RESUMEN
Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) and known carcinogen in the Top 10 on the United States' list of priority pollutants. Humans are exposed through a variety of sources including tobacco smoke, grilled foods and fossil fuel combustion. Recent studies of children exposed to higher levels of PAHs during pregnancy and early life have identified numerous adverse effects on the brain and behavior that persist into school age and adolescence. Our studies were designed to look for genotype and sex differences in susceptibility to gestational and lactational exposure to BaP using a mouse model with allelic differences in the aryl hydrocarbon receptor and the xenobiotic metabolizing enzyme CYP1A2. Pregnant dams were exposed to 10 mg/kg/day of BaP in corn oil-soaked cereal or the corn oil vehicle alone from gestational day 10 until weaning at postnatal day 25. Neurobehavioral testing began at P60 using one male and one female per litter. We found main effects of sex, genotype and treatment as well as significant gene x treatment and sex x treatment interactions. BaP-treated female mice had shorter latencies to fall in the Rotarod test. BaP-treated high-affinity AhrbCyp1a2(-/-) mice had greater impairments in Morris water maze. Interestingly, poor-affinity AhrdCyp1a2(-/-) mice also had deficits in spatial learning and memory regardless of treatment. We believe our findings provide future directions in identifying human populations at highest risk of early life BaP exposure, because our model mimics known human variation in our genes of interest. Our studies also highlight the value of testing both males and females in all neurobehavioral studies.
Asunto(s)
Benzo(a)pireno , Receptores de Hidrocarburo de Aril , Animales , Benzo(a)pireno/toxicidad , Citocromo P-450 CYP1A2/genética , Femenino , Genotipo , Masculino , Embarazo , Receptores de Hidrocarburo de Aril/genética , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Context: Pharmacogenomic analysis may improve the efficacy or safety of the drugs used in palliative care. Decision support systems may promote clinical integration of this information. Objectives: To determine the feasibility and acceptability of a pharmacist-directed pharmacogenomic decision support system in the care of patients with advanced illness and explore the drug-gene and drug-drug interactions that occur in this population. Methods: Physicians or nurse practitioners from two U.S. hospice agencies identified opioid-treated patients receiving multiple other drugs. Buccal samples and clinical data were obtained from consenting patients. A pharmacist used the proprietary MedWise™ platform to evaluate the current medications in terms of genotype and phenotype, created a standardized report describing potential interactions and recommended actions that may reduce the associated risk. Clinicians could access the report online and completed Likert-type scales to assess use and satisfaction with the system. Results: Twenty clinicians and 100 patients participated. The reports revealed that 74 drugs were subject to 462 drug-gene interactions and 77 were involved in 691 drug-drug interactions; only 4 and 16 patients, respectively, had no drug-gene or drug-drug interactions. Clinicians routinely checked the reports and used the information to change ≥1 treatments in 55 (55%) patients. Almost all clinicians rated the system likely to improve the quality of care and all "agreed" or "strongly agreed" to recommend the system to colleagues. Conclusion: This pharmacist-directed pharmacogenomic decision support system was perceived positively and was integrated into practice. Further studies are warranted to its clinical integration and its outcomes.
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Enfermería de Cuidados Paliativos al Final de la Vida , Farmacogenética , Estudios de Factibilidad , Humanos , Cuidados Paliativos , FarmacéuticosRESUMEN
The mammalian brain goes through final maturation during late adolescence and early adulthood with sex differences in timing. The key cellular processes, including changes in neurotransmitter receptor density and synaptic pruning, make this age uniquely vulnerable to neurotoxic insults. Teenagers and young adults are the major consumers of energy drinks, which contain high levels of taurine and caffeine. Taurine is one of the most abundant amino acids in the central nervous system, but the effects of supplemental taurine consumption during adolescence has not been well studied. We conducted an initial short-term exposure study with 0.12% taurine in drinking water and a long-term exposure dose-response study using 0.06 and 0.12% taurine in male and female C57BL/6J mice. We examined a broad range of cognitive functions and behaviors and measured neurotransmitter levels. We found no significant differences in anxiety, open field locomotor activity, or sensorimotor gating. However, we found impairments in novel object recognition and sex differences in Morris water maze. When taurine treatment stopped before behavioral experiments began, male mice had significant impairments in spatial learning and memory. In the dose-response study when taurine treatment continued throughout behavioral experiments, females had significant impairments. We also found sex differences in neurotransmitter levels with females having higher levels of glutamate, DOPAC and 5-HIAA. We conclude that both females and males are at risk from excess taurine consumption during final brain maturation.
Asunto(s)
Aminoácidos/análisis , Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas/análisis , Cognición/efectos de los fármacos , Taurina/administración & dosificación , Factores de Edad , Animales , Cafeína/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Femenino , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Reconocimiento en Psicología/efectos de los fármacos , Factores SexualesAsunto(s)
Dolor en Cáncer/complicaciones , Morfinanos/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Estreñimiento Inducido por Opioides/tratamiento farmacológico , Selección de Paciente , Polietilenglicoles/uso terapéutico , Administración Oral , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Método Doble Ciego , Familia , Estudios de Factibilidad , Cuidados Paliativos al Final de la Vida , Humanos , Morfinanos/efectos adversos , Antagonistas de Narcóticos/efectos adversos , Neoplasias/complicaciones , Estreñimiento Inducido por Opioides/etiología , Estreñimiento Inducido por Opioides/psicología , Cuidados Paliativos , Polietilenglicoles/efectos adversosRESUMEN
BACKGROUND: Although limited, the descriptions of Community-Based Palliative Care (CBPC) demonstrates variability in team structures, eligibility, and standardization across care settings. OBJECTIVE: In 2014, Four Seasons Compassion for Life, a nonprofit hospice and palliative care (PC) organization in Western North Carolina (WNC), was awarded a Centers for Medicare and Medicaid Services Health Care Innovation (CMMI) Award to expand upon their existing innovative model to implement, evaluate, and demonstrate CBPC in the United States. The objective of this article is to describe the processes and challenges of scaling and standardizing the CBPC model. DESIGN: Four Season's CBPC model serves patients in both inpatient and outpatient settings using an interdisciplinary team to address symptom management, psychosocial/spiritual care, advance care planning, and patient/family education. Medicare beneficiaries who are ≥65 years of age with a life-limiting illness were eligible for the CMMI project. RESULTS: The CBPC model was scaled across numerous counties in WNC and Upstate South Carolina. Over the first two years of the project, scaling occurred into 21 counties with the addition of 2 large hospitals, 52 nursing facilities, and 2 new clinics. To improve efficiency and effectiveness, a PC screening referral guide and a risk stratification approach were developed and implemented. Care processes, including patient referral and initial visit, were mapped. CONCLUSION: This article describes an interdisciplinary CBPC model in all care settings to individuals with life-limiting illness and offers guidance for risk stratification assessments and mapping care processes that may help PC programs as they develop and work to improve efficiencies.
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Servicios de Salud Comunitaria/economía , Servicios de Salud Comunitaria/normas , Cuidados Paliativos al Final de la Vida/economía , Cuidados Paliativos al Final de la Vida/normas , Cuidados Paliativos/economía , Cuidados Paliativos/normas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Modelos Organizacionales , North Carolina , South CarolinaRESUMEN
BACKGROUND: Although limited, the evidence base for Community-Based Palliative Care (CBPC) has shown that it improves patient health outcomes, increases satisfaction, and decreases cost. Minimal data exist comparing points of entry into palliative care and patient transition outcomes. OBJECTIVES: In 2014, Four Seasons Compassion for Life was awarded a Centers for Medicare & Medicaid Services Healthcare Innovation Award to expand an existing CBPC model into additional counties and to propose a new payment approach. The goal of this article is to evaluate the tracking of point of entry into palliative care and patient transition outcomes in the model. DESIGN: All participant transition outcomes are tracked from point of entry, including large and small hospitals, nursing facilities, and home/clinic. Evaluation of tracking data was conducted over the first two years of the project (September 1, 2014-September 1, 2016). RESULTS: A total of 2482 patients entered the project, 905 through smaller hospitals (<300 beds, 32%), 474 through larger hospital systems (>500 beds, 17%), 823 from nursing facilities (29%), and 640 in the home/clinic (22%). Hospice transition was highest with home/clinic referrals, followed by nursing facilities, smaller hospitals, and larger hospitals. Palliative care deaths and discharges are higher in larger hospitals. Re-enrollment back into palliative care after previous discharge occurred in 177 (17.8%) of discharged patients. CONCLUSION: CBPC leads to the highest percentage of hospice transitions coming from the home/clinic setting. Differences between small and large hospitals demonstrate a different patient population with higher transitions to hospice and lower palliative care deaths in smaller hospitals.
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Servicios de Salud Comunitaria/estadística & datos numéricos , Cuidados Paliativos al Final de la Vida/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Cuidados Paliativos/estadística & datos numéricos , Alta del Paciente/estadística & datos numéricos , Transferencia de Pacientes/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Medicare , Estados UnidosRESUMEN
CONTEXT: The Palliative Care Research Cooperative Group (PCRC) is the first clinical trials cooperative for palliative care in the U.S. OBJECTIVES: To describe barriers and strategies for recruitment during the inaugural PCRC clinical trial. METHODS: The parent study was a multisite randomized controlled trial enrolling adults with life expectancy anticipated to be one to six months, randomized to discontinue statins (intervention) vs. to continue on statins (control). To study recruitment best practices, we conducted semistructured interviews with 18 site principal investigators (PIs) and clinical research coordinators (CRCs) and reviewed recruitment rates. Interviews covered three topics: 1) successful strategies for recruitment, 2) barriers to recruitment, and 3) optimal roles of the PI and CRC. RESULTS: All eligible site PIs and CRCs completed interviews and provided data on statin protocol recruitment. The parent study completed recruitment of 381 patients. Site enrollment ranged from 1 to 109 participants, with an average of 25 enrolled per site. Five major barriers included difficulty locating eligible patients, severity of illness, family and provider protectiveness, seeking patients in multiple settings, and lack of resources for recruitment activities. Five effective recruitment strategies included systematic screening of patient lists, thoughtful messaging to make research relevant, flexible protocols to accommodate patients' needs, support from clinical champions, and the additional resources of a trials cooperative group. CONCLUSION: The recruitment experience from the multisite PCRC yields new insights into methods for effective recruitment to palliative care clinical trials. These results will inform training materials for the PCRC and may assist other investigators in the field.
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Cuidados Paliativos , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Entrevistas como Asunto , Estudios Multicéntricos como Asunto , Cuidados Paliativos/métodos , Estados UnidosRESUMEN
PURPOSE: Cancer-related fatigue (CRF) is the most common symptom in patients with advanced cancer. The primary objective of this prospective, randomized, double-blind, placebo-controlled study was to compare the effect of dexamethasone and placebo on CRF. PATIENTS AND METHODS: Patients with advanced cancer with ≥ three CRF-related symptoms (ie, fatigue, pain, nausea, loss of appetite, depression, anxiety, or sleep disturbance) ≥ 4 of 10 on the Edmonton Symptom Assessment Scale (ESAS) were eligible. Patients were randomly assigned to either dexamethasone 4 mg or placebo orally twice per day for 14 days. The primary end point was change in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F) subscale from baseline to day 15. Secondary outcomes included anorexia, anxiety, depression, and symptom distress scores. RESULTS: A total of 84 patients were evaluable (dexamethasone, 43; placebo, 41). Mean (± standard deviation) improvement in the FACIT-F subscale at day 15 was significantly higher in the dexamethasone than in the placebo group (9 [± 10.3] v 3.1 [± 9.59]; P = .008). The improvement in FACIT-F total quality-of-life scores was also significantly better for the dexamethasone group at day 15 (P = .03). The mean differences in the ESAS physical distress scores at day 15 were significantly better for the dexamethasone group (P = .013, respectively). No differences were observed for ESAS overall symptom distress (P = .22) or psychological distress score (P = .76). Frequency of adverse effects was not significantly different between groups (41 of 62 v 44 of 58; P = .14). CONCLUSION: Dexamethasone is more effective than placebo in improving CRF and quality of life in patients with advanced cancer.
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Dexametasona/uso terapéutico , Fatiga/tratamiento farmacológico , Neoplasias/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/efectos adversos , Método Doble Ciego , Fatiga/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/psicología , Estudios Prospectivos , Calidad de VidaRESUMEN
OBJECTIVES: Excessive blood loss during liver surgery contributes to postoperative morbidity and mortality and the minimizing of blood loss improves outcomes. This study examines pre- and intraoperative factors contributing to blood loss and identifies areas for improvement. METHODS: All patients who underwent elective hepatic resection between June 2007 and June 2009 were identified. Detailed information on the pre- and perioperative clinical course was analysed. Univariate and multivariate analyses were used to identify factors associated with intraoperative blood loss. RESULTS: A total of 175 patients were studied, of whom 95 (54%) underwent resection of three or more segments. Median blood loss was 782 ml. Greater blood loss occurred during major resections and prolonged surgery and was associated with an increase in postoperative complications (P= 0.026). Peak central venous pressure (CVP) of >10 cm H(2)O was associated with increased blood loss (P= 0.01). Although no differences in case mix were identified, blood loss varied significantly among anaesthetists, as did intraoperative volumes of i.v. fluids and transfusion practices. CONCLUSIONS: This study confirms a relationship between CVP and blood loss in hepatic resection. Intraoperative CVP values were higher than those described in other studies. There was variation in the intraoperative management of patients. Collaboration between surgical and anaesthesia teams is required to minimize blood loss and the standardization of intraoperative anaesthesia practice may improve outcomes following liver surgery.
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Pérdida de Sangre Quirúrgica/prevención & control , Hepatectomía/efectos adversos , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Anestesia General/efectos adversos , Presión Venosa Central , Distribución de Chi-Cuadrado , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Atención Perioperativa , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Escocia , Reacción a la Transfusión , Adulto JovenRESUMEN
OBJECTIVES: Epidural analgesia is often considered the reference standard for pain relief following major abdominal surgery; however, the provision of analgesia in the context of liver surgery raises unique challenges. This study investigated the effectiveness of analgesia and the postoperative course of patients who did or did not receive epidural analgesia following liver resection. METHODS: Data were collected retrospectively on 177 patients who underwent open liver resection between June 2007 and June 2009. Patients were divided into two groups consisting, respectively, of those who received epidural analgesia (Epidural group, n= 148) and those who did not (No-Epidural group, n= 29). RESULTS: In the Epidural group, 27 patients (18%) required i.v. opiate analgesia on the day of surgery (DoS) or the first postoperative day (POD1). The Epidural group received significantly more i.v. colloid solution on the DoS (median: 1500 ml vs. 750 ml, range: 0-12,000 ml vs. 0-3500 ml; P= 0.004) and POD1 (median: 0 ml vs. 0 ml, range: 0-5000 ml vs. 0-1000 ml; P= 0.018), and total fluid on the DoS and POD1 combined (median: 6522 ml vs. 5453 ml, range: 2150-21 300 ml vs. 2875-15,886 ml; P= 0.032). CONCLUSIONS: Epidural analgesia provided inadequate postoperative pain relief in approximately 20% of liver resection patients and was associated with the administration of significantly greater volumes of i.v. colloid solution.