Seizures were associated with moderate to severe abnormalities on imaging, after adjusting for ECPR and congenital heart disease. This study adds to recent literature describing the risk of seizures in patients on extracorporeal membrane oxygenation and highlights the presence of brain injuries that may be identified by routine EEG surveillance.

5.
Crit Care Explor ; 2(10): e0236, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33063036

RESUMO

Although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical Kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. Original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. Emerging reports suggest that a robust immune suppression may be more relevant and predominant. Recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. Likewise, understanding development of certain clinical findings to changes in the immune system is lacking. Case Summary: We report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal RNA polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. Unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and C-reactive protein) were increased. He subsequently was discharged on day 12 of hospitalization with complete recovery. Conclusion: Our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or Kawasaki disease development. This report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies.

6.
J Surg Educ ; 77(6): 1377-1391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32773335

RESUMO

OBJECTIVE: Mental skills training (MST) in surgical education varies greatly in quality and outcomes. This systematic review assessed the effectiveness of MST on surgical trainee performance in simulated and operating room (OR) settings. DESIGN: We searched PubMed/MEDLINE, EMBASE, and PsycINFO for randomized controlled trials using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Peer-reviewed studies published in the English language between January 1, 2000 and March 1, 2020 were considered for inclusion. Articles that did not study surgical residents, assess surgical performance as an outcome, or report findings were excluded. Study characteristics, methodologies, and outcomes were qualitatively analyzed. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to measure the quality of the studies, and the Oxford quality scoring system for risk of bias ratings. RESULTS: Seven randomized controlled trials met study inclusion criteria; interventions were mental practice, relaxation exercises, action observation, and Mindfulness-Based Stress Reduction. Targeted interventions based on mental practice, relaxation exercises, and MBSR significantly improved surgical performance in four (57%) studies. Risk of bias was low for all included studies, and quality of evidence was moderate for both simulated and OR performance. CONCLUSIONS: Mental practice, relaxation, and mindfulness training improved simulation and OR performance for surgical residents. There was insufficient evidence to support other MST interventions or the intermediate- and long-term efficacy of MST.

7.
Mol Cancer Ther ; 19(10): 2105-2116, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32847983

RESUMO

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

8.
Crit Care Explor ; 2(6): e0139, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32696002

RESUMO

Objectives: The severe acute respiratory syndrome coronavirus 2 pandemic has stretched ICU resources in an unprecedented fashion and outstripped personal protective equipment supplies. The combination of a novel disease, resource limitations, and risks to medical personnel health have created new barriers to implementing the ICU Liberation ("A" for Assessment, Prevention, and Manage pain; "B" for Both Spontaneous Awakening Trials and Spontaneous Breathing Trials; "C" for Choice of Analgesia and Sedation; "D" for Delirium Assess, Prevent, and Manage; "E" for Early Mobility and Exercise; and "F" for Family Engagement and Empowerment [ABCDEF]) Bundle, a proven ICU care approach that reduces delirium, shortens mechanical ventilation duration, prevents post-ICU syndrome, and reduces healthcare costs. This narrative review acknowledges barriers and offers strategies to optimize Bundle performance in coronavirus disease 2019 patients requiring mechanical ventilation. Data Sources Study Selection and Data Extraction: The most relevant literature, media reports, and author experiences were assessed for inclusion in this narrative review including PubMed, national newspapers, and critical care/pharmacology textbooks. Data Synthesis: Uncertainty regarding coronavirus disease 2019 clinical course, shifts in attitude, and changes in routine behavior have hindered Bundle use. A domino effect results from: 1) changes to critical care hierarchy, priorities, and ICU team composition; 2) significant personal protective equipment shortages cause; 3) reduced/restricted physical bedside presence favoring; 4) increased depth of sedation and use of neuromuscular blockade; 5) which exacerbate drug shortages; and 6) which require prolonged use of limited ventilator resources. Other identified barriers include manageable knowledge deficits among non-ICU clinicians unfamiliar with the Bundle or among PICU specialists deploying pediatric-based Bundle approaches who are unfamiliar with adult medicine. Both groups have been enlisted to augment the adult ICU work force to meet demand. Strategies were identified to facilitate Bundle performance to liberate patients from the ICU. Conclusions: We acknowledge current challenges that interfere with comprehensive management of critically ill patients during the coronavirus disease 2019 pandemic. Rapid response to new circumstances precisely requires established safety mechanisms and protocols like the ABCDEF Bundle to increase ICU and ventilator capacity and help survivors maximize recovery from coronavirus disease 2019 as early as possible.

10.
J Geophys Res Atmos ; 125(7): e2019JD031922, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32728501

RESUMO

Improved observational understanding of urban CO2 emissions, a large and dynamic global source of fossil CO2, can provide essential insights for both carbon cycle science and mitigation decision making. Here we compare three distinct global CO2 emissions inventory representations of urban CO2 emissions for five Middle Eastern cities (Riyadh, Mecca, Tabuk, Jeddah, and Baghdad) and use independent satellite observations from the Orbiting Carbon Observatory-2 (OCO-2) satellite to evaluate the inventory representations of afternoon emissions. We use the column version of the Stochastic Time-Inverted Lagrangian Transport (X-STILT) model to account for atmospheric transport and link emissions to observations. We compare XCO2 simulations with observations to determine optimum inventory scaling factors. Applying these factors, we find that the average summed emissions for all five cities are 100 MtC year-1 (50-151, 90% CI), which is 2.0 (1.0, 3.0) times the average prior inventory magnitudes. The total adjustment of the emissions of these cities comes out to ~7% (0%, 14%) of total Middle Eastern emissions (~700 MtC year-1). We find our results to be insensitive to the prior spatial distributions in inventories of the cities' emissions, facilitating robust quantitative assessments of urban emission magnitudes without accurate high-resolution gridded inventories.

11.
Sci Transl Med ; 12(549)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581132

RESUMO

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of "costimulatory bispecifics" that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti-PD-1 approach and endow responsiveness-as well as long-term immune memory-against tumors that otherwise do not respond to anti-PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and "off the shelf" combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.

13.
Crit Care Med ; 48(4): 562-570, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32205603

RESUMO

OBJECTIVES: Daily ICU interprofessional team rounds, which incorporate the ICU Liberation ("A" for Assessment, Prevention, and Manage Pain; "B" for Both Spontaneous Awakening Trials and Spontaneous Breathing Trials; "C" for Choice of Analgesia and Sedation; "D" for Delirium Assess, Prevent, and Manage; "E" for Early Mobility and Exercise; "F" for Family Engagement and Empowerment [ABCDEF]) Bundle, support both the care coordination and regular provider communication necessary for Bundle execution. This article describes evidence-based practices for conducting effective interprofessional team rounds in the ICU to improve Bundle performance. DESIGN: Best practice synthesis. METHODS: The authors, each extensively involved in the Society of Critical Care Medicine's ICU Liberation Campaign, reviewed the pertinent literature to identify how ICU interprofessional team rounds can be optimized to increase ICU Liberation adherence. RESULTS: Daily ICU interprofessional team rounds that foster ICU Liberation Bundle use support both care coordination and regular provider communication within and between teams. Evidence-based best practices for conducting effective interprofessional team rounds in the ICU include the optimal structure for ICU interprofessional team rounds; the importance of conducting rounds at patients' bedside; essential participants in rounds; the inclusion of ICU patients and their families in rounds-based discussions; and incorporation of the Bundle into the Electronic Health Record. Interprofessional team rounds in the ICU ideally employ communication strategies to foster inclusive and supportive behaviors consistent with interprofessional collaboration in the ICU. Patient care discussions during interprofessional team rounds benefit from being patient-centered and goal-oriented. Documentation of ICU Liberation Bundle elements in the Electronic Health Record may help facilitate team communication and decision-making. CONCLUSIONS: Conducting high-quality interprofessional team rounds in the ICU is a key strategy to support ICU Liberation Bundle use.

14.
Sci Rep ; 10(1): 1379, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992727

RESUMO

Production of oil and natural gas in North America is at an all-time high due to the development and use of horizontal drilling and hydraulic fracturing. Methane emissions associated with this industrial activity are a concern because of the contribution to climate radiative forcing. We present new measurements from the space-based TROPOspheric Monitoring Instrument (TROPOMI) launched in 2017 that show methane enhancements over production regions in the United States. In the Uintah Basin in Utah, TROPOMI methane columns correlated with in-situ measurements, and the highest columns were observed over the deepest parts of the basin, consistent with the accumulation of emissions underneath inversions. In the Permian Basin in Texas and New Mexico, methane columns showed maxima over regions with the highest natural gas production and were correlated with nitrogen-dioxide columns at a ratio that is consistent with results from in-situ airborne measurements. The improved detail provided by TROPOMI will likely enable the timely monitoring from space of methane emissions associated with oil and natural gas production.

15.
Front Pediatr ; 7: 422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681719

RESUMO

Objective: Evaluate hemostatic dysfunction in pediatric severe sepsis by thromboelastography (TEG) and determine if TEG parameters are associated with new or progressive multiple organ dysfunction syndrome (NPMODS) or shock, defined as a lactate ≥2mmol/L. We explored the relationship between TEG variables, selective cytokines, and endothelial factors. Design: Prospective observational. Setting: Single-center, quaternary care pediatric intensive care unit. Patients: Children aged 6- months to 14- years with severe sepsis with expected PICU stay for >72 h. Interventions: None. Measurements and Main Results: Twenty-eight children were enrolled with median (IQR) age of 7.3 years (4.4-11.4), PELOD score (study day-1) of 11(1.25-13), and PICU length of stay of 10 days (5-28). TEG-defined hypercoagulable state occurred most commonly in 73% (94/129) of samples, followed by hypocoagulable state in 7.8% (10/129) and mixed coagulation state in 1.5% (2/129) of samples in the study cohort. In contrast, hypocoagulable state occurred most commonly in 66% (98/148) of samples based on standard coagulation parameters. In the seven children who developed shock with NPMODS compared to eight patients with shock without NPMODS and 12 patients with severe sepsis only, we found more profound coagulopathy [thrombocytopenia (p = 0.04), elevated INR (p = 0.038), low fibrinogen level (p = 0.049), and low TEG-G value (p = 0.01)] and higher peak of interleukin-6 (p = 0.0014) and IL-10 (p = 0.007). Peak lactate in the first 5 study days had moderate correlation with standard coagulation assays, TEG parameters, and selective cytokines. Peak lactate did not correlate with markers of endothelial activation. Lowest TEG -G value had moderate correlation with peak IL-10 (ρ -0.442, p =0.019), peak VCAM (ρ - 0.495, p = 0.007), and peak lactate (ρ -0.542, p = 0.004) in the first 5 study days. A combination of TEG-G value and IL-6 concentration best discriminated children with shock and NPMODS [AUC 0.979 (95%CI 0.929-1.00), p < 0.001]. Conclusion: This exploratory analysis of hemostasis dysfunction on TEG in pediatric severe sepsis suggests that while hypercoagulability is more common, a hypocoagulable state is associated with shock and NPMODS. In addition, TEG abnormalities are also associated with immune and endothelial factors. A larger cohort study is needed to validate these findings.

16.
AIAA J ; 57(8): 3322-3338, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31631891

RESUMO

Active flow control (AFC) subscale experiments were conducted at the Lucas Wind Tunnel of the California Institute of Technology. Tests were performed on a generic vertical tail model at low speeds. Fluidic oscillators were used at the trailing edge of the main element (vertical stabilizer) to redirect the flow over the rudder and delay or prevent flow separation. Side force increases in excess of 50% were achieved with a 2% momentum coefficient (C µ ) input. The results indicated that a collective C µ of about 1% could increase the side force by 30-50%. This result is achieved by reducing the spanwise flow on the swept back wings that contributes to early flow separation near their tips. These experiments provided the technical backdrop to test the full-scale Boeing 757 vertical tail model equipped with a fluidic oscillator system at the National Full-scale Aerodynamics Complex 40-by 80-foot Wind Tunnel, NASA Ames Research Center. The C µ is shown to be an important parameter for scaling a fluidic oscillator AFC system from subscale to full-scale wind tunnel tests. The results of these tests provided the required rationale to use a fluidic oscillator AFC configuration for a follow-on flight test on the Boeing 757 ecoDemonstrator.

17.
Pediatr Crit Care Med ; 20(12): 1137-1146, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31568246

RESUMO

OBJECTIVES: Ongoing adult sepsis clinical trials are assessing therapies that target three inflammation phenotypes including 1) immunoparalysis associated, 2) thrombotic microangiopathy driven thrombocytopenia associated, and 3) sequential liver failure associated multiple organ failure. These three phenotypes have not been assessed in the pediatric multicenter setting. We tested the hypothesis that these phenotypes are associated with increased macrophage activation syndrome and mortality in pediatric sepsis. DESIGN: Prospective severe sepsis cohort study comparing children with multiple organ failure and any of these phenotypes to children with multiple organ failure without these phenotypes and children with single organ failure. SETTING: Nine PICUs in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PATIENTS: Children with severe sepsis and indwelling arterial or central venous catheters. INTERVENTIONS: Clinical data collection and twice weekly blood sampling until PICU day 28 or discharge. MEASUREMENTS AND MAIN RESULTS: Of 401 severe sepsis cases enrolled, 112 (28%) developed single organ failure (0% macrophage activation syndrome 0/112; < 1% mortality 1/112), whereas 289 (72%) developed multiple organ failure (9% macrophage activation syndrome 24/289; 15% mortality 43/289). Overall mortality was higher in children with multiple organ and the phenotypes (24/101 vs 20/300; relative risk, 3.56; 95% CI, 2.06-6.17). Compared to the 188 multiple organ failure patients without these inflammation phenotypes, the 101 multiple organ failure patients with these phenotypes had both increased macrophage activation syndrome (19% vs 3%; relative risk, 7.07; 95% CI, 2.72-18.38) and mortality (24% vs 10%; relative risk, 2.35; 95% CI, 1.35-4.08). CONCLUSIONS: These three inflammation phenotypes were associated with increased macrophage activation syndrome and mortality in pediatric sepsis-induced multiple organ failure. This study provides an impetus and essential baseline data for planning multicenter clinical trials targeting these inflammation phenotypes in children.


Assuntos
Inflamação/etiologia , Inflamação/fisiopatologia , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Sepse/complicações , Adolescente , Cateteres de Demora , Criança , Pré-Escolar , Cuidados Críticos , Feminino , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Falência Hepática/etiologia , Masculino , Paralisia/etiologia , Fenótipo , Estudos Prospectivos , Sepse/fisiopatologia , Trombocitopenia/etiologia
18.
Angew Chem Int Ed Engl ; 58(45): 16172-16176, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31496012

RESUMO

Conversion of CO2 into valuable molecules is a field of intensive investigation with the aim of developing scalable technologies for making fuels using renewable energy sources. While electrochemical reduction into CO and formate are approaching industrial maturity, a current challenge is obtaining more reduced products like methanol. However, literature on the matter is scarce, and even more for the use of molecular catalysts. Here, we demonstrate that cobalt phthalocyanine, a well-known catalyst for the electrochemical conversion of CO2 to CO, can also catalyze the reaction from CO2 or CO to methanol in aqueous electrolytes at ambient conditions of temperature and pressure. The studies identify formaldehyde as a key intermediate and an unexpected pH effect on selectivity. This paves the way for establishing a sequential process where CO2 is first converted to CO which is subsequently used as a reactant to produce methanol. Under ideal conditions, the reaction shows a global Faradaic efficiency of 19.5 % and chemical selectivity of 7.5 %.

19.
Sci Rep ; 9(1): 12031, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427700

RESUMO

Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.


Assuntos
Anticorpos Biespecíficos/imunologia , Proteínas do Sistema Complemento/imunologia , Citotoxicidade Imunológica , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia
20.
Clin Cancer Res ; 25(21): 6501-6510, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31358539

RESUMO

PURPOSE: Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize the tumor microenvironment for the frequency of GITR expression in T-cell subsets from seven different human solid tumors.Experimental Design: For mouse experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single-cell level using flow cytometry (FC). A total of 213 samples were evaluated for GITR expression by IHC, 63 by FC, and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. RESULTS: The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that NSCLC, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4+ Foxp3+ T regulatory cells. IHC and FC data showed similar trends with a good correlation between both techniques. CONCLUSIONS: Human tumor data suggest that NSCLC, renal cell carcinoma, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.


Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Melanoma Experimental/genética , Subpopulações de Linfócitos T/imunologia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/antagonistas & inibidores , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Receptores de IgG/imunologia , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
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