RESUMO
BACKGROUND: Advancements in the cystic fibrosis (CF) field have resulted in longer lifespans for individuals with CF. This has led to more responsibility for complex care regimens, frequent health care, and prescription medication utilization that are costly and may not be fully covered by health insurance. There are outstanding questions about unmet medical needs among the U.S. population with CF and how the financial burden of CF is associated with debt, housing instability, and food insecurity. METHODS: Researchers developed the CF Health Insurance Survey (CF HIS) to survey a convenience sample of people living with CF in the U.S. The sample was weighted to reflect the parameters of the 2019 Cystic Fibrosis Foundation Patient Registry Annual Data Report, and chi-square tests and multiple logistic regression models were conducted. RESULTS: A total of 1,856 CF patients in the U.S. were included in the study. Of these, 64% faced a financial burden: 55% of respondents faced debt issues, 26% housing issues, and 33% food insecurity issues. A third reported at least one unmet medical need: 24% faced unmet prescription needs, 12% delayed or shortened a hospitalization, and 10% delayed or skipped a care center visit as a result of the cost of care. CONCLUSIONS: People with CF in the U.S. experience high financial burden, which is associated with unmet medical needs. Income is the biggest risk factor for financial burden for people with CF, with people dually covered by Medicare and Medicaid particularly at risk.
Assuntos
Fibrose Cística , Medicare , Humanos , Estados Unidos/epidemiologia , Idoso , Habitação , Fibrose Cística/epidemiologia , Fibrose Cística/terapia , Instabilidade Habitacional , Acessibilidade aos Serviços de Saúde , Serviços de Saúde , Insegurança AlimentarRESUMO
Consumer cost-sharing has been shown to diminish utilization of preventive services. Recent efforts, including provisions within the Affordable Care Act, have sought to increase use of preventive care through elimination of cost-sharing for clinically indicated services. We conducted a rapid review of the literature to determine the impact of cost-share elimination on utilization of preventive services. Searches were conducted in PubMed, Scopus, and CINAHL Complete databases as well as in grey literature. A total of 35 articles were included in qualitative synthesis and findings were summarized for three clinical service categories: cancer screenings, contraceptives, and additional services. Impacts of cost-sharing elimination varied depending on clinical service, with a majority of findings showing increases in use. Studies that included socioeconomic status reported that those who were financially vulnerable incurred substantial increases in utilization. Future investigations on additional clinical services are warranted as is research to better elucidate populations who most benefit from cost-sharing elimination.
Assuntos
Custo Compartilhado de Seguro , Patient Protection and Affordable Care Act , Bases de Dados Factuais , Detecção Precoce de Câncer , Humanos , Serviços Preventivos de Saúde , Estados UnidosRESUMO
BACKGROUND: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models. METHODS: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats. RESULTS: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued. CONCLUSION: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.
Assuntos
Injúria Renal Aguda/prevenção & controle , Anticoagulantes/farmacologia , Heparina/análogos & derivados , Heparina/farmacologia , Rim/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Proteoglicanas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/sangue , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Proteínas de Fase Aguda , Angiopoietina-2/sangue , Animais , Anticoagulantes/farmacocinética , Biomarcadores/sangue , Biotransformação , Coagulação Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Quimioterapia Combinada , Heparina/farmacocinética , Ácido Hialurônico/sangue , Imunidade Inata/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lipocalina-2 , Lipocalinas/sangue , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacocinética , Testes de Função Plaquetária , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteoglicanas/farmacocinética , Tempo de Protrombina , Proteínas Proto-Oncogênicas/sangue , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Sindecana-1/sangue , Distribuição TecidualRESUMO
Complement protein C1q is induced in the brain in response to a variety of neuronal injuries, including Alzheimer disease (AD), and blocks fibrillar amyloid-ß (fAß) neurotoxicity in vitro. Here, we show that C1q protects immature and mature primary neurons against fAß toxicity, and we report for the first time that C1q prevents toxicity induced by oligomeric forms of amyloid-ß (Aß). Gene expression analysis reveals C1q-activated phosphorylated cAMP-response element-binding protein and AP-1, two transcription factors associated with neuronal survival and neurite outgrowth, and increased LRP1B and G protein-coupled receptor 6(GPR6) expression in fAß-injured neurons. Silencing of cAMP-response element-binding protein, LRP1B or GPR6 expression inhibited C1q-mediated neuroprotection from fAß-induced injury. In addition, C1q altered the association of oligomeric Aß and fAß with neurons. In vivo, increased hippocampal expression of C1q, LRP1B, and GPR6 is observed as early as 2 months of age in the 3 × Tg mouse model of AD, whereas no such induction of LRP1B and GPR6 was seen in C1q-deficient AD mice. In contrast, expression of C1r and C1s, proteases required to activate the classical complement pathway, and C3 showed a significant age-dependent increase only after 10-13 months of age when Aß plaques start to accumulate in this AD model. Thus, our results identify pathways by which C1q, up-regulated in vivo early in response to injury without the coordinate induction of other complement components, can induce a program of gene expression that promotes neuroprotection and thus may provide protection against Aß in preclinical stages of AD and other neurodegenerative processes.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Complemento C1q/metabolismo , Regulação da Expressão Gênica , Receptores Acoplados a Proteínas G/fisiologia , Receptores de LDL/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Modelos Biológicos , Doenças Neurodegenerativas/metabolismo , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. In this study, we developed an autologous system using primary human lymphocytes and human monocyte-derived macrophages (HMDMs) to characterize the effect of C1q on macrophage gene expression profiles during the uptake of apoptotic cells. C1q bound to autologous apoptotic lymphocytes modulated expression of genes associated with JAK/STAT signaling, chemotaxis, immunoregulation, and NLRP3 inflammasome activation in LPS-stimulated HMDMs. Specifically, C1q sequentially induced type I IFNs, IL-27, and IL-10 in LPS-stimulated HMDMs and IL-27 in HMDMs when incubated with apoptotic lymphocyte conditioned media. Coincubation with C1q tails prevented the induction of type I IFNs and IL-27 in a dose-dependent manner, and neutralization of type I IFNs partially prevented IL-27 induction by C1q. Finally, C1q decreased procaspase-1 cleavage and caspase-1-dependent cleavage of IL-1ß suggesting a potent inhibitory effect of C1q on inflammasome activation. These results identify specific molecular pathways induced by C1q to suppress macrophage inflammation and provide potential therapeutic targets to control macrophage polarization and thus inflammation and autoimmunity.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Polaridade Celular/imunologia , Complemento C1q/fisiologia , Inflamassomos/imunologia , Macrófagos/imunologia , Caspase 1/metabolismo , Inibidores de Caspase , Adesão Celular/imunologia , Células Cultivadas , Quimiocinas/biossíntese , Citocinas/biossíntese , Humanos , Inflamassomos/antagonistas & inibidores , Interleucina-1beta/metabolismo , Lipopolissacarídeos/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Macrófagos/citologia , Macrófagos/metabolismoRESUMO
RATIONALE: The short-term prognosis of pulmonary embolism (PE) depends on hemodynamic status and underlying disease. The prognostic value of right ventricular dysfunction and injury is less well established. OBJECTIVES: To evaluate prognostic factors of PE in a multicenter prospective cohort study. METHODS: Echocardiography, brain natriuretic peptide (BNP), N-terminal-proBNP and cardiac troponin I measurements were done on admission of 570 consecutive patients with an acute PE. A predictive model was based on independent predictors of 30-day adverse events defined as death, secondary cardiogenic shock, or recurrent venous thromboembolism. MEASUREMENTS AND MAIN RESULTS: At 30 days, 42 patients (7.4%; 95% confidence interval [CI], 5.5-9.8%) had adverse events. On multivariate analysis, altered mental state (odds ratio [OR] 6.8; 95% confidence interval [CI], 2.0-23.3), shock on admission (OR 2.8; 95% CI, 1.1-7.5), cancer (OR 2.9; 95% CI, 1.2-6.9), BNP (OR 1.3 for an increase of 250 ng/L; 95% CI, 1.1-1.6) and right to left ventricle diameter ratio (OR 1.2 for an increase of 0.1; 95% CI, 1.1-1.4) were associated with 30-days of adverse events. The predictive performance of the model was good (area under receiver operating characteristics curve 0.84 [95% CI, 0.78-0.90]), making it possible to develop a bedside prognostic score. CONCLUSIONS: BNP and echocardiography may be useful determinants of the short-term outcome for patients with PE, together with clinical findings. Patients with PE can be stratified according to the initial risk of adverse outcome, using a simple score based on clinical, echocardiographic, and biochemical variables.
Assuntos
Embolia Pulmonar/genética , Embolia Pulmonar/fisiopatologia , Doença Aguda , Idoso , Causas de Morte , Estudos de Coortes , Ecocardiografia , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Análise Multivariada , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Estudos Prospectivos , Recidiva , Medição de Risco , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Taxa de Sobrevida , Troponina I/sangue , Tromboembolia Venosa/mortalidade , Tromboembolia Venosa/fisiopatologiaRESUMO
BACKGROUND: Arterial blood gases are essential for the diagnostic and therapeutic management of severely ill patients. The pre-analytic phase is crucial to the quality and interpretation of the results. Whole blood specimens used for blood gas analysis must be thoroughly mixed prior to analysis. Producing a homogeneous sample is important to obtain accurate results. The availability of a new system able to automate the standardization of the sample mixing would be a way to improve this step. We evaluated the quality of automatic mixing with the use of SafePICO syringes and ABL 825 FLEX blood-gas analyser. METHODS: Quantitative measurements of total hemoglobin and potassium were performed on ABL 825 FLEX from 216 whole blood specimens collected in SafePICO syringes and were compared with those obtained with LH 750 for hemoglobin and LX 20 for potassium. RESULTS: Quantitative results showed excellent agreement with a reference analyser for the analytes with correlation coefficients greater than 0.97. No bias was observed for hemoglobin and the small difference observed for potassium is not clinically significant and was not due to hemolysis but to the differences between the methods. CONCLUSIONS: ABL 825 FLEX produces a homogeneous specimen which minimizes the pre-analytical errors manipulator dependent.
Assuntos
Automação/métodos , Gasometria/instrumentação , Magnetismo/métodos , Seringas , Intervalos de Confiança , Hemoglobinas/análise , Humanos , Análise de RegressãoRESUMO
Converging studies have shown that M1 and M2 macrophages are functionally polarized in response to microorganisms and host mediators. Gene expression profiling of macrophages reveals that various Gram-negative and Gram-positive bacteria induce the transcriptional activity of a "common host response," which includes genes belonging to the M1 program. However, excessive or prolonged M1 polarization can lead to tissue injury and contribute to pathogenesis. The so-called M2 macrophages play a critical role in the resolution of inflammation by producing anti-inflammatory mediators. These M2 cells cover a continuum of cells with different phenotypic and functional properties. In addition, some bacterial pathogens induce specific M2 programs in macrophages. In this review, we discuss the relevance of macrophage polarization in three domains of infectious diseases: resistance to infection, infectious pathogenesis, and chronic evolution of infectious diseases.
Assuntos
Regulação da Expressão Gênica/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/patologia , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Diferenciação Celular/imunologia , Infecções por Bactérias Gram-Negativas/prevenção & controle , Infecções por Bactérias Gram-Positivas/prevenção & controle , Humanos , Imunidade Inata , Macrófagos/classificação , Macrófagos/microbiologiaRESUMO
Patients with valvulopathy have the highest risk to develop infective endocarditis (IE), although the relationship between valvulopathy and IE is not clearly understood. Q fever endocarditis, an IE due to Coxiella burnetii, is accompanied by immune impairment. Patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes, as determined by the measurement of active caspases and nucleosome determination. The binding of apoptotic cells to monocytes and macrophages, the hosts of C. burnetii, may be responsible for the immune impairment observed in Q fever endocarditis. Apoptotic lymphocytes (AL) increased C. burnetii replication in monocytes and monocyte-derived macrophages in a cell-contact dependent manner, as determined by quantitative PCR and immunofluorescence. AL binding induced a M2 program in monocytes and macrophages stimulated with C. burnetii as determined by a cDNA chip containing 440 arrayed sequences and functional tests, but this program was in part different in monocytes and macrophages. While monocytes that had bound AL released high levels of IL-10 and IL-6, low levels of TNF and increased CD14 expression, macrophages that had bound AL released high levels of TGF-beta1 and expressed mannose receptor. The neutralization of IL-10 and TGF-beta1 prevented the replication of C. burnetii due to the binding of AL, suggesting that they were critically involved in bacterial replication. In contrast, the binding of necrotic cells to monocytes and macrophages led to C. burnetii killing and typical M1 polarization. Finally, interferon-gamma corrected the immune deactivation induced by apoptotic cells: it prevented the replication of C. burnetii and re-directed monocytes and macrophages toward a M1 program, which was deleterious for C. burnetii. We suggest that leukocyte apoptosis associated with valvulopathy may be critical for the pathogenesis of Q fever endocarditis by deactivating immune cells and creating a favorable environment for bacterial persistence.
Assuntos
Apoptose/fisiologia , Coxiella burnetii/fisiologia , Endocardite Bacteriana/microbiologia , Leucócitos Mononucleares/microbiologia , Macrófagos/microbiologia , Febre Q/microbiologia , Adulto , Idoso , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Endocardite Bacteriana/imunologia , Endocardite Bacteriana/patologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Febre Q/imunologia , Febre Q/patologiaRESUMO
Coxiella burnetii is an obligate intracellular bacterium, responsible for Q fever, which survives in macrophages by interfering with their microbicidal competence. As functional polarization of macrophages is critical for their microbicidal activity, we studied the activation program of monocyte-derived macrophages (MDM) stimulated with C. burnetii. This program was markedly distinct from that induced by lipopolysaccharides (LPS), a canonical inducer of M1 polarization. Indeed, C. burnetii up-regulated the expression of genes associated with M2 polarization, including TGF-beta1, IL-1 receptor antagonist (IL-1ra), CCL18, the mannose receptor and arginase-1, and only up-regulated the expression of two genes associated with M1 polarization, namely IL-6 and CXCL8. In contrast, C. burnetii down-regulated the expression of genes associated with M1 polarization such as TNF, CD80, CCR7 and TLR-2. Functional analyses showed that C. burnetii-stimulated MDM produced high levels of TGF-beta1 and CCL18, and expressed the mannose receptor and arginase-1, the latter being associated with the prevention of nitric oxide production by MDM. Finally, C. burnetii induced the release of IL-6 and CXCL8 at a lower level than LPS-stimulated MDM. Our results suggest that C. burnetii stimulated an atypical M2 activation program that may account for the persistence of C. burnetii in macrophages.
Assuntos
Coxiella burnetii/imunologia , Macrófagos/imunologia , Febre Q/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/imunologia , Transcrição Gênica/genéticaRESUMO
Respiratory syncytial viruses (RSV) are one of the most important respiratory pathogens of humans and cattle, and there is currently no safe and effective vaccine prophylaxis. In this study, we designed two codon-optimized plasmids encoding the bovine RSV fusion (F) and nucleocapsid (N) proteins and assessed their immunogenicity in young calves. Two administrations of both plasmids elicited low antibody levels but primed a strong cell-mediated immunity characterized by lymphoproliferative response and gamma interferon production in vitro and in vivo. Interestingly, this strong cellular response drastically reduced viral replication, clinical signs, and pulmonary lesions after a highly virulent challenge. Moreover, calves that were further vaccinated with a killed-virus vaccine developed high levels of neutralizing antibody and were fully protected following challenge. These results indicate that DNA vaccination could be a promising alternative to the classical vaccines against RSV in cattle and could therefore open perspectives for vaccinating young infants.
Assuntos
Doenças dos Bovinos/prevenção & controle , Proteínas do Nucleocapsídeo/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/veterinária , Vírus Sincicial Respiratório Bovino/imunologia , Vacinas de DNA/imunologia , Proteínas Virais de Fusão/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Células COS , Bovinos , Doenças dos Bovinos/genética , Doenças dos Bovinos/imunologia , Chlorocebus aethiops , Imunidade Celular/efeitos dos fármacos , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/genética , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Bovino/genética , Vacinas de DNA/genética , Vacinas de DNA/farmacologia , Células Vero , Proteínas Virais de Fusão/genética , Vacinas Virais/farmacologiaRESUMO
Multidimensional fingerprinting (MDF) utilizes measurable peptide characteristics to identify proteins. In this study, 3-D fingerprinting, namely, parent protein molecular weight, peptide mass, and peptide retention time on RPLC, is used to identify 331 differentially expressed proteins between normal and human colon cancer plasma membrane samples. A false discovery rate (FDR) procedure is introduced to evaluate the performance of MDF on the colon cancer dataset. This evaluation establishes a false protein identification rate below 15% for this dataset. Western blot analysis is performed to validate the differential expression of the MDF-identified protein VDAC1 on the original tissue samples. The limits of MDF are further assessed by a simulation study where key parameters such as database size, query size, and mass accuracy are varied. The results of this simulation study demonstrate that fingerprinting with three dimensions yields low FDR values even for large queries on the complete human proteome without the need for prior peptide sequencing by tandem mass spectrometry. Specifically, when mass accuracy is 10â ppm or lower, full human proteome searches can achieve FDR values of 10% or less.
RESUMO
The interpretation of loss of heterozygosity (LOH) in cancers is complicated as genes that map to LOH regions may be transcriptionally active (Xa) or inactive (Xi) due to X chromosome inactivation (XCI). We have analyzed the chromosome X transcriptome in four epithelial ovarian cancer (EOC) cell lines (TOV21G, TOV81D, TOV112D, and OV90) and 12 primary cultures of normal ovarian surface epithelial (NOSE) cells in relation to chromosome X integrity. Two-way comparative analysis using HuGeneFL Affymetrix GeneChips of TOV21G, TOV81D and OV90 relative to the NOSE samples was highly correlated (> 89%) in contrast to that of TOV112D (56-69%). TOV112D, followed by TOV21G, exhibited the largest number of up-regulated genes. XIST expression by RT-PCR was not detectable in TOV112D or TOV21G. Allele-specific transcription by cDNA sequence analysis of genes known to be subjected to XCI revealed maintenance of XCI in TOV81D and OV90, but not TOV21G. Biallelic expression could not be assessed in TOV112D due to reduction to hemizygosity of chromosome X. Chromosome X rearrangements were observed in FISH analysis of TOV112D and TOV21G, and both of these EOC cell lines were negative for Barr body analysis. The differentially expressed genes did not appear to map to any particular region of the X chromosome in any EOC cell line. The absence of XIST expression is consistent with Barr body loss in TOV112D and TOV21G. The combined evidence is consistent with two proposed mechanisms to account for absence of Xi in female cancers: Xi loss followed by Xa duplication (exemplified by TOV112D) and transcriptional reactivation of Xi (exemplified by TOV21G). Despite an alteration in XIST expression and differences in allelic content in the EOC cell lines, the chromosome X transcriptome was modified modestly when compared with that of NOSE samples.