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2.
Ann Surg Oncol ; 31(3): 1714-1724, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38006526

RESUMEN

BACKGROUND: Prior studies have shown tumor specificity on the impact of longer time interval from diagnosis to surgery, however in gastric cancer (GC) this remains unclear. We aimed to determine if a longer time interval from diagnosis to surgery had an impact on lymph node (LN) upstaging and overall survival (OS) outcomes among patients with clinically node negative (cN0) GC. PATIENTS AND METHODS: Patients diagnosed with cN0 GC undergoing surgery between 2004-2018 were identified in the National Cancer Database (NCDB) and divided into intervals between time of diagnosis and surgery [short interval (SI): ≥ 4 days to < 8 weeks and long interval (LI): ≥ 8 weeks]. Multivariable regression analysis evaluated the independent impact of surgical timing on LN upstaging and a Cox proportional hazards analysis and Kaplan-Meier curves evaluated survival outcomes. RESULTS: Of 1824 patients with cN0 GC, 71.8% had a SI to surgery and 28.1% had a LI to surgery. LN upstaging was seen more often in the SI group when compared to LI group (82% versus 76%, p = 0.004). LI to surgery showed to be an independent factor protective against LN upstaging [adjusted odds ratio = 0.62, 95% CI: (0.39-0.99)]. Multivariate Cox regression analysis indicated that time to surgery was not associated with a difference in overall survival [hazard ratio (HR) = 0.91, 95% CI: (0.71-1.17)], however uncontrolled Kaplan-Meier curves showed OS difference between the SI and LI to surgery groups (p = 0.037). CONCLUSION: Timing to surgery was not a predictor of LN upstaging or overall survival, suggesting that additional medical optimization in preparation for surgery and careful preoperative staging may be appropriate in patients with node negative early stage GC without affecting outcomes.


Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Estadificación de Neoplasias , Ganglios Linfáticos/patología , Modelos de Riesgos Proporcionales , Análisis Multivariante , Estudios Retrospectivos , Escisión del Ganglio Linfático
3.
Nat Med ; 29(11): 2742-2747, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37884626

RESUMEN

Blind and deaf individuals comprise large populations that often experience health disparities, with those from marginalized gender, racial, ethnic and low-socioeconomic communities commonly experiencing compounded health inequities. Including these populations in precision medicine research is critical for scientific benefits to accrue to them. We assessed representation of blind and deaf people in the All of Us Research Program (AoURP) 2018-2023 cohort of participants who provided electronic health records and compared it with the Centers for Disease Control and Prevention 2018 national estimates by key demographic characteristics and intersections thereof. Blind and deaf AoURP participants are considerably underrepresented in the cohort, especially among working-age adults (younger than age 65 years), as well as Asian and multi-racial participants. Analyses show compounded underrepresentation at the intersection of multiple marginalization (that is, racial or ethnic minoritized group, female sex, low education and low income), most substantively for working-age blind participants identifying as Black or African American female with education levels lower than high school (representing one-fifth of their national prevalence). Underrepresentation raises concerns about the generalizability of findings in studies that use these data and limited benefits for the already underserved blind and deaf populations.


Asunto(s)
Ceguera , Sordera , Poblaciones Minoritarias, Vulnerables y Desiguales en Salud , Salud Poblacional , Determinantes Sociales de la Salud , Adulto , Anciano , Femenino , Humanos , Negro o Afroamericano/estadística & datos numéricos , Etnicidad , Salud Poblacional/estadística & datos numéricos , Grupos Raciales/etnología , Grupos Raciales/estadística & datos numéricos , Persona de Mediana Edad , Ceguera/epidemiología , Sordera/epidemiología , Poblaciones Minoritarias, Vulnerables y Desiguales en Salud/estadística & datos numéricos , Asiático/estadística & datos numéricos , Estados Unidos/epidemiología , Masculino , Factores Sexuales , Determinantes Sociales de la Salud/etnología , Determinantes Sociales de la Salud/estadística & datos numéricos , Escolaridad
4.
Preprint en Inglés | medRxiv | ID: ppmedrxiv-22281010

RESUMEN

Post-acute sequelae of SARS-CoV-2 infection (PASC) affects a wide range of organ systems among a large proportion of patients with SARS-CoV-2 infection. Although studies have identified a broad set of patient-level risk factors for PASC, little is known about the contextual and spatial risk factors for PASC. Using electronic health data of patients with COVID-19 from two large clinical research networks in New York City and Florida, we identified contextual and spatial risk factors from nearly 200 environmental characteristics for 23 PASC symptoms and conditions of eight organ systems. We conducted a two-phase environment-wide association study. In Phase 1, we ran a mixed effects logistic regression with 5-digit ZIP Code tabulation area (ZCTA5) random intercepts for each PASC outcome and each contextual and spatial factor, adjusting for a comprehensive set of patient-level confounders. In Phase 2, we ran a mixed effects logistic regression for each PASC outcome including all significant (false positive discovery adjusted p-value < 0.05) contextual and spatial characteristics identified from Phase I and adjusting for confounders. We identified air toxicants (e.g., methyl methacrylate), criteria air pollutants (e.g., sulfur dioxide), particulate matter (PM2.5) compositions (e.g., ammonium), neighborhood deprivation, and built environment (e.g., food access) that were associated with increased risk of PASC conditions related to nervous, respiratory, blood, circulatory, endocrine, and other organ systems. Specific contextual and spatial risk factors for each PASC condition and symptom were different across New York City area and Florida. Future research is warranted to extend the analyses to other regions and examine more granular contextual and spatial characteristics to inform public health efforts to help patients recover from SARS-CoV-2 infection.

5.
Proc Natl Acad Sci U S A ; 119(25): e2202932119, 2022 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-35696563

RESUMEN

The primary insect steroid hormone ecdysone requires a membrane transporter to enter its target cells. Although an organic anion-transporting polypeptide (OATP) named Ecdysone Importer (EcI) serves this role in the fruit fly Drosophila melanogaster and most likely in other arthropod species, this highly conserved transporter is apparently missing in mosquitoes. Here we report three additional OATPs that facilitate cellular incorporation of ecdysone in Drosophila and the yellow fever mosquito Aedes aegypti. These additional ecdysone importers (EcI-2, -3, and -4) are dispensable for development and reproduction in Drosophila, consistent with the predominant role of EcI. In contrast, in Aedes, EcI-2 is indispensable for ecdysone-mediated development, whereas EcI-4 is critical for vitellogenesis induced by ecdysone in adult females. Altogether, our results indicate unique and essential functions of these additional ecdysone importers in mosquito development and reproduction, making them attractive molecular targets for species- and stage-specific control of ecdysone signaling in mosquitoes.


Asunto(s)
Aedes , Ecdisona , Proteínas de Insectos , Transportadores de Anión Orgánico , Aedes/crecimiento & desarrollo , Aedes/fisiología , Animales , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ecdisona/metabolismo , Femenino , Proteínas de Insectos/metabolismo , Transportadores de Anión Orgánico/metabolismo , Vitelogénesis
6.
Insect Biochem Mol Biol ; 139: 103669, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34666189

RESUMEN

In vertebrates and invertebrates, the insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) cascade is highly conserved and plays a vital role in many different physiological processes. Among the many tissues that respond to IIS in mosquitoes, the fat body has a central role in metabolism, lifespan, reproduction, and innate immunity. We previously demonstrated that fat body specific expression of active Akt, a key IIS signaling molecule, in adult Anopheles stephensi and Aedes aegypti activated the IIS cascade and extended lifespan. Additionally, we found that transgenic females produced more vitellogenin (Vg) protein than non-transgenic mosquitoes, although this did not translate into increased fecundity. These results prompted us to further examine how IIS impacts immunity, metabolism, growth and development of these transgenic mosquitoes. We observed significant changes in glycogen, trehalose, triglycerides, glucose, and protein in young (3-5 d) transgenic mosquitoes relative to non-transgenic sibling controls, while only triglycerides were significantly changed in older (18 d) transgenic mosquitoes. More importantly, we demonstrated that enhanced fat body IIS decreased both the prevalence and intensity of Plasmodium falciparum infection in transgenic An. stephensi. Additionally, challenging transgenic An. stephensi with Gram-positive and Gram-negative bacteria altered the expression of several antimicrobial peptides (AMPs) and two anti-Plasmodium genes, nitric oxide synthase (NOS) and thioester complement-like protein (TEP1), relative to non-transgenic controls. Increased IIS in the fat body of adult female An. stephensi had little to no impact on body size, growth or development of progeny from transgenic mosquitoes relative to non-transgenic controls. This study both confirms and expands our understanding of the critical roles insulin signaling plays in regulating the diverse functions of the mosquito fat body.


Asunto(s)
Anopheles/fisiología , Cuerpo Adiposo/metabolismo , Interacciones Huésped-Patógeno , Insulina/fisiología , Transducción de Señal , Animales , Anopheles/microbiología , Anopheles/parasitología , Femenino , Bacterias Gramnegativas/fisiología , Bacterias Grampositivas/fisiología , Interacciones Huésped-Parásitos , Plasmodium falciparum/fisiología
7.
Int Nurs Rev ; 67(1): 19-34, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31364775

RESUMEN

AIM: To review published literature descriptions of advanced practice nurses' roles in low- and lower middle-income countries. BACKGROUND: Advanced practice nurse roles have the potential to address insufficient healthcare resources in low- and lower middle-income countries. INTRODUCTION: This integrative review highlights advanced practice nurses' roles in the delivery of healthcare services in low- and lower middle-income countries. METHODS: Three electronic databases PubMed, CINAHL complete and ProQuest Health & Medicine were searched. No limits by year or language were set. The names for low- and lower middle-income countries and combinations 'related to advanced practice nurses' titles were used to identify papers. In addition, a review of publication type was performed. Themes found within the publications were assessed against the advanced practice nurses' International Council of Nurses' characteristics. An integrative review facilitated an appraisal of the papers identified. RESULTS: The initial search identified 5778 publications in 16 languages. This number was reduced to 23, from 18 low- and lower middle-income once exclusion criteria were applied. Six publications were from 1977 to 1999, and six between 2000 and 2010, with the remaining 11 from 2011 to 2018. Zambia had the most publications. Notably, 63 countries were not represented. Of those meeting inclusion criteria, the majority addressed education with a lesser extent focusing on practice and regulation of advanced practice nurse's roles. The majority were published during the last decade. DISCUSSION: This review of the published literature identified advanced practice nurses' roles and function within some healthcare systems. However, not all components were reported. Examination of the grey literature could provide additional information about the actual and potential benefits of advanced practice nurses' in low- and lower middle-income countries. CONCLUSION: The published literature that referred to advanced practice nurses' identified their contribution to positive impacts on health care over the last 40 years. However, with only 11 publications identified in the last 7 years, further review is required to understand the advanced practice nurses' roles in these countries. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: Further development of advanced practice nurses' in low- and lower middle-income countries is supported by the lack of published literature.


Asunto(s)
Enfermería de Práctica Avanzada , Países en Desarrollo , Rol de la Enfermera , Atención a la Salud , Humanos
8.
J Insect Physiol ; 118: 103932, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31445957

RESUMEN

Insulin-like peptides (ILPs) and the insulin/insulin-like growth factor 1 signaling (IIS) cascade regulate numerous physiological functions, including lifespan, reproduction, immunity, and metabolism, in diverse eukaryotes. We previously demonstrated that in female Anopheles stephensi and Aedes aegypti mosquitoes, activation of the IIS cascade in the fat body led to a significant increase in lifespan. In this work, we elucidated two putative mechanisms in A. stephensi behind the observed lifespan extension and assessed whether this lifespan extension confers an overall fitness advantage to the mosquito. Specifically, we demonstrated that increased Akt signaling in the mosquito fat body following a blood meal significantly suppressed the expression of ILP2 in the head. Moreover, overexpression of active Akt in the fat body altered the expression of a putative insulin binding protein ortholog, Imaginal morphogenesis protein-Late 2 (Imp-L2), in response to transgene expression. Combined, these two factors may act to reduce overall levels of circulating ILP2 or other ILPs in the mosquito, in turn conferring increased survival. We also examined the impact increased fat body IIS had on lifetime fecundity and demonstrated that transgenic female mosquito populations had higher lifetime fecundity relative to non-transgenic sibling controls. These studies provide new insights into the complex hormonal and molecular mechanisms regulating the interplay between IIS, aging, and reproduction in this important vector of human malaria parasites.


Asunto(s)
Anopheles/metabolismo , Cuerpo Adiposo/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Animales Modificados Genéticamente , Anopheles/genética , Anopheles/crecimiento & desarrollo , Sangre , Femenino , Fertilidad/genética , Fertilidad/fisiología , Humanos , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Longevidad/genética , Longevidad/fisiología , Transducción de Señal
9.
Transplant Proc ; 50(3): 891-894, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29588065

RESUMEN

Skin and soft tissue infections (SSTIs) are one of most frequent infectious causes for referral to the emergency department and one of the most frequent infectious causes of hospital admissions. Escherichia coli, the most commonly occurring gram-negative pathogen involved in these infections, contributes to about 7% of all SSTIs cases where gram-positive organisms reign dominant. Patients are more susceptible to these gram-negative SSTIs if they are neutropenic, have hematologic malignancies, have undergone solid organ or hematopoietic transplantation, or have cirrhotic liver disease. Due to their immunocompromised state, the prognosis is very poor and not well understood. We report a case of an atypical presentation of an E coli monomicrobial necrotizing fasciitis in a renal transplant patient. Our findings support improved mortality with rapid aggressive interventions, such as amputation, in immunocompromised patients.


Asunto(s)
Infecciones por Escherichia coli/inmunología , Fascitis Necrotizante/inmunología , Huésped Inmunocomprometido , Trasplante de Riñón/efectos adversos , Amputación Quirúrgica , Femenino , Humanos , Persona de Mediana Edad
10.
ACS Chem Neurosci ; 9(3): 431-445, 2018 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-29393619

RESUMEN

Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrPC) into disease-associated conformers (PrPSc) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrPSc species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease patho-biology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time-consuming, and it can be problematic to clearly discern evidence of direct PrPSc neurotoxicity in the overall context of pathogenesis. In vitro models, in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic, and overall there remains a relative paucity of validated, biologically relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we provide an overview of the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies.


Asunto(s)
Síndromes de Neurotoxicidad/metabolismo , Proteínas PrPSc/metabolismo , Enfermedades por Prión/metabolismo , Priones/metabolismo , Animales , Humanos , Modelos Biológicos , Neuronas/metabolismo
11.
Int J Equity Health ; 17(1): 28, 2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29458379

RESUMEN

BACKGROUND: Disparities in access to primary care (PC) have been demonstrated within and between health systems. However, few studies have assessed the factors associated with multiple barriers to access occurring along the care-seeking process in different healthcare systems. METHODS: In this secondary analysis of the 2016 Commonwealth Fund International Health Policy Survey of Adults, access was represented through participant responses to questions relating to access barriers either before or after reaching the PC practice in 11 countries (Australia, Canada, France, Germany, Norway, the Netherlands, New Zealand, Sweden, Switzerland, the United Kingdom, and United States). The number of respondents in each country ranged from 1000 to 7000 and the response rates ranged from 11% to 47%. We used multivariable logistic regression models within each of eleven countries to identify disparities in response to the access barriers by age, sex, immigrant status, income and the presence of chronic conditions. RESULTS: Overall, one in five adults (21%) experienced multiple barriers before reaching PC practices. After reaching care, an average of 16% of adults had two or more barriers. There was a sixfold difference between nations in the experience of these barriers to access. Vulnerable groups experiencing multiple barriers were relatively consistent across countries. People with lower income were more likely to experience multiple barriers, particularly before reaching primary care practices. Respondents with mental health problems and those born outside the country displayed substantial vulnerability in terms of barriers after reaching care. CONCLUSION: A greater understanding of the multiple barriers to access to PC across the stages of the care-seeking process may help to inform planning and performance monitoring of disparities in access. Variation across countries may reveal organisational and system drivers of access, and inform efforts to improve access to PC for vulnerable groups. The cumulative nature of these barriers remains to be assessed.


Asunto(s)
Encuestas de Atención de la Salud/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/estadística & datos numéricos , Internacionalidad , Atención Primaria de Salud , Factores de Edad , Anciano , Femenino , Salud Global , Humanos , Masculino , Factores Sexuales , Factores Socioeconómicos , Estados Unidos
12.
Methods Mol Biol ; 1658: 347-354, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28861800

RESUMEN

Across the spectrum of sporadic human prion diseases (also known as transmissible spongiform encephalopathies: TSE), there is considerable phenotypic diversity. Cumulative scientific evidence supports that prions, the infectious agents of prion diseases, are constituted predominantly, if not exclusively, by misfolded, typically protease-resistant, disease-associated isoforms of the prion protein (PrPres). Consequently, tissue deposition of PrPres is considered a hallmark of prion disease pathology, and this can be visualized by Western blotting after tissue homogenization and treatment with proteinases, particularly proteinase K (PK). Indeed, Western blot profiles of PrPres are utilized as one marker of different prion strains, with such strains thought to contribute to at least part of the phenotypic variation observed in sporadic human prion disease. Typically, Western blotting of PrPres demonstrates three bands of different electrophoretic mobility, depicting the di-glycosylated, mono-glycosylated and unglycosylated species although further subclassification and the delineation of novel sporadic disease subtypes, such as variably protease-sensitive prionopathy, has contributed greater complexity. Nevertheless, it is the mobility of the unglycosylated PrPres band, the relative abundance of the two glycosylated bands or overall profile of the banding post-PK, in combination with the prion protein gene (PRNP) codon 129 genotype that allows the categorisation of molecular subtypes of sporadic human prion disease. These subtypes appear to correlate with distinct clinico-pathological profiles of sporadic Creutzfeldt-Jakob disease.


Asunto(s)
Western Blotting/métodos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Electroforesis en Gel de Poliacrilamida/métodos , Proteínas PrPC/química , Proteínas Priónicas/clasificación , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Endopeptidasa K/química , Expresión Génica , Glicosilación , Humanos , Fenotipo , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Proteínas Priónicas/química , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Pliegue de Proteína
13.
Curr Oncol ; 24(1): 23-27, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28270721

RESUMEN

BACKGROUND: The treatment of children with cancer is associated with significant burden for the entire family. Frequent clinic visits and extended hospital stays can negatively affect quality of life for children and their families. METHODS: Here, we describe the development of a Hospital at Home program (H@H) that delivers therapy to pediatric hematology, oncology, and blood and marrow transplant (bmt) patients in their homes. The services provided include short infusions of chemotherapy, supportive-care interventions, antibiotics, post-chemotherapy hydration, and teaching. RESULTS: From 2013 to 2015, the H@H program served 136 patients, making 1701 home visits, for patients mainly between the ages of 1 and 4 years. Referrals came from oncology in 82% of cases, from hematology in 11%, and from bmt in 7%. Since inception of the program, no adverse events have been reported. Family surveys suggested less disruption in daily routines and appreciation of specialized care by hematology and oncology nurses. Staff surveys highlighted a perceived benefit of H@H in contributing to early discharge of patients by supporting out-of-hospital monitoring and teaching. CONCLUSIONS: The development of a H@H program dedicated to the pediatric hematology, oncology, or bmt patient appears feasible. Our pilot program offers a potential contribution to improvement in patient quality of life and in cost-benefit for parents and the health care system.

14.
J Affect Disord ; 208: 662-669, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27866709

RESUMEN

INTRODUCTION: Depressive symptoms occur frequently in people with Multiple Sclerosis (MS) and rates of suicide ideation are higher than the general population. There is evidence for a direct association between disability and depression, disability and suicide ideation, and depression and suicide ideation in MS. However, the relationship between all three, i.e. the mediating role of depression between disability and suicidal ideation, has not been investigated. Exploring this relationship could highlight risk factors, alerting clinicians to the need for timely intervention. METHOD: Seventy five people with progressive MS attending two out-patient clinics took part in this cross-sectional study. Participants completed the Beck Suicide Scale, Beck Depression Inventory, Multiple Sclerosis Impact Scale and Guy's Neurological Disability Scale. RESULTS: Depressive symptoms mediated the relationship between perceived and actual disability and suicide ideation. Different types of disability were associated with suicidality, including: 'tremors' and 'taking longer to do things'. A small sub-group of participants were identified who reported suicide ideation in the presence of only mild levels of depression. LIMITATIONS: There may be a sample bias in this study as all participants were attending out-patient clinics and receiving support which may not be available to everyone with MS. CONCLUSION: It is important for clinicians to screen regularly for both depression and suicide ideation, to be alert to specific types of disability for which a higher level of suicide ideation might be present and to consider the possibility of suicidal thoughts being present in people who show minimal or no depressive symptoms.


Asunto(s)
Depresión/epidemiología , Personas con Discapacidad/estadística & datos numéricos , Esclerosis Múltiple/epidemiología , Ideación Suicida , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Suicidio/estadística & datos numéricos
15.
Artículo en Inglés | MEDLINE | ID: mdl-27063376

RESUMEN

INTRODUCTION: Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. METHODS: From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. RESULTS: Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. DISCUSSION: Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes.


Asunto(s)
Pruebas de Función Cardíaca/métodos , Corazón/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Animales , Antiarrítmicos/farmacología , Atenolol/farmacología , Presión Sanguínea/efectos de los fármacos , Cardiotónicos/farmacología , Perros , Evaluación Preclínica de Medicamentos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Macaca fascicularis , Masculino , Contracción Miocárdica , Piridazinas/farmacología , Valores de Referencia , Telemetría
16.
Clin Microbiol Infect ; 22(6): 563.e9-563.e17, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26932518

RESUMEN

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments.


Asunto(s)
Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/genética , Predisposición Genética a la Enfermedad , Interleucina-1beta/genética , Leucemia Mieloide Aguda/complicaciones , Polimorfismo de Nucleótido Simple , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Prospectivos , Medición de Riesgo
17.
Bone Marrow Transplant ; 51(5): 680-6, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26752147

RESUMEN

Adverse reactions (ARs) during the infusion of cellular therapy products (CTPs) are common in patients undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively studied pediatric patients undergoing autologous and allogeneic HSCT to determine the incidence and grade of ARs during stem cell infusion and their predictors. We analyzed data from 213 patients (120 allogeneic and 93 autologous) who received at least 1 CTP, totaling 361 infusion episodes. Serious ARs, defined as grade 2 and 3, occurred in 25 and 11% of infusions, respectively. No grade 4 or 5 ARs were noted. Independent risk factors for developing a serious AR included stem cell source (PBSC vs marrow (odds ratio (OR) 1.8, 95% confidence interval (CI): 0.4-9); cord vs marrow (OR 7.3, 95% CI: 1.3-40), overall P=0.0001) but manipulated CTPs were protective (OR 0.4, 95% CI: 0.2-0.7, P=0.004). Unlike previous adult studies, WBC and granulocyte content were not found to be risk factors in this pediatric population. These data suggest that children tolerate higher WBC content during infusion of CTPs and support the use of manipulated CTP, as indicated, to reduce the risk of adverse infusion reactions.


Asunto(s)
Trasplante de Células Madre/efectos adversos , Niño , Preescolar , Femenino , Granulocitos , Humanos , Leucocitos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Trasplante de Células Madre/estadística & datos numéricos , Células Madre/citología , Trasplante Autólogo , Trasplante Homólogo
18.
Vet Parasitol ; 210(1-2): 64-8, 2015 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-25801226

RESUMEN

A clinical field investigation was conducted to evaluate the safety and efficacy of 10% imidacloprid/2.5% moxidectin for the treatment of ear mites (Otodectes cynotis) in dogs. The study was a multi-centered, blinded, positive controlled, randomized clinical trial conducted under field conditions with privately owned pets. A total of 17 veterinary clinics enrolled cases for the study. An otoscopic examination was performed to confirm the presence of O. cynotis residing in the ear of the dog prior to enrollment. A single-dog household was enrolled in the study if the dog had 5 or more ear mites and an acceptable physical examination. A multi-dog household was eligible if at least one dog in the household had 5 or more mites and all dogs in the household had acceptable physical exams and met the inclusion criteria. Qualified households were randomly assigned to treatments to receive either 10% imidacloprid+2.5% moxidectin topical solution or topical selamectin solution (positive control product) according to a pre-designated enrollment ratio of 2:1, respectively. If more than one dog in a multiple dog household had adequate numbers of ear mites, one dog was randomly selected to represent the household for efficacy evaluation prior to treatment. Treatments were administered twice per label and dose banding directions for each product approximately 28 days apart (Days 0 and 28), by the dog's owner at the study site. All dogs in a household were treated on the same day and with the same product. The owners completed a post-treatment observation form one day after each treatment. Post-treatment otoscopic examinations were performed by the investigators or attending veterinarian on Days 28 and 56. Physical examinations were performed on Days 0 and 56. One hundred and four (104) households were evaluated for efficacy on SD 28, and 102 households were evaluated for efficacy on SD 56. The dogs' ages ranged from 2 months to 16 years. A total of 247 dogs were evaluated for safety. Percent efficacy was based on the percentage of dogs cleared of ear mites. Mite clearance on Day 28 was 71% for the imidacloprid+moxidectin group and 69% for the selamectin group. Mite clearance on Day 56 was 82% for the imidacloprid+moxidectin group and 74% for the selamectin group. No serious adverse events associated with either product were observed during the study. The study demonstrated that 10% imidacloprid+2.5% moxidectin applied using two topical treatments, 28 days apart, was safe and achieved similar efficacy against O. cynotis as selamectin treatments applied and evaluated under the same conditions.


Asunto(s)
Enfermedades de los Perros/parasitología , Enfermedades del Oído/veterinaria , Imidazoles/uso terapéutico , Macrólidos/uso terapéutico , Infestaciones por Ácaros/veterinaria , Nitrocompuestos/uso terapéutico , Animales , Enfermedades de los Perros/tratamiento farmacológico , Perros , Combinación de Medicamentos , Enfermedades del Oído/parasitología , Imidazoles/administración & dosificación , Insecticidas/administración & dosificación , Insecticidas/uso terapéutico , Ivermectina/análogos & derivados , Ivermectina/uso terapéutico , Macrólidos/administración & dosificación , Neonicotinoides , Nitrocompuestos/administración & dosificación
19.
FASEB J ; 29(4): 1404-13, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25550465

RESUMEN

Akt signaling regulates diverse physiologies in a wide range of organisms. We examine the impact of increased Akt signaling in the fat body of 2 mosquito species, the Asian malaria mosquito Anopheles stephensi and the yellow fever mosquito Aedes aegypti. Overexpression of a myristoylated and active form of A. stephensi and Ae. aegypti Akt in the fat body of transgenic mosquitoes led to activation of the downstream signaling molecules forkhead box O (FOXO) and p70 S6 kinase in a tissue and blood meal-specific manner. In both species, increased Akt signaling in the fat body after blood feeding significantly increased adult survivorship relative to nontransgenic sibling controls. In A. stephensi, survivorship was increased by 15% to 45%, while in Ae. aegypti, it increased 14% to 47%. Transgenic mosquitoes fed only sugar, and thus not expressing active Akt, had no significant difference in survivorship relative to nontransgenic siblings. Expression of active Akt also increased expression of fat body vitellogenin, but the number of viable eggs did not differ significantly between transgenic and nontransgenic controls. This work demonstrates a novel mechanism of enhanced survivorship through increased Akt signaling in the fat bodies of multiple mosquito genera and provides new tools to unlock the molecular underpinnings of aging in eukaryotic organisms.


Asunto(s)
Aedes/metabolismo , Anopheles/metabolismo , Cuerpo Adiposo/metabolismo , Proteínas de Insectos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Aedes/genética , Aedes/crecimiento & desarrollo , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Animales Modificados Genéticamente , Anopheles/genética , Anopheles/crecimiento & desarrollo , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas de Insectos/genética , Longevidad/genética , Longevidad/fisiología , Proteínas Proto-Oncogénicas c-akt/genética , Reproducción/genética , Reproducción/fisiología , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal , Especificidad de la Especie , Vitelogeninas/genética , Vitelogeninas/metabolismo
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