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1.
N Engl J Med ; 390(22): 2083-2097, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38767252

RESUMO

BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).


Assuntos
Testes de Função Respiratória , Insuficiência Respiratória , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Pneumopatias/diagnóstico , Pneumopatias/economia , Pneumopatias/etnologia , Pneumopatias/terapia , Transplante de Pulmão/estatística & dados numéricos , Inquéritos Nutricionais/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/economia , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/terapia , Grupos Raciais , Testes de Função Respiratória/classificação , Testes de Função Respiratória/economia , Testes de Função Respiratória/normas , Espirometria , Estados Unidos/epidemiologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/economia , Insuficiência Respiratória/etnologia , Insuficiência Respiratória/terapia , Negro ou Afro-Americano/estatística & dados numéricos , Brancos/estatística & dados numéricos , Avaliação da Deficiência , Ajuda a Veteranos de Guerra com Deficiência/classificação , Ajuda a Veteranos de Guerra com Deficiência/economia , Ajuda a Veteranos de Guerra com Deficiência/estatística & dados numéricos , Pessoas com Deficiência/classificação , Pessoas com Deficiência/estatística & dados numéricos , Doenças Profissionais/diagnóstico , Doenças Profissionais/economia , Doenças Profissionais/etnologia , Financiamento Governamental/economia , Financiamento Governamental/estatística & dados numéricos
2.
J Am Chem Soc ; 144(30): 13851-13864, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35875870

RESUMO

The clinical manufacturing of chimeric antigen receptor (CAR) T cells includes cell selection, activation, gene transduction, and expansion. While the method of T-cell selection varies across companies, current methods do not actively eliminate the cancer cells in the patient's apheresis product from the healthy immune cells. Alarmingly, it has been found that transduction of a single leukemic B cell with the CAR gene can confer resistance to CAR T-cell therapy and lead to treatment failure. In this study, we report the identification of a novel high-affinity DNA aptamer, termed tJBA8.1, that binds transferrin receptor 1 (TfR1), a receptor broadly upregulated by cancer cells. Using competition assays, high resolution cryo-EM, and de novo model building of the aptamer into the resulting electron density, we reveal that tJBA8.1 shares a binding site on TfR1 with holo-transferrin, the natural ligand of TfR1. We use tJBA8.1 to effectively deplete B lymphoma cells spiked into peripheral blood mononuclear cells with minimal impact on the healthy immune cell composition. Lastly, we present opportunities for affinity improvement of tJBA8.1. As TfR1 expression is broadly upregulated in many cancers, including difficult-to-treat T-cell leukemias and lymphomas, our work provides a facile, universal, and inexpensive approach for comprehensively removing cancerous cells from patient apheresis products for safe manufacturing of adoptive T-cell therapies.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Leucócitos Mononucleares , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores da Transferrina/metabolismo , Linfócitos T
3.
Proc Natl Acad Sci U S A ; 113(26): 7071-6, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27298370

RESUMO

Tridymite, a low-pressure, high-temperature (>870 °C) SiO2 polymorph, was detected in a drill sample of laminated mudstone (Buckskin) at Marias Pass in Gale crater, Mars, by the Chemistry and Mineralogy X-ray diffraction instrument onboard the Mars Science Laboratory rover Curiosity The tridymitic mudstone has ∼40 wt.% crystalline and ∼60 wt.% X-ray amorphous material and a bulk composition with ∼74 wt.% SiO2 (Alpha Particle X-Ray Spectrometer analysis). Plagioclase (∼17 wt.% of bulk sample), tridymite (∼14 wt.%), sanidine (∼3 wt.%), cation-deficient magnetite (∼3 wt.%), cristobalite (∼2 wt.%), and anhydrite (∼1 wt.%) are the mudstone crystalline minerals. Amorphous material is silica-rich (∼39 wt.% opal-A and/or high-SiO2 glass and opal-CT), volatile-bearing (16 wt.% mixed cation sulfates, phosphates, and chlorides-perchlorates-chlorates), and has minor TiO2 and Fe2O3T oxides (∼5 wt.%). Rietveld refinement yielded a monoclinic structural model for a well-crystalline tridymite, consistent with high formation temperatures. Terrestrial tridymite is commonly associated with silicic volcanism, and detritus from such volcanism in a "Lake Gale" catchment environment can account for Buckskin's tridymite, cristobalite, feldspar, and any residual high-SiO2 glass. These cogenetic detrital phases are possibly sourced from the Gale crater wall/rim/central peak. Opaline silica could form during diagenesis from high-SiO2 glass, as amorphous precipitated silica, or as a residue of acidic leaching in the sediment source region or at Marias Pass. The amorphous mixed-cation salts and oxides and possibly the crystalline magnetite (otherwise detrital) are primary precipitates and/or their diagenesis products derived from multiple infiltrations of aqueous solutions having variable compositions, temperatures, and acidities. Anhydrite is post lithification fracture/vein fill.

4.
Mol Pharm ; 15(6): 2268-2276, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29672061

RESUMO

Messenger RNA (mRNA) is a biomolecule with a wide range of promising clinical applications. However, the unstable nature of mRNA and its susceptibility to degradation by ribonucleases (RNases) necessitate the use of specialized formulations for delivery. Polycations are an emerging class of synthetic carriers capable of packaging nucleic acids, and may serve as suitable RNase-resistant formulations for mRNA administration. Here, we explore the application of VIPER and sunflower polycations, two polycations previously synthesized by our group, for the delivery of mRNA in comparison to branched poly(ethylenimine); all three polycations have been shown to efficiently deliver plasmid DNA (pDNA) to cultured cells. Despite successful mRNA condensation and packaging, transfection studies reveal that these three polycations can only efficiently deliver mRNA under serum-free conditions, while pDNA delivery is achieved even in the presence of serum. RNase resistance studies confirm that nuclease degradation of mRNA cargo remains a significant barrier to mRNA delivery using these polycations. These results emphasize the need for additional strategies for nuclease protection of mRNA cargo beyond electrostatic complexation with polycation.


Assuntos
DNA/administração & dosagem , Portadores de Fármacos/química , Poliaminas/química , RNA Mensageiro/administração & dosagem , DNA/genética , Terapia Genética/métodos , Células HeLa , Helianthus/química , Humanos , Plasmídeos/administração & dosagem , Plasmídeos/genética , Polieletrólitos , RNA Mensageiro/metabolismo , Ribonucleases/metabolismo , Transfecção/métodos
5.
J Calif Dent Assoc ; 44(2): 121-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26930755

RESUMO

Standard oral cancer therapy generally includes a combination of surgery with chemotherapy and/or radiotherapy. This treatment paradigm has not changed in some time. In this paper, we propose a chemopreventive nanodiamond platform for the delivery of celecoxib (Celebrex) to oral cancer lesions. This innovative platform allows for sustained drug release under physiological conditions, potentially enhancing chemopreventive efficacy of celecoxib without the physical and toxicological damage associated with conventional means of drug delivery.


Assuntos
Celecoxib/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias Bucais/prevenção & controle , Nanodiamantes/administração & dosagem , Anticarcinógenos/uso terapêutico , Quimioprevenção , Preparações de Ação Retardada , Portadores de Fármacos , Humanos , Nanodiamantes/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química
7.
J Bacteriol ; 194(3): 617-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22123249

RESUMO

Lateral gene transfer (LGT) is essential for generating between-strain genomic recombinants of Chlamydia trachomatis to facilitate the organism's evolution. Because there is no reliable laboratory-based gene transfer system for C. trachomatis, in vitro generation of recombinants from antibiotic-resistant strains is being used to study LGT. However, selection pressures imposed on in vitro recombinants likely affect statistical properties of recombination relative to naturally occurring clinical recombinants, including prevalence at particular loci. We examined multiple loci for 16 in vitro-derived recombinants of ofloxacin- and rifampin-resistant L(1) and D strains, respectively, grown with both antibiotics, and compared these with the same sequenced loci among 11 clinical recombinants. Breakpoints and recombination frequency were examined using phylogenetics, bioinformatics, and statistics. In vitro and clinical isolates clustered perfectly into two groups, without misclassification, using Ward's minimum variance based on breakpoint data. As expected, gyrA (confers ofloxacin resistance) and rpoB (confers rifampin resistance) had significantly more breakpoints among in vitro recombinants than among clinical recombinants (P < 0.0001 and P = 0.02, respectively, using the Wilcoxon rank sum test). Unexpectedly, trpA also had significantly more breakpoints for in vitro recombinants (P < 0.0001). There was also significant selection at other loci. The strongest bias was for ompA in strain D (P = 3.3 × 10(-8)). Our results indicate that the in vitro model differs statistically from natural recombination events. Additional genomic studies are needed to determine the factors responsible for the observed selection biases at unexpected loci and whether these are important for LGT to inform approaches for genetically manipulating C. trachomatis.


Assuntos
Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/genética , Farmacorresistência Bacteriana , Recombinação Genética , Antibacterianos/farmacologia , Sequência de Bases , Chlamydia trachomatis/classificação , Chlamydia trachomatis/efeitos dos fármacos , Chlamydia trachomatis/metabolismo , Engenharia Genética , Humanos , Dados de Sequência Molecular , Filogenia
8.
Nature ; 439(7075): 490-2, 2006 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-16437116

RESUMO

In viruses, as in eukaryotes, elaborate mechanisms have evolved to protect the genome and to ensure its timely replication and reliable transmission to progeny. Influenza A viruses are enveloped, spherical or filamentous structures, ranging from 80 to 120 nm in diameter. Inside each envelope is a viral genome consisting of eight single-stranded negative-sense RNA segments of 890 to 2,341 nucleotides each. These segments are associated with nucleoprotein and three polymerase subunits, designated PA, PB1 and PB2; the resultant ribonucleoprotein complexes (RNPs) resemble a twisted rod (10-15 nm in width and 30-120 nm in length) that is folded back and coiled on itself. Late in viral infection, newly synthesized RNPs are transported from the nucleus to the plasma membrane, where they are incorporated into progeny virions capable of infecting other cells. Here we show, by transmission electron microscopy of serially sectioned virions, that the RNPs of influenza A virus are organized in a distinct pattern (seven segments of different lengths surrounding a central segment). The individual RNPs are suspended from the interior of the viral envelope at the distal end of the budding virion and are oriented perpendicular to the budding tip. This finding argues against random incorporation of RNPs into virions, supporting instead a model in which each segment contains specific incorporation signals that enable the RNPs to be recruited and packaged as a complete set. A selective mechanism of RNP incorporation into virions and the unique organization of the eight RNP segments may be crucial to maintaining the integrity of the viral genome during repeated cycles of replication.


Assuntos
Vírus da Influenza A/química , Vírus da Influenza A/ultraestrutura , Ribonucleoproteínas/química , Ribonucleoproteínas/ultraestrutura , Proteínas Virais/química , Proteínas Virais/ultraestrutura , Vírion/ultraestrutura , Animais , Linhagem Celular , Cães , Patos/virologia , Humanos , Vírus da Influenza A/classificação , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Ribonucleoproteínas/metabolismo , Suínos/virologia , Proteínas Virais/metabolismo , Vírion/química , Montagem de Vírus
9.
Int J Vasc Med ; 2022: 4224975, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35036009

RESUMO

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62 ± 0.56 vs. 1.54 ± 0.47, p < 0.001). VRI was inversely but mildly correlated with age (r = -0.19, p < 0.001). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

10.
Adv Healthc Mater ; 11(9): e2101651, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34706166

RESUMO

Peptide-based cancer vaccines offer production and safety advantages but have had limited clinical success due to their intrinsic instability, rapid clearance, and low cellular uptake. Nanoparticle-based delivery vehicles can improve the in vivo stability and cellular uptake of peptide antigens. Here, a well-defined, self-assembling mannosylated polymer is developed for anticancer peptide antigen delivery. The amphiphilic polymer is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the peptide antigens are conjugated to the pH-sensitive hydrophobic block through the reversible disulfide linkage for selective release after cell entry. The polymer-peptide conjugates self-assemble into sub-100 nm micelles at physiological pH and dissociate at endosomal pH. The mannosylated micellar corona increases the accumulation of vaccine cargoes in the draining inguinal lymph nodes and facilitates nanoparticle uptake by professional antigen presenting cells. In vivo studies demonstrate that the mannosylated micelle formulation improves dendritic cell activation and enhances antigen-specific T cell responses, resulting in higher antitumor immunity in tumor-bearing mice compared to free peptide antigen. The mannosylated polymer is therefore a simple and promising platform for the delivery of peptide cancer vaccines.


Assuntos
Vacinas Anticâncer , Neoplasias , Animais , Antígenos , Sistemas de Liberação de Medicamentos , Camundongos , Micelas , Neoplasias/terapia , Peptídeos , Polímeros/química , Vacinas de Subunidades Antigênicas
11.
Nature ; 436(7047): 62-5, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-16001062

RESUMO

The ubiquitous atmospheric dust on Mars is well mixed by periodic global dust storms, and such dust carries information about the environment in which it once formed and hence about the history of water on Mars. The Mars Exploration Rovers have permanent magnets to collect atmospheric dust for investigation by instruments on the rovers. Here we report results from Mössbauer spectroscopy and X-ray fluorescence of dust particles captured from the martian atmosphere by the magnets. The dust on the magnets contains magnetite and olivine; this indicates a basaltic origin of the dust and shows that magnetite, not maghemite, is the mineral mainly responsible for the magnetic properties of the dust. Furthermore, the dust on the magnets contains some ferric oxides, probably including nanocrystalline phases, so some alteration or oxidation of the basaltic dust seems to have occurred. The presence of olivine indicates that liquid water did not play a dominant role in the processes that formed the atmospheric dust.


Assuntos
Atmosfera/química , Poeira/análise , Meio Ambiente Extraterreno/química , Marte , Clima Desértico , Compostos Férricos/análise , Óxido Ferroso-Férrico , Ferro/análise , Compostos de Ferro/análise , Compostos de Magnésio/análise , Magnetismo , Óxidos/análise , Silicatos/análise , Espectrometria por Raios X , Espectroscopia de Mossbauer , Água/análise
12.
Nature ; 436(7047): 66-9, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-16001063

RESUMO

Gusev crater was selected as the landing site for the Spirit rover because of the possibility that it once held a lake. Thus one of the rover's tasks was to search for evidence of lake sediments. However, the plains at the landing site were found to be covered by a regolith composed of olivine-rich basaltic rock and windblown 'global' dust. The analyses of three rock interiors exposed by the rock abrasion tool showed that they are similar to one another, consistent with having originated from a common lava flow. Here we report the investigation of soils, rock coatings and rock interiors by the Spirit rover from sol (martian day) 1 to sol 156, from its landing site to the base of the Columbia hills. The physical and chemical characteristics of the materials analysed provide evidence for limited but unequivocal interaction between water and the volcanic rocks of the Gusev plains. This evidence includes the softness of rock interiors that contain anomalously high concentrations of sulphur, chlorine and bromine relative to terrestrial basalts and martian meteorites; sulphur, chlorine and ferric iron enrichments in multilayer coatings on the light-toned rock Mazatzal; high bromine concentration in filled vugs and veins within the plains basalts; positive correlations between magnesium, sulphur and other salt components in trench soils; and decoupling of sulphur, chlorine and bromine concentrations in trench soils compared to Gusev surface soils, indicating chemical mobility and separation.


Assuntos
Meio Ambiente Extraterreno/química , Sedimentos Geológicos/química , Marte , Solo/análise , Água/química , Bromo/análise , Cloro/análise , Enxofre/análise
13.
Nature ; 436(7047): 49-54, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-16001059

RESUMO

The mineralogical and elemental compositions of the martian soil are indicators of chemical and physical weathering processes. Using data from the Mars Exploration Rovers, we show that bright dust deposits on opposite sides of the planet are part of a global unit and not dominated by the composition of local rocks. Dark soil deposits at both sites have similar basaltic mineralogies, and could reflect either a global component or the general similarity in the compositions of the rocks from which they were derived. Increased levels of bromine are consistent with mobilization of soluble salts by thin films of liquid water, but the presence of olivine in analysed soil samples indicates that the extent of aqueous alteration of soils has been limited. Nickel abundances are enhanced at the immediate surface and indicate that the upper few millimetres of soil could contain up to one per cent meteoritic material.


Assuntos
Poeira/análise , Meio Ambiente Extraterreno/química , Sedimentos Geológicos/química , Marte , Solo/análise , Bromo/análise , Compostos de Ferro/análise , Compostos de Magnésio/análise , Minerais/análise , Minerais/química , Níquel/análise , Silicatos/análise , Silicatos/química , Espectrofotometria Infravermelho , Espectroscopia de Mossbauer , Água/análise , Água/química
14.
Crit Care Explor ; 1(8): e0038, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32166279

RESUMO

We present a unique case of a broken fragment of a hypodermic needle breaking and embolizing to the heart. This needle subsequently penetrated the right ventricle and the patient developed hemopericardium which resulted in cardiac tamponade physiology. DATA SOURCES: None. STUDY SELECTION: None. DATA EXTRACTION: None. DATA SYNTHESIS: Recognizing the potential for unusual and serious complications of IV illicit drug use is an important part of providing effective and timely medical care in this vulnerable population. CONCLUSIONS: An embolic needle phenomenon can have significant sequela, including direct cardiac trauma leading to tamponade and subsequent cardiac collapse. Partnering with the patient to take a detailed history was critical in uncovering the underlying etiology of this patient's cardiogenic shock.

15.
J Am Heart Assoc ; 7(22): e009476, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30571498

RESUMO

Background Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease ( CVD ) in certain high-risk individuals, therefore missing opportunities for intensive therapy and preventing CVD events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning ( ML ) to tackle this problem. Methods and Results We developed a ML Risk Calculator based on Support Vector Machines ( SVM s) using a 13-year follow up data set from MESA (the Multi-Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD-free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort. ACC / AHA Risk Calculator, based on 7.5% 10-year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and AUC 0.71. In contrast, ML Risk Calculator recommended only 11.4% to take statin, and only 14.4% of "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and AUC 0.92. Similar results were found for prediction of "All CVD " events. Conclusions The ML Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the ML model in other cohorts and to explore its ability in short-term CVD risk prediction.


Assuntos
Doenças Cardiovasculares/diagnóstico , Aprendizado de Máquina , Medição de Risco/métodos , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/prevenção & controle , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sensibilidade e Especificidade , Máquina de Vetores de Suporte
16.
Sci Adv ; 4(6): eaar3330, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29881776

RESUMO

Clay minerals provide indicators of the evolution of aqueous conditions and possible habitats for life on ancient Mars. Analyses by the Mars Science Laboratory rover Curiosity show that ~3.5-billion year (Ga) fluvio-lacustrine mudstones in Gale crater contain up to ~28 weight % (wt %) clay minerals. We demonstrate that the species of clay minerals deduced from x-ray diffraction and evolved gas analysis show a strong paleoenvironmental dependency. While perennial lake mudstones are characterized by Fe-saponite, we find that stratigraphic intervals associated with episodic lake drying contain Al-rich, Fe3+-bearing dioctahedral smectite, with minor (3 wt %) quantities of ferripyrophyllite, interpreted as wind-blown detritus, found in candidate aeolian deposits. Our results suggest that dioctahedral smectite formed via near-surface chemical weathering driven by fluctuations in lake level and atmospheric infiltration, a process leading to the redistribution of nutrients and potentially influencing the cycling of gases that help regulate climate.

17.
Arch Neurol ; 63(8): 1139-43, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16908741

RESUMO

BACKGROUND: In recent years, considerable effort has been made to improve the treatment of patients with amyotrophic lateral sclerosis (ALS). However, despite the increased use of supportive measures, controversy still exists about overall trends in disease progression and survival. OBJECTIVE: To analyze whether survival and disease progression in patients with ALS have changed during the past 20 years. DESIGN: By using the Kaplan-Meier life-table method, we compared disease progression (measured as time to a 20-point increase in the Appel ALS score) and survival in 1041 patients diagnosed as having ALS between January 1, 1984, and January 1, 1999 (historical group, n = 647), and between January 2, 1999, and November 1, 2004 (contemporary group, n = 394). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: The median survival from symptom onset was 4.32 years (95% confidence interval [CI], 3.81-4.84 years) in the contemporary group compared with 3.22 years (95% CI, 3.04-3.41 years) in the historical group (P<.001). The contemporary patients progressed more slowly (10 months to a 20-point increase; 95% CI, 9-13 months) compared with patients in the historical group (9 months to a 20-point increase; 95% CI, 8-9 months) (P<.001). In the multivariate Cox proportional hazards model, the observed outcome improvement over time was independent of confounding factors, such as age, sex, diagnostic delay, site of symptom onset, baseline forced vital capacity, and baseline Appel ALS score, and independent of the use of potentially outcome-modifying therapies (riluzole, noninvasive ventilation, and percutaneous gastrostomy). CONCLUSIONS: Contemporary patients had significantly prolonged survival and slower disease progression compared with patients from the historical group. The improved outcome seemed independent of specific ALS outcome-modifying therapies, but we cannot rule out an effect of comorbid conditions, which could have influenced medical treatment and survival. Nevertheless, our observations suggest the possibility that disease course has changed and that ALS is becoming less aggressive over time. Further studies are needed to determine whether there has been a fundamental change in the natural history of the disease or whether our results are because of other unmeasured aspects of improved multidisciplinary care.


Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/patologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores , Dipeptídeos/metabolismo , Progressão da Doença , Feminino , Humanos , Inositol/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Fatores de Tempo
18.
J Neurol ; 253(11): 1428-36, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16773270

RESUMO

OBJECTIVE: In order to define the predictors of prolonged survival available at the time of first examination we performed a historical cohort study of amyotrophis sclerosis (ALS) patients referred to our ALS Clinic over the last 20 years. METHODS: In a group of 1034 patients with the diagnosis of definite or probable ALS the effects of individual prognostic factors on tracheostomy-free survival were assessed with the Kaplan-Meier life-table method. The prognostic value of each factor was estimated using univariate and multivariate Cox proportional hazard analyses. RESULTS: The median survival time was 3.45 years, (95%CI 3.27-3.74). Both the univariate and multivariate Cox models indicated that younger age, limb site of onset, longer diagnostic delay, lower Appel ALS score (AALSS) at first examination, lower AALSS-rate of change between first symptom and first exam (preslope), and higher baseline forced vital capacity (FVC) were associated with longer survival. In addition, four factors: age, diagnostic delay, baseline FVC and AALSS preslope have been identified as independent predictors of survival in our patient population. CONCLUSIONS: The identification of younger age, limb site of onset and longer diagnostic delay as predictors of prolonged survival in ALS clinic population supports the findings of several, earlier studies that were based on smaller groups of patients. More significantly, several additional variables assessed at the first examination predict longer survival: lower baseline AALSS, lower AALSS- preslope and higher baseline FVC. All of these parameters are of value in patient management and in clinical trial development.


Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Capacidade Vital
19.
Int J Vasc Med ; 2016: 1348028, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27830091

RESUMO

Background. Endothelial function is viewed as a barometer of cardiovascular health and plays a central role in vascular reactivity. Several studies showed digital thermal monitoring (DTM) as a simple noninvasive method to measure vascular reactivity that is correlated with atherosclerosis risk factors and coronary artery disease. Objectives. To further evaluate the relations between patient characteristics and DTM indices in a large patient registry. Methods. DTM measures were correlated with age, sex, heart rate, and systolic and diastolic blood pressure in 6084 patients from 18 clinics. Results. DTM vascular reactivity index (VRI) was normally distributed and inversely correlated with age (r = -0.21, p < 0.0001). Thirteen percent of VRI tests were categorized as poor vascular reactivity (VRI < 1.0), 70 percent as intermediate (1.0 ≤ VRI < 2.0), and 17 percent as good (VRI ≥ 2.0). Poor VRI (<1.0) was noted in 6% of <50 y, 10% of 50-70 y, and 18% of ≥70 y. In multiple linear regression analyses, age, sex, and diastolic blood pressure were significant but weak predictors of VRI. Conclusions. As the largest database of finger-based vascular reactivity measurement, this report adds to prior findings that VRI is a meaningful physiological marker and reflects a high level of residual risk found in patients currently under care.

20.
J Geophys Res Planets ; 121(1): 75-106, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27134806

RESUMO

The Windjana drill sample, a sandstone of the Dillinger member (Kimberley formation, Gale Crater, Mars), was analyzed by CheMin X-ray diffraction (XRD) in the MSL Curiosity rover. From Rietveld refinements of its XRD pattern, Windjana contains the following: sanidine (21% weight, ~Or95); augite (20%); magnetite (12%); pigeonite; olivine; plagioclase; amorphous and smectitic material (~25%); and percent levels of others including ilmenite, fluorapatite, and bassanite. From mass balance on the Alpha Proton X-ray Spectrometer (APXS) chemical analysis, the amorphous material is Fe rich with nearly no other cations-like ferrihydrite. The Windjana sample shows little alteration and was likely cemented by its magnetite and ferrihydrite. From ChemCam Laser-Induced Breakdown Spectrometer (LIBS) chemical analyses, Windjana is representative of the Dillinger and Mount Remarkable members of the Kimberley formation. LIBS data suggest that the Kimberley sediments include at least three chemical components. The most K-rich targets have 5.6% K2O, ~1.8 times that of Windjana, implying a sediment component with >40% sanidine, e.g., a trachyte. A second component is rich in mafic minerals, with little feldspar (like a shergottite). A third component is richer in plagioclase and in Na2O, and is likely to be basaltic. The K-rich sediment component is consistent with APXS and ChemCam observations of K-rich rocks elsewhere in Gale Crater. The source of this sediment component was likely volcanic. The presence of sediment from many igneous sources, in concert with Curiosity's identifications of other igneous materials (e.g., mugearite), implies that the northern rim of Gale Crater exposes a diverse igneous complex, at least as diverse as that found in similar-age terranes on Earth.

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