RESUMEN
Poly(styrenyl acetal trehalose) (pSAT), composed of trehalose side chains linked to a polystyrene backbone via acetals, stabilizes a variety of proteins and enzymes against fluctuations in temperature. A promising application of pSAT is conjugation of the polymer to therapeutic proteins to reduce renal clearance. To explore this possibility, the safety of the polymer was first studied. Investigation of acute toxicity of pSAT in mice showed that there were no adverse effects of the polymer at a high (10 mg/kg) concentration. The immune response (antipolymer antibody and cytokine production) in mice was also studied. No significant antipolymer IgG was detected for pSAT, and only a transient and low level of IgM was elicited. pSAT was also safe in terms of cytokine response. The polymer was then conjugated to a granulocyte colony stimulating factor (GCSF), a therapeutic protein that is approved by the Federal Drug Administration, in order to study the biodistribution of a pSAT conjugate. A site-selective, two-step synthesis approach was developed for efficient conjugate preparation for the biodistribution study resulting in 90% conjugation efficiency. The organ distribution of GCSF-pSAT was measured by positron emission tomography and compared to controls GCSF and GCSF-poly(ethylene glycol), which confirmed that the trehalose polymer conjugate improved the in vivo half-life of the protein by reducing renal clearance. These findings suggest that trehalose styrenyl polymers are promising for use in therapeutic protein-polymer conjugates for reduced renal clearance of the biomolecule.
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Acetales , Trehalosa , Animales , Factor Estimulante de Colonias de Granulocitos , Ratones , Polímeros/química , Proteínas/química , Distribución Tisular , Trehalosa/químicaRESUMEN
Five colleges and universities in Upstate New York, United States, created the 'Route-90 Collaborative' to support faculty implementing the Institute of Medicine's (IOM) Framework for Educating Health Professionals to Address the Social Determinants of Health. The two courses described herein used a flipped classroom approach in which students from 14 different nations were responsible for facilitating individual classes. This descriptive study used an educational intervention in two interprofessional courses - reproductive health and global health - based on the IOM Framework into two courses. The evaluation used quantitative and open-ended text response data from students. Course evaluations indicated the students found the courses helped them to learn more about health issues and service delivery in various countries, expand their knowledge base on sociocultural and ecological influences on health care, and broaden their perspectives on various health topics so they will be able to provide higher quality healthcare. Although this is the first effort of our Collaborative to implement the Framework, given the student feedback, we believe implementing the Framework in various courses has the potential to enhance healthcare service delivery and reduce the negative impact of social determinants of health.
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Empleos en Salud/educación , Relaciones Interprofesionales , Grupo Paritario , Determinantes Sociales de la Salud , Enseñanza/organización & administración , Competencia Clínica , Conducta Cooperativa , Curriculum , Conocimientos, Actitudes y Práctica en Salud , Disparidades en el Estado de Salud , Humanos , New York , Proyectos Piloto , Factores SocioeconómicosRESUMEN
Dental caries is the most common chronic disease of childhood with approximately 25% of children from low-income families entering kindergarten without ever having seen a dentist ( Larsen, Larsen, Handwerker, Kim, & Rosenthal, 2009 ). Youth, poverty, and race are characteristics of populations susceptible to oral disease (Dye, Xianfen, & Thorton-Evans, 2012). Services delivering oral health care to underserved populations are referred to as dental safety-net clinics. This article explores the impact of the dental safety-net on improving access to oral health care for underserved children in the United States.
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Atención Dental para Niños , Poblaciones Vulnerables , Niño , Atención Dental para Niños/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Humanos , Proveedores de Redes de Seguridad/organización & administración , Estados Unidos/epidemiología , Poblaciones Vulnerables/estadística & datos numéricosRESUMEN
We have identified a CD8âºCXCR5⺠T cell that prevents the development of oviduct dilation following C. muridarum genital infection. Phenotypic studies show that CD8âºCXCR5⺠cells express markers of T regulatory cells (FoxP3, CD25, and GITR) but do not express a necessary component of cytotoxic cells (perforin). Cxcr5â»/â» mice have significantly lower numbers of CD8⺠cells and lack the CD8âºCXCR5⺠population while the total number of CD4⺠cells is equivalent between mouse strains. The transfer of CD8⺠splenocytes from WT mice reduces the oviduct dilation seen in Cxcr5â»/â» mice following C. muridarum infection. Future studies will investigate the mechanism by which this cell type regulates genital tract pathology.
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Linfocitos T CD8-positivos/metabolismo , Infecciones por Chlamydia/inmunología , Chlamydia muridarum , Receptores CXCR5/metabolismo , Infecciones del Sistema Genital/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Chlamydia/patología , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Infecciones del Sistema Genital/patologíaRESUMEN
OBJECTIVE: This study aims to eliminate Mycoplasma spp. contamination from laboratory stocks of Chlamydia spp. by in vivo passage or by plaque assay. RESULTS: We have described two methods of eliminating Mycoplasma contamination from Chlamydia laboratory stocks. We conclude that Mycoplasma species commonly contaminating chlamydial stocks do not survive passage in mice. Chlamydia may also be derived Mycoplasma-free by plaque assay.
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Chlamydia , Técnicas Genéticas , Técnicas Microbiológicas/métodos , Mycoplasma , Animales , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVES: In the United States, minimum standards for quality control (QC) are specified in federal law under the Clinical Laboratory Improvement Amendment and its revisions. Beyond meeting this required standard, laboratories have flexibility to determine their overall QC program. METHODS: We surveyed chemistry and immunochemistry QC procedures at 21 clinical laboratories within leading academic medical centers to assess if standardized QC practices exist for chemistry and immunochemistry testing. RESULTS: We observed significant variation and unexpected similarities in practice across laboratories, including QC frequency, cutoffs, number of levels analyzed, and other features. CONCLUSIONS: This variation in practice indicates an opportunity exists to establish an evidence-based approach to QC that can be generalized across institutions.
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Centros Médicos Académicos/normas , Química Clínica/normas , Servicios de Laboratorio Clínico/normas , Inmunoquímica/normas , Control de Calidad , Humanos , Laboratorios/normas , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Chlamydiae are bacterial pathogens which have evolved efficient strategies to enter, replicate, and survive inside host epithelial cells, resulting in acute and chronic diseases in humans and other animals. Several candidate molecules in the host receptor complex have been identified, but the precise mechanisms of infection have not been elucidated. Epithelial membrane protein-2 (EMP2), a 4-transmembrane protein, is highly expressed in epithelial cells in sites of chlamydial infections. Here we show that infectivity of the Chlamydia muridarum (MoPn) is associated with host cellular expression of EMP2 in multiple cell lines. Recombinant knockdown of EMP2 impairs infectivity, whereas infectivity is augmented in cells recombinantly modified to over-express EMP2. An epithelial cell line without native expression of EMP2 is relatively resistant to MoPn infection, whereas infectivity is markedly increased by recombinant expression of EMP2 in that cell line. Blockade of surface EMP2 using a specific anti-EMP2 antibody significantly reduces chlamydial infection efficiency. In addition, MoPn infectivity as measured in the EMP2 overexpressing cell line is not heparin-dependent, suggesting a possible role for EMP2 in the non-reversible phase of early infection. These findings identify EMP2 as a candidate host protein involved in infection of C. muridarum (MoPn).
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Chlamydia muridarum/patogenicidad , Células Epiteliales/metabolismo , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Secuencia de Aminoácidos , Línea Celular , Células Epiteliales/inmunología , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Datos de Secuencia Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
CXCR3 is a chemokine receptor expressed on a wide range of leukocytes, and it is involved in leukocyte migration throughout the blood and lymphatics. Specifically, CXCR3 is required for lymphocyte homing to the genital mucosa. When compared to wild type (WT) mice, CXCR3 deficiency (CXCR3-/-) mice infected with Chlamydia muridarum (C. muridarum) did not display impaired clearance and resolution of infection. However, they possessed significantly higher bacterial burden and lower levels of IFN-γ-producing TH1 cells. The knockouts also demonstrated a significant decrease in the level of activated conventional dendritic cells in the GT, ultimately leading to the decrease in activated TH1 cells. In addition, few activated plasmacytoid dendritic cells, which possess an inflammatory phenotype, were found in the lymph node of infected mice. This reduction in pDCs may be responsible for the decrease in neutrophils, which are acute inflammatory cells, in the CXCR3-/- mice. Due to the significantly reduced level of acute inflammation, these mice also possess a decrease in dilation and pathology in the oviduct. This demonstrates that the CXCR3-/- mice possess the ability to clear C. muridarum infections, but they do so without the increased inflammation and pathology in the GT.
RESUMEN
Requisite leachables testing of pharmaceutical products is commonly conducted with pre-defined analytical methods on a subset of materials intended to be representative of the marketed product. Throughout product development, leachables may occasionally be detected in other methods not specifically intended for monitoring such impurities. We have identified two leachables, ethyl 4-ethoxybenzoate (E4E) and 2,6-di(t-butyl)-4-hydroxy-4-methyl-2,5-cyclohexadien-1-one (BHT-OH) in a low concentration product stored in prefilled syringes (PFS). The leachables were initially detected by size exclusion chromatography (SEC) as late-eluting impurity peaks. Syringe component extraction studies indicated that the impurities were related to the syringe stoppers. Positive identification of E4E was accomplished by reversed phase liquid chromatography- tandem mass spectrometry (RPLC-MS/MS). Positive identification of BHT-OH required RPLC-solid phase extraction-cryoflow NMR (RPLC-SPE-NMR), as initial RPLC-MS/MS investigations were unsuccessful in elucidating the structure. We focus specifically on the efforts required to identify the leachables, and the fortuitous mixed mode separation mechanism and low concentration nature of the product, which were the main factors contributing to the unlikely detection of the leachables by SEC. We note that our investigations were conducted independently of formal leachables and extractables (L&E) studies and we discuss challenges with designing and conducting such studies in a manner that captures the comprehensive L&E profile of a product.
Asunto(s)
Cromatografía en Gel/métodos , Cromatografía de Fase Inversa/métodos , Contaminación de Medicamentos , Embalaje de Medicamentos/instrumentación , Jeringas , Espectrometría de Masas en Tándem/métodos , Embalaje de Medicamentos/métodos , Espectroscopía de Resonancia Magnética/métodosRESUMEN
BACKGROUND: An estimated 4% of hospital admissions acquired healthcare-associated infections (HAIs) and accounted for $9.8 (USD) billion in direct cost during 2011. In 2010, nearly 140 000 of the 3.5 million potentially preventable hospitalizations (PPHs) may have acquired an HAI. There is a knowledge gap regarding the co-occurrence of these events. AIMS: To estimate the period occurrences and likelihood of acquiring an HAI for the PPH population. METHODS: Retrospective, cross-sectional study using logistic regression analysis of 2011 Texas Inpatient Discharge Public Use Data File including 2.6 million admissions from 576 acute care hospitals. Agency for Healthcare Research and Quality Prevention Quality Indicator software identified PPH, and existing administrative data identification methodologies were refined for Clostridium difficile infection, central line-associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia. Odds of acquiring HAIs when admitted with PPH were adjusted for demographic, health status, hospital, and community characteristics. FINDINGS: We identified 272 923 PPH, 14 219 HAI, and 986 admissions with PPH and HAI. Odds of acquiring an HAI for diabetic patients admitted for lower extremity amputation demonstrated significantly increased odds ratio of 2.9 (95% confidence interval: 2.16-3.91) for Clostridium difficile infection. Other PPH patients had lower odds of acquiring HAI compared to non-PPH patients, and results were frequently significant. CONCLUSIONS: Clinical implications include increased risk of HAI among diabetic patients admitted for lower extremity amputation. Methodological implications include identification of rare events for inpatient subpopulations and the need for improved codification of HAIs to improve cost and policy analyses regarding allocation of resources toward clinical improvements.
RESUMEN
Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4) cells with attributes capable of halting genital infection and inflammation. Previously, we described a natural nanocapsule called the vault which was engineered to contain major outer membrane protein (MOMP) and was an effective vaccine which significantly reduced early infection and favored development of a cellular immune response in a mouse model. In the current study, we used another chlamydial antigen, a polymorphic membrane protein G-1 (PmpG) peptide, to track antigen-specific cells and evaluate, in depth, the vault vaccine for its protective capacity in the absence of an added adjuvant. We found PmpG-vault immunized mice significantly reduced the genital bacterial burden and histopathologic parameters of inflammation following a C. muridarum challenge. Immunization boosted antigen-specific CD4 cells with a multiple cytokine secretion pattern and reduced the number of inflammatory cells in the genital tract making the vault vaccine platform safe and effective for chlamydial genital infection. We conclude that vaccination with a Chlamydia-vault vaccine boosts antigen-specific immunities that are effective at eradicating infection and preventing reproductive tract inflammation.
RESUMEN
Chlamydiae alter apoptosis of host target cells, which regulates their growth. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostaglandin E2 (PGE2) production, modulates epithelial cell survival. We addressed whether endogenous PGE2 alters chlamydial growth or apoptosis of epithelial cells infected with Chlamydia muridarum. PGE2 is secreted by infected host cells in the genital tract (GT). Using immunohistochemical techniques, we found that COX-2 enzyme was localized to epithelial cells in the GT in vivo. Pellets of the COX-2 enzyme inhibitor, NS-398, and placebo were implanted in mice subcutaneously and released a constant amount of these chemicals throughout the infection. NS-398-treated mice were found to exhibit 10-fold lower bacterial load than the placebo group on day 3 post infection, suggesting disruption of the chlamydial developmental cycle. To prove this, the human lung adenocarcinoma cell line A549 was then infected with different MOIs of C. muridarum in the presence of multiple concentrations of NS-398 in vitro. There was no difference in inclusion forming units (IFUs) between NS-389-treated and untreated cells. We also found no alterations in C. muridarum IFUs in A549 cells transfected with a 2.0 kb cDNA fragment of human COX-2 cloned in the sense (S) or anti-sense (AS) orientation. However, the inclusion size was reduced and the number of EB was significantly diminished during reinfection in AS-transfected cells. In addition, the absence of COX-2 did not significantly modify apoptosis in infected cells. In total, COX-2 deficiency reduces the infectious burden in vivo and may modulate transmission of the organism.
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Chlamydia muridarum/patogenicidad , Ciclooxigenasa 2/metabolismo , Células Epiteliales/microbiología , Animales , Apoptosis , Línea Celular Tumoral , Infecciones por Chlamydia/microbiología , Chlamydia muridarum/crecimiento & desarrollo , Ciclooxigenasa 2/genética , Dinoprostona/metabolismo , Femenino , Enfermedades de los Genitales Femeninos/microbiología , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Vagina/microbiologíaRESUMEN
BACKGROUND: Measurement of tacrolimus using the ARCHITECT immunoassay analyzer requires a manual extraction step that puts clinical laboratory workers at risk for ergonomic injury. Therefore, we developed 2 batched extraction systems for tacrolimus measurement on the ARCHITECT analyzer and describe their features herein. METHODS: Two batched extraction methods were developed at 2 different laboratories. The batched extraction methods allow processing of at least 20 specimens at a time. We evaluated the analytical performance of those methods and compared them with the United States Food and Drug Administration (FDA)-cleared process for manually extracting individual specimens. RESULTS: Comparing the performance of batched- and individual-extraction methods revealed that both methods had comparable between-day imprecision, high patient-results correlation (R2 values ≥0.9869), equivalent functional sensitivity (0.48 ng/mL), and good linearity between 1 ng per mL and 25 ng per mL. Further, we observed decreased delta check-identified errors using the batched method. CONCLUSION: The 2 developed batched extraction methods for tacrolimus measurement that we describe herein demonstrate excellent performance and can replace individual specimen extraction.
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Inmunoensayo/métodos , Inmunosupresores/sangre , Manejo de Especímenes/métodos , Tacrolimus/sangre , Humanos , Sensibilidad y Especificidad , Estados UnidosRESUMEN
The full potential of vaccines relies on development of effective delivery systems and adjuvants and is critical for development of successful vaccine candidates. We have shown that recombinant vaults engineered to encapsulate microbial epitopes are highly stable structures and are an ideal vaccine vehicle for epitope delivery which does not require the inclusion of an adjuvant. We studied the ability of vaults which were engineered for use as a vaccine containing an immunogenic epitope of Chlamydia trachomatis, polymorphic membrane protein G (PmpG), to be internalized into human monocytes and behave as a "natural adjuvant". We here show that incubation of monocytes with the PmpG-1-vaults activates caspase-1 and stimulates IL-1ß secretion through a process requiring the NLRP3 inflammasome and that cathepsin B and Syk are involved in the inflammasome activation. We also observed that the PmpG-1-vaults are internalized through a pathway that is transiently acidic and leads to destabilization of lysosomes. In addition, immunization of mice with PmpG-1-vaults induced PmpG-1 responsive CD4(+) cells upon re-stimulation with PmpG peptide in vitro, suggesting that vault vaccines can be engineered for specific adaptive immune responses. We conclude that PmpG-1-vault vaccines can stimulate NLRP3 inflammasomes and induce PmpG-specific T cell responses.
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Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas Bacterianas/inmunología , Proteínas Portadoras/inmunología , Chlamydia trachomatis/inmunología , Inflamasomas/inmunología , Nanopartículas , Adyuvantes Inmunológicos , Animales , Linfocitos T CD4-Positivos/inmunología , Caspasa 1/metabolismo , Catepsina B/metabolismo , Chlamydia trachomatis/genética , Epítopos/inmunología , Humanos , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisosomas/metabolismo , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Tirosina Quinasas/metabolismo , Quinasa SykRESUMEN
Chlamydia trachomatis is one of the major causes of bacterial sexually transmitted disease worldwide. The initial infection of endocervical epithelium in females is asymptomatic and commonly ascends to fallopian tubes when left untreated. Immunity to Chlamydia develops after infection and appears to provide short-term protection. Consequently, a significant rate of reinfection occurs among sexually active individuals, which can result in reproductive disability. T helper type 1 responses are implicated in providing protective immunity but may also contribute to tubal infertility. The purpose of this chapter is to review the factors that regulate the induction and recruitment of protective cellular immune responses within the local genital mucosa. An understanding of these events is important for the design of a protective vaccine and control of immunopathologic reactions.
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Infecciones por Chlamydia/inmunología , Chlamydia trachomatis , Enfermedades de los Genitales Femeninos/inmunología , Inmunidad Celular , Animales , Vacunas Bacterianas/inmunología , Infecciones por Chlamydia/epidemiología , Infecciones por Chlamydia/patología , Citocinas/biosíntesis , Femenino , Enfermedades de los Genitales Femeninos/epidemiología , Enfermedades de los Genitales Femeninos/patología , Genitales Femeninos/inmunología , Humanos , Inmunidad Innata , Masculino , Ratones , Subgrupos de Linfocitos T/inmunología , Estados Unidos/epidemiologíaRESUMEN
CONTEXT: Monoclonal proteins can interfere with the conjugated bilirubin assay on the Beckman Coulter AU5400 and AU2700 instruments and produce spurious results. Protein depletion eliminates the interference, suggesting that monoclonal proteins cause the problem. OBJECTIVES: To determine the interference rate with the Beckman Coulter AU5400 and AU2700 conjugated bilirubin assay and to identify the interfering substance. DESIGN: Beckman Coulter bilirubin results from 33,720 samples analyzed during 6 months were evaluated for interference. On a subset of samples, protein G columns were used to specifically remove immunoglobulin G (IgG) to determine the cause of the interference. Another 117 samples containing a (known) monoclonal protein were selected to determine the interference rate. RESULTS: From 26 different patients, 103 samples had conjugated bilirubin results greater than the total bilirubin for a false-positive rate of 0.3%. Removal of IgG from a subset of those samples with IgG monoclonal protein and increased polyclonal IgG eliminated the conjugated bilirubin interference. In separate, selected samples containing monoclonal proteins, the false-positive interference rate was 7.7% (9 of 117) and was greatest when the monoclonal protein concentration was greater than 4 g/dL. Another 11 of the 117 samples (9.4%) with monoclonal proteins exhibited assay interference by producing false-negative results. The overall interference rate, therefore, was 17.1%. CONCLUSION: The false-positive interference rate for the Beckman Coulter conjugated bilirubin assay was 0.3% for routinely analyzed serum/plasma samples. In addition to monoclonal proteins, we found that polyclonal immunoglobulins can also interfere with the conjugated bilirubin assay. The overall interference rate was 17.1% for samples with a monoclonal protein.
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Bilirrubina/análogos & derivados , Análisis Químico de la Sangre/métodos , Inmunoglobulinas/sangre , Anciano , Bilirrubina/sangre , Electroforesis de las Proteínas Sanguíneas , Reacciones Falso Positivas , Femenino , Humanos , Inmunoensayo , Inmunoglobulina G/sangre , Persona de Mediana Edad , Paraproteínas/análisisRESUMEN
OBJECTIVES: To determine how infant feeding recommendations can maximize HIV-free survival (HFS) among HIV-exposed, uninfected African infants, balancing risks of breast milk-associated HIV infection with setting-specific risks of illness and death associated with replacement feeding. DESIGN: Validated mathematical model of HIV-exposed, uninfected infants, with published data from Africa. METHODS: We projected 24-month HFS using combinations of: maternal CD4, antiretroviral drug availability, and relative risk of mortality among replacement-fed compared to breastfed infants ('RR-RF', range 1.0-6.0). For each combination, we identified the 'optimal' breastfeeding duration (0-24 months) maximizing HFS. We compared HFS under an 'individualized' approach, based on the above parameters, to the WHO 'public health approach' (12 months breastfeeding for all HIV-infected women). RESULTS: Projected HFS was 65-93%. When the value of RR-RF is 1.0, replacement feeding from birth maximized HFS. At a commonly reported RR-RF value (2.0), optimal breastfeeding duration was 3-12 months, depending on maternal CD4 and antiretroviral drug availability. As the value of RR-RF increased, optimal breastfeeding duration increased. Compared to the public health approach, an individualized approach improved absolute HFS by less than 1% if RR-RF value was 2.0-4.0, by 3% if RR-RF value was 1.0 or 6.0, and by greater amounts if access to antiretroviral drugs was limited. CONCLUSION: Tailoring breastfeeding duration to maternal CD4, antiretroviral drug availability, and local replacement feeding safety can optimize HFS among HIV-exposed infants. An individualized approach leads to moderate gains in HFS, but only when mortality risks from replacement feeding are very low or very high, or antiretroviral drug availability is limited. The WHO public health approach is beneficial in most resource-limited settings.
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Lactancia Materna , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Modelos Teóricos , Adulto , África , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Preescolar , Femenino , Guías como Asunto , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Lactante , Recién Nacido , Embarazo , Organización Mundial de la SaludRESUMEN
BACKGROUND: We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART). METHODS: We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY. RESULTS: For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving. CONCLUSIONS: Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Adulto , Estudios de Cohortes , Simulación por Computador , Análisis Costo-Beneficio , Femenino , Terapia Genética , Infecciones por VIH/economía , Humanos , Esperanza de Vida , Masculino , Persona de Mediana Edad , Años de Vida Ajustados por Calidad de Vida , Recurrencia , Trasplante de Células MadreRESUMEN
Mucosal surfaces, including in the gastrointestinal, urogenital, and respiratory tracts, provide portals of entry for pathogens, such as viruses and bacteria. Mucosae are also inductive sites in the host to generate immunity against pathogens, such as the Peyers patches in the intestinal tract and the nasal-associated lymphoreticular tissue in the respiratory tract. This unique feature brings mucosal immunity as a crucial player of the host defense system. Many studies have been focused on gastrointestinal and respiratory mucosal sites. However, there has been little investigation of reproductive mucosal sites. The genital tract mucosa is the primary infection site for sexually transmitted diseases (STD), including bacterial and viral infections. STDs are one of the most critical health challenges facing the world today. Centers for Disease Control and Prevention estimates that there are 19 million new infectious every year in the United States. STDs cost the U.S. health care system $17 billion every year, and cost individuals even more in immediate and life-long health consequences. In order to confront this challenge, a greater understanding of reproductive mucosal immunity is needed and isolating lymphocytes is an essential component of these studies. Here, we present a method to reproducibly isolate lymphocytes from murine female genital tracts for immunological studies that can be modified for adaption to other species. The method described below is based on one mouse.