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At interphase, de-condensed chromosomes have a non-random three-dimensional architecture within the nucleus, however, little is known about the extent to which nuclear organisation might influence expression or vice versa. Here, using imprinting as a model, we use 3D RNA- and DNA-fluorescence-in-situ-hybridisation in normal and mutant mouse embryonic stem cell lines to assess the relationship between imprinting control, gene expression and allelic distance from the nuclear periphery. We compared the two parentally inherited imprinted domains at the Dlk1-Dio3 domain and find a small but reproducible trend for the maternally inherited domain to be further away from the periphery however we did not observe an enrichment of inactive alleles in the immediate vicinity of the nuclear envelope. Using Zfp57KO ES cells, which harbour a paternal to maternal epigenotype switch, we observe that expressed alleles are significantly further away from the nuclear periphery. However, within individual nuclei, alleles closer to the periphery are equally likely to be expressed as those further away. In other words, absolute position does not predict expression. Taken together, this suggests that whilst stochastic activation can cause subtle shifts in localisation for this locus, there is no dramatic relocation of alleles upon gene activation. Our results suggest that transcriptional activity, rather than the parent-of-origin, defines subnuclear localisation at an endogenous imprinted domain.
Assuntos
Proteínas de Ligação ao Cálcio , Impressão Genômica , Iodeto Peroxidase , Proteínas de Membrana , Alelos , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Expressão Gênica , Impressão Genômica/genética , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , PaisRESUMO
Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.
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BACKGROUND: Prior studies using aggregated data suggest that better care coordination is associated with higher performance on measures of clinical care process; it is unclear whether this relationship reflects care coordination activities of health plans or physician practices. OBJECTIVE: Estimate within-plan relationships between beneficiary-reported care coordination measures and HEDIS measures of clinical process for the same individuals. DESIGN: Mixed-effect regression models in cross-sectional data. PARTICIPANTS: 2013 Medicare Advantage CAHPS respondents (n=152,069) with care coordination items linked to independently collected HEDIS data on clinical processes. MAIN MEASURES: Care coordination measures assessed follow-up, whether doctors had medical records during visits, whether doctors discussed medicines being taken, how informed doctors seemed about specialist care, and help received with managing care among different providers. HEDIS measures included mammography, colorectal cancer screening, cardiovascular LDL-C screening, controlling blood pressure, 5 diabetes care measures (LDL-C screening, retinal eye exam, nephropathy, blood sugar/HbA1c <9%, LCL-C<100 mg/dL), glaucoma screening in older adults, BMI assessment, osteoporosis management for women with a fracture, and rheumatoid arthritis therapy. KEY RESULTS: For 9 of the 13 HEDIS measures, within health plans, beneficiaries who reported better care coordination also received better clinical care (p<0.05) and none of the associations went in the opposite direction; HEDIS differences between those with excellent and poor coordination exceeded 5 percentage points for 7 measures. Nine measures had positive associations (breast cancer screening, colorectal cancer screening, cardiovascular care LDL-C screening, 4 of 5 diabetes care measures, osteoporosis management, and rheumatoid arthritis therapy). CONCLUSIONS: Within health plans, beneficiaries who report better care coordination also received higher-quality clinical care, particularly for care processes that entail organizing patient care activities and sharing information among different healthcare providers. These results extend prior research showing that health plans with better beneficiary-reported care coordination achieved higher HEDIS performance scores.
Assuntos
Medicare Part C , Idoso , Estudos Transversais , Feminino , Humanos , Assistência ao Paciente , Medidas de Resultados Relatados pelo Paciente , Qualidade da Assistência à Saúde , Estados Unidos/epidemiologiaRESUMO
Genomic imprinting is a process that causes genes to be expressed according to their parental origin. Imprinting appears to have evolved gradually in two of the three mammalian subclasses, with no imprinted genes yet identified in prototheria and only six found to be imprinted in marsupials to date. By interrogating the genomes of eutherian suborders, we determine that imprinting evolved at the majority of eutherian specific genes before the eutherian radiation. Theories considering the evolution of imprinting often relate to resource allocation and recently consider maternal-offspring interactions more generally, which, in marsupials, places a greater emphasis on lactation. In eutherians, the imprint memory is retained at least in part by zinc finger protein 57 (ZFP57), a Kruppel associated box (KRAB) zinc finger protein that binds specifically to methylated imprinting control regions. Some imprints are less dependent on ZFP57invivo and it may be no coincidence that these are the imprints that are found in marsupials. Because marsupials lack ZFP57, this suggests another more ancestral protein evolved to regulate imprints in non-eutherian subclasses, and contributes to imprinting control in eutherians. Hence, understanding the mechanisms acting at imprinting control regions across mammals has the potential to provide valuable insights into our understanding of the origins and evolution of genomic imprinting.
Assuntos
Metilação de DNA , Impressão Genômica , Mamíferos/genética , Animais , Evolução Molecular , Marsupiais/genéticaRESUMO
The paternally expressed imprinted retrotransposon-like 1 (Rtl1) is a retrotransposon-derived gene that has evolved a function in eutherian placentation. Seven miRNAs, including miR-127, are processed from a maternally expressed antisense Rtl1 transcript (Rtl1as) and regulate Rtl1 levels through RNAi-mediated post-transcriptional degradation. To determine the relative functional role of Rtl1as miRNAs in Rtl1 dosage, we generated a mouse specifically deleted for miR-127. The miR-127 knockout mice exhibit placentomegaly with specific defects within the labyrinthine zone involved in maternal-fetal nutrient transfer. Although fetal weight is unaltered, specific Rtl1 transcripts and protein levels are increased in both the fetus and placenta. Phenotypic analysis of single (ΔmiR-127/Rtl1 or miR-127/ΔRtl1) and double (ΔmiR-127/ΔRtl1) heterozygous miR-127- and Rtl1-deficient mice indicate that Rtl1 is the main target gene of miR-127 in placental development. Our results demonstrate that miR-127 is an essential regulator of Rtl1, mediated by a trans-homologue interaction between reciprocally imprinted genes on the maternally and paternally inherited chromosomes.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/metabolismo , Placenta/fisiologia , Proteínas da Gravidez/metabolismo , Animais , Cromossomos/metabolismo , Cromossomos/ultraestrutura , Cruzamentos Genéticos , Éxons , Feminino , Deleção de Genes , Impressão Genômica , Heterozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Família Multigênica , Fenótipo , Placenta/metabolismo , Placentação/genética , Gravidez , Interferência de RNARESUMO
Genomic imprinting is an epigenetic process causing expression of a subset of genes in a parent-of-origin-specific manner. Among vertebrates, only therian mammals have been demonstrated to imprint, indicating that placentation and imprinting arose at similar time points in evolution and that imprinting may be involved in key mammal-specific processes. However, although several theories have been posited to explain the evolution of imprinting, each has shortcomings and none fully explains the wide variety of genes regulated by imprinting. In this review, we catalog the phenotypes associated with genetic mutation and overexpression at particular imprinted loci in order to consider the wide impact of imprinted genes on development. In addition to the well-described roles of imprinted genes in prenatal growth and placentation, more recent data emphasize that imprinted genes are critical for specific aspects of postnatal mammalian development involving adaptive processes, metabolism, and behavior.
Assuntos
Genoma , Impressão Genômica/genética , Mutação/genética , Animais , Cromossomos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Modelos Animais , FenótipoRESUMO
Clustered imprinted genes are regulated by differentially methylated imprinting control regions (ICRs) that affect gene activity and repression in cis over a large region. Although a primary imprint signal for each of these clusters is DNA methylation, different mechanisms are used to establish and maintain these marks. The majority of ICRs are methylated in the maternal germline and are usually promoters for antisense transcripts whose elongation is associated with imprinting control in the domain. In contrast, ICRs methylated in the paternal germline do not appear to act as promoters and are located between genes. At least one, at the Igf2/H19 locus, is known to function as an insulator. Analysis of ICRs suggests that maternal and paternal methylation imprints function in distinct ways.
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Regulação da Expressão Gênica , Impressão Genômica , Família Multigênica , Animais , Metilação de DNA , Humanos , Regiões Promotoras GenéticasRESUMO
The roots of Salvia miltiorrhiza ("Danshen") are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke. Extracts of S. miltiorrhiza roots in the formulation "Compound Danshen Dripping Pill" are undergoing clinical trials in the United States. To date, the active components of this material have not been conclusively identified. We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones. K(i) values in the nM range were determined for inhibition of both the liver and intestinal CEs. As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed. Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material and that drug hydrolysis is significantly reduced. Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts. It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents and that patients should be warned of the potential drug-drug interaction that may occur with this material.
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Abietanos/isolamento & purificação , Abietanos/farmacologia , Camptotecina/análogos & derivados , Carboxilesterase/antagonistas & inibidores , Medicamentos de Ervas Chinesas/farmacologia , Fenantrolinas/farmacologia , Salvia miltiorrhiza/química , Abietanos/química , Abietanos/farmacocinética , Algoritmos , Camptotecina/química , Camptotecina/farmacologia , Ensaios Clínicos Fase I como Assunto , Interações Ervas-Drogas , Humanos , Irinotecano , Medicina Tradicional Chinesa , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
Genomic imprinting is an epigenetic process whereby genes are monoallelically expressed in a parent-of-origin-specific manner. Imprinted genes are frequently found clustered in the genome, likely illustrating their need for both shared regulatory control and functional inter-dependence. The Dlk1-Dio3 domain is one of the largest imprinted clusters. Genes in this region are involved in development, behavior, and postnatal metabolism: failure to correctly regulate the domain leads to Kagami-Ogata or Temple syndromes in humans. The region contains many of the hallmarks of other imprinted domains, such as long non-coding RNAs and parental origin-specific CTCF binding. Recent studies have shown that the Dlk1-Dio3 domain is exquisitely regulated via a bipartite imprinting control region (ICR) which functions differently on the two parental chromosomes to establish monoallelic expression. Furthermore, the Dlk1 gene displays a selective absence of imprinting in the neurogenic niche, illustrating the need for precise dosage modulation of this domain in different tissues. Here, we discuss the following: how differential epigenetic marks laid down in the gametes cause a cascade of events that leads to imprinting in the region, how this mechanism is selectively switched off in the neurogenic niche, and why studying this imprinted region has added a layer of sophistication to how we think about the hierarchical epigenetic control of genome function.
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In mouse and human, genes subjected to genomic imprinting have been shown to function in development, behavior, and post-natal adaptations. Failure to correctly imprint genes in human is associated with developmental syndromes, adaptive, and metabolic disorders during life as well as numerous forms of cancer. In recent years researchers have turned to RNA-seq technologies applied to reciprocal hybrid strains of mice to identify novel imprinted genes, causing a threefold increase in genes reported as having a parental origin-specific expression bias. The functional relevance of parental origin-specific expression bias is not fully appreciated especially since many are reported with only minimal parental bias (e.g. 51:49). Here, we present an in-depth meta-analysis of previously generated RNA-seq data and show that the methods used to generate and analyze libraries greatly influence the calling of allele-specific expression. Validation experiments show that most novel genes called with parental-origin-specific allelic bias are artefactual, with the mouse strain contributing a larger effect on expression biases than parental origin. Of the weak novel genes that do validate, most are located at the periphery of known imprinted domains, suggesting they may be affected by local allele- and tissue-specific conformation. Together these findings highlight the need for robust tools, definitions, and validation of putative imprinted genes to provide meaningful information within imprinting databases and to understand the functional and mechanistic implications of the process.
Assuntos
Perfilação da Expressão Gênica , Impressão Genômica , Humanos , Animais , Camundongos , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Alelos , Metilação de DNARESUMO
Mammalian parental imprinting represents an exquisite form of epigenetic control regulating the parent-specific monoallelic expression of genes in clusters. While imprinting perturbations are widely associated with developmental abnormalities, the intricate regional interplay between imprinted genes makes interpreting the contribution of gene dosage effects to phenotypes a challenging task. Using mouse models with distinct deletions in an intergenic region controlling imprinting across the Dlk1-Dio3 domain, we link changes in genetic and epigenetic states to allelic-expression and phenotypic outcome in vivo. This determined how hierarchical interactions between regulatory elements orchestrate robust parent-specific expression, with implications for non-imprinted gene regulation. Strikingly, flipping imprinting on the parental chromosomes by crossing genotypes of complete and partial intergenic element deletions rescues the lethality of each deletion on its own. Our work indicates that parental origin of an epigenetic state is irrelevant as long as appropriate balanced gene expression is established and maintained at imprinted loci.
Assuntos
Cromossomos , Impressão Genômica , Alelos , Animais , Metilação de DNA/genética , DNA Intergênico , Dosagem de Genes , Impressão Genômica/genética , Mamíferos/genética , CamundongosRESUMO
Genomic imprinting causes genes to be expressed or repressed depending on their parental origin. The majority of imprinted genes identified to date map in clusters and much of our knowledge of the mechanisms, function and evolution of imprinting have emerged from their analysis. The cluster of imprinted genes delineated by the delta-like homolog 1 gene and the type III iodothyronine deiodinase gene (Dlk1-Dio3) is located on distal mouse chromosome 12 and human chromosome 14. Its developmental importance is exemplified by severe phenotypes associated with altered dosage of these genes in mice and humans. The domain contains three imprinted protein-coding genes, Dlk1, Rtl1 and Dio3, expressed from the paternally inherited chromosome and several imprinted large and small noncoding RNA genes expressed from the maternally inherited homolog. Here, we discuss the function and regulation of imprinting at this domain.
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Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Iodeto Peroxidase/química , Mamíferos/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Animais , Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 14 , Regulação da Expressão Gênica , Impressão Genômica , Humanos , Iodeto Peroxidase/genética , Camundongos , Modelos Biológicos , Estrutura Terciária de ProteínaRESUMO
A comprehensive, domain-wide comparative analysis of genomic imprinting between mammals that imprint and those that do not can provide valuable information about how and why imprinting evolved. The imprinting status, DNA methylation, and genomic landscape of the Dlk1-Dio3 cluster were determined in eutherian, metatherian, and prototherian mammals including tammar wallaby and platypus. Imprinting across the whole domain evolved after the divergence of eutherian from marsupial mammals and in eutherians is under strong purifying selection. The marsupial locus at 1.6 megabases, is double that of eutherians due to the accumulation of LINE repeats. Comparative sequence analysis of the domain in seven vertebrates determined evolutionary conserved regions common to particular sub-groups and to all vertebrates. The emergence of Dlk1-Dio3 imprinting in eutherians has occurred on the maternally inherited chromosome and is associated with region-specific resistance to expansion by repetitive elements and the local introduction of noncoding transcripts including microRNAs and C/D small nucleolar RNAs. A recent mammal-specific retrotransposition event led to the formation of a completely new gene only in the eutherian domain, which may have driven imprinting at the cluster.
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Evolução Molecular , Impressão Genômica/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Iodeto Peroxidase/genética , Proteínas de Membrana/genética , Proteínas da Gravidez/genética , Animais , Proteínas de Ligação ao Cálcio , Sequência Conservada , Genoma , Humanos , Mamíferos , FilogeniaRESUMO
Carboxylesterases (CE) are ubiquitous enzymes found in both human and animal tissues and are responsible for the metabolism of xenobiotics. This includes numerous natural products, as well as a many clinically used drugs. Hence, the activity of these agents is likely dependent upon the levels and location of CE expression. We have recently identified benzil is a potent inhibitor of mammalian CEs, and in this study, we have assessed the ability of analogues of this compound to inhibit these enzymes. Three different classes of molecules were assayed: one containing different atoms vicinal to the carbonyl carbon atom and the benzene ring [PhXC(O)C(O)XPh, where X=CH2, CHBr, N, S, or O]; a second containing a panel of alkyl 1,2-diones demonstrating increasing alkyl chain length; and a third consisting of a series of 1-phenyl-2-alkyl-1,2-diones. In general, with the former series of molecules, heteroatoms resulted in either loss of inhibitory potency (when X=N), or conversion of the compounds into substrates for the enzymes (when X=S or O). However, the inclusion of a brominated methylene atom resulted in potent CE inhibition. Subsequent analysis with the alkyl diones [RC(O)C(O)R, where R ranged from CH3 to C8H17] and 1-phenyl-2-alkyl-1,2-diones [PhC(O)C(O)R where R ranged from CH3 to C6H13], demonstrated that the potency of enzyme inhibition directly correlated with the hydrophobicity (clogP) of the molecules. We conclude from these studies that that the inhibitory power of these 1,2-dione derivatives depends primarily upon the hydrophobicity of the R group, but also on the electrophilicity of the carbonyl group.
Assuntos
Carboxilesterase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Animais , Carboxilesterase/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Etano/síntese química , Etano/química , Etano/farmacologia , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica MolecularRESUMO
Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P(R) enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P(S) isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P(S) isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.
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Hidrolases de Éster Carboxílico/química , Substâncias para a Guerra Química/química , Inibidores Enzimáticos/química , Compostos Organofosforados/química , Sarina/química , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Cristalização , Humanos , Hidrólise , Modelos Moleculares , Compostos Organofosforados/farmacologia , Oximas/farmacologia , Sarina/farmacologia , EstereoisomerismoRESUMO
Carboxylesterases (CES) have important roles in pesticide and drug metabolism and contribute to the clearance of ester-containing xenobiotics in mammals. Tissues with the highest levels of CES expression are the liver and small intestine. In addition to xenobiotics, CES also harness their broad substrate specificity to hydrolyze endobiotics, such as cholesteryl esters and triacylglycerols. Here, we determined if two human CES isoforms, CES1 and CES2, hydrolyze the endocannabinoids 2-arachidonoylglycerol (2AG) and anandamide (AEA), and two prostaglandin glyceryl esters (PG-Gs), which are formed by COX-mediated oxygenation of 2AG. We show that recombinant CES1 and CES2 efficiently hydrolyze 2AG to arachidonic acid (AA) but not amide-containing AEA. Steady-state kinetic parameters for CES1- and CES2-mediated 2AG hydrolysis were, respectively, kcat, 59 and 43 min(-1); Km, 49 and 46 µM; and kcat/Km, 1.2 and 0.93 µM(-1) min(-1). kcat/Km values are comparable to published values for rat monoacylglycerol lipase (MAGL)-catalyzed 2AG hydrolysis. Furthermore, we show that CES1 and CES2 also efficiently hydrolyze PGE2-G and PGF2α-G. In addition, when cultured human THP1 macrophages were treated with exogenous 2AG or PG-G (10 µM, 1 h), significant quantities of AA or PGs were detected in the culture medium; however, the ability of macrophages to metabolize these compounds was inhibited (60-80%) following treatment with paraoxon, the toxic metabolite of the insecticide parathion. Incubation of THP1 cell lysates with small-molecule inhibitors targeting CES1 (thieno[3,2-e][1]benzothiophene-4,5-dione or JZL184) significantly reduced lipid glyceryl ester hydrolase activities (40-50% for 2AG and 80-95% for PG-Gs). Immunodepletion of CES1 also markedly reduced 2AG and PG-G hydrolase activities. These results suggested that CES1 is in part responsible for the hydrolysis of 2AG and PG-Gs in THP1 cells, although it did not rule out a role for other hydrolases, especially with regard to 2AG metabolism since a substantial portion of its hydrolysis was not inactivated by the inhibitors. An enzyme (Mr 31-32 kDa) of unknown function was detected by serine hydrolase activity profiling of THP1 cells and may be a candidate. Finally, the amounts of in situ generated 2AG and PG-Gs in macrophages were enhanced by treating the cells with bioactive metabolites of OP insecticides. Collectively, the results suggest that in addition to MAGL and fatty-acid amide hydrolase (FAAH), which have both been documented to terminate endocannabinoid signaling, CES may also have a role. Furthermore, since PG-Gs have been shown to possess biological activities in their own right, CES may represent an important enzyme class that regulates their in vivo levels.
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Carboxilesterase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Inseticidas/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Paraoxon/toxicidade , Amidoidrolases/metabolismo , Ácidos Araquidônicos/metabolismo , Carboxilesterase/genética , Hidrolases de Éster Carboxílico/genética , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Endocanabinoides , Glicerídeos/metabolismo , Humanos , Hidrólise , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Espectrometria de Massas , Monócitos/imunologia , Alcamidas Poli-Insaturadas/metabolismo , Prostaglandinas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: The concept of evidence has become firmly rooted in health care, with most importance placed on the outcome of research in clinical and economic spheres. Much less emphasis is placed on the patient's contribution to evidence which remains relatively vague, of low status and often difficult to integrate with other forms of knowledge. AIM: This article proposes a concept of patient-based evidence, to complement clinical and economic forms of evidence, and demonstrates one way in which it has been operationalized. The PRIME project developed a patient evidence-base to capture the lived experience of individuals with myalgic encephalitis (ME) or chronic fatigue syndrome (CFS). DESIGN: Interviews were performed with 40 individuals with ME/CFS who varied in a range of demographic characteristics, including age, gender, and how severely affected individuals were. RESULTS: PRIME has developed a patient evidence-base which has an extensive array of experiences data to provide researchers, clinicians and others with an in-depth insight into the lived experience of ME/CFS that can be used and analysed. Data are grouped into a wide range of themes, which can be downloaded and used in a variety of ways as a source of evidence to enable understanding of the lived experience of ME/CFS and so contribute to the development of a more patient-focused research agenda in ME/CFS. CONCLUSIONS: While patient-based evidence used in the PRIME Project provides a useful start, further work is required to develop this area conceptually and methodologically, particularly in relation to how patient-based evidence can be considered alongside clinical and economic evidence.
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Síndrome de Fadiga Crônica/psicologia , Adaptação Psicológica , Adulto , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores SocioeconômicosRESUMO
BACKGROUND: Medicare beneficiaries annually select fee-for-service Medicare or a private Medicare insurance (managed care) plan; information about plan performance on quality measures can inform their decisions. Although there is drill-down information available regarding quality variation by race and ethnicity, there remains a dearth of evidence regarding the extent to which care varies by other key beneficiary characteristics, such as gender. We measured gender differences for six patient experience measures and how gender gaps differ across Medicare plans. METHODS: We used data from 300,979 respondents to the 2015-2016 Medicare Advantage Consumer Assessment of Healthcare Providers and Systems surveys. We fit case mix-adjusted linear mixed-effects models to estimate gender differences and evaluate heterogeneity in differences across health plans. RESULTS: Nationally, women's experiences were better than men's (p < .05) by 1 percentage point on measures involving interactions with administrative staff (+1.6 percentage point for customer service) and timely access to care (+1.1 percentage point for getting care quickly), but worse on a measure that may involve negotiation with physicians (getting needed care). Gender gaps varied across plans, particularly for getting care quickly and getting needed care, where plan-level differences of up to 5 to 6 percentage points were observed. CONCLUSIONS: Although the average national differences in patient experience by gender were generally small, gender gaps were larger in some health plans and for specific measures. This finding indicates opportunities for health plans with larger gender gaps to implement quality improvement efforts.
Assuntos
Medicare Part C , Idoso , Feminino , Humanos , Masculino , Programas de Assistência Gerenciada , Avaliação de Resultados da Assistência ao Paciente , Caracteres Sexuais , Fatores Sexuais , Estados UnidosRESUMO
BACKGROUND: Patients are hospitalized for disparate conditions and procedures. Patient experiences with care may depend on hospitalization type (HT). OBJECTIVES: Determine whether the contributions of patient experience composite measures to overall hospital ratings on the Hospital Consumer Assessment of Healthcare Providers and Systems Survey vary by HT. RESEARCH DESIGN: In cross-sectional observational data, we defined 24 HTs using major diagnostic category and service line (medical, surgical, or obstetrical). To assess the importance of each composite for each HT, we calculated the simultaneous partial correlations of 7 composite scores with an overall hospital rating, controlling for patient demographics. SUBJECTS: Nineteen thousand seven hundred twenty English- or Spanish-speaking adults with nonpsychiatric primary diagnoses discharged home 12/02-1/03 after an overnight inpatient stay in any of 132 general acute care hospitals in 3 states. MEASURES: Patient-reported doctor communication, nurse communication, staff responsiveness, physical environment, new medicines explained, pain control, and postdischarge information; overall 0 to 10 rating of care. RESULTS: Nurse communication was most important overall, with a 0.34 average partial correlation (range: 0.17-0.49; P < 0.05 and among the 3 most important composites for all HTs). Discharge information was least important (0.05 average partial correlation; P < 0.05 for 10 of 24 HTs). Interactions demonstrated significant (P < 0.05) variation in partial correlations by HT for 5 of 7 composites (all but responsiveness and environment), with nurse communication, doctor communication, and pain control showing the most variation (F > 2, P < 0.05). CONCLUSIONS: The importance of patient experience dimensions differs substantially and varies by HT. Quality improvement efforts should target those aspects of patient experience that matter most for each HT.
Assuntos
Comunicação , Hospitalização/estatística & dados numéricos , Satisfação do Paciente , Qualidade da Assistência à Saúde/classificação , Qualidade da Assistência à Saúde/organização & administração , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Pesquisa sobre Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Relações Enfermeiro-Paciente , Dor/tratamento farmacológico , Dor/prevenção & controle , Alta do Paciente , Educação de Pacientes como Assunto , Recursos Humanos em Hospital , Relações Médico-Paciente , Fatores Socioeconômicos , Adulto JovemRESUMO
OBJECTIVE: Spanish-preferring Medicare beneficiaries are underrepresented in national patient experience surveys. We test a method for improving their representation via higher response rates. DATA SOURCES/STUDY SETTING: 2009-2010 Medicare CAHPS surveys; Medicare population. STUDY DESIGN: We used surname and address to predict Spanish-language preference for a national sample of 177 139 beneficiaries. We randomized half of the 10 000 non-Puerto Rico beneficiaries with the highest predicted probabilities of Spanish preference (>10 percent) to bilingual mailings (intervention) and half to standard English-only mailings (control). DATA COLLECTION: Medicare CAHPS Survey data were collected through mail surveys with telephone follow-up of nonrespondents. PRINCIPAL FINDINGS: Mail response rate was higher for intervention (28.7 percent) than control (23.9 percent) (P < 0.0001); phone response rates among mail nonrespondents were similar in intervention and control arms (15.8 percent vs 15.7 percent, P = 0.90). Targeted bilingual mailings induced 6.5 percent of those who would not have responded to respond by mail and 54.0 percent of those who would have responded in English to respond in Spanish. Beneficiaries with greater Spanish probabilities showed greater increases in response rates, a higher proportion of responses in Spanish, and lower control response rates among. CONCLUSIONS: Targeted bilingual mailing of mixed-mode surveys using commonly available surname and address information can efficiently increase representation of this underrepresented group.