Disparities in underserved white populations: the case of cancer-related disparities in Appalachia

There are meaningful cancer-related disparities in the Appalachian region of the U.S. To address these disparities, the Appalachia Community Cancer Network (ACCN), a collaboration of investigators and community partners in five states (Kentucky, Ohio, Pennsylvania, Virginia, and West Virginia), is involved in increasing cancer education and awareness, conducting community-based participatory research (CBPR), and creating mentorship and training opportunities. The primary objective of this paper is to describe cancer-related disparities in the Appalachian region of the U.S. as an example of the disparities experienced by underserved, predominantly white, rural populations, and to describe ACCN activities designed to intervene regarding these disparities. An ACCN overview/history and the diverse activities of ACCN-participating states are presented in an effort to suggest potential useful strategies for working to reduce health-related disparities in underserved white populations. Strengths that have emerged from the ACCN approach (e.g., innovative collaborations, long-standing established networks) and remaining challenges (e.g., difficulties with continually changing communities, scarce resources) are described. Important recommendations that have emerged from the ACCN are also presented, including the value of allowing communities to lead CBPR efforts. Characteristics of the community-based work of the ACCN provide a framework for reducing health-related disparities in Appalachia and in other underserved white and rural populations.     

Invasive mediastinal staging of non-small-cell lung cancer: a clinical practice guideline

Introduction

In non-small-cell lung cancer (nsclc), invasive mediastinal staging is typically used to guide treatment decision-making. Here, we present clinical practice guideline recommendations for invasive mediastinal staging in nsclc patients who have been staged T1–4, N0–3, with no distant metastases.

Methods

Draft recommendations were formulated based on the best available evidence gathered by a systematic review and a consensus of expert opinion. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline.

Results

In general, most clinical experts agreed with the guideline, approving it for methodologic rigour. More than 80% of the surveyed practitioners gave it a high quality rating. The expert reviewers also provided written comments, with some of the suggested changes being incorporated into the final version of the guideline.

Conclusions

In the clinical practice guideline, invasive mediastinal staging of nsclc is recommended in all cases except those involving patients with normal-sized lymph nodes, negative combine positron-emission tomography and computed tomography, and peripheral clinical stage 1A tumour. When performing mediastinoscopy, 5 nodal stations (2R/L, 4R/L, and 7) should routinely be examined.     

Barriers to Expanding Advanced Pharmacy Practice Experience Site Availability in an Experiential Education Consortium

Objectives

To compare 2006-2007 and projected 2010-2011 advanced pharmacy practice experience (APPE) availability and needs for 4 colleges and schools of pharmacy in Georgia and Alabama and to examine barriers and offer potential solutions to increase APPE site and preceptor availability.

Methods

Data on APPE needs and availability were gathered prospectively and evaluated relative to current and projected enrollment and planned programmatic changes.

Results

Combined 2006-2007 non-community APPE needs and availabilities were 3,590 and 4,427, respectively, with a surplus availability of 837. Combined projected 2010-2011 non-community APPEs were estimated at 4,309. Assuming 2006-2007 non-community availability remained unchanged, the surplus availability declined to 118.

Conclusions

The need for quality experiential education represents a significant barrier and rate-limiting step to the matriculation of the increased numbers of pharmacists. Barriers to expanding APPE availability include: introductory pharmacy practice experience (IPPE) and APPE expansion, growth of new and existing pharmacy programs, financial instability of acute care facilities, and lack of preceptor development resources. Regional experiential education consortiums can provide a constructive approach to improve access to quality sites and preceptors through standardizing processes and leveraging resources.     

Cytokines in central nervous system trypanosomiasis: cause, effect or both?

The late, or encephalitic, stage of human African trypanosomiasis (HAT), or sleeping sickness, is typified by a diffuse meningoencephalitis characterised neuropathologically by perivascular infiltration of inflammatory cells. While the cause of this neuroinflammatory reaction is not understood, there is evidence for the roles of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha and counter-inflammatory cytokines such as IL-10, with the balance of these influencing disease outcome. Because of the practical difficulties of obtaining serial measurements in patients, it has proved difficult to assign either cause or effect properties to measured cytokines, but mechanistic animal modelling studies are proving helpful.     

The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.     

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.     

Novel peroxisome proliferator-activated receptor alpha agonists lower low-density lipoprotein and triglycerides, raise high-density lipoprotein, and synergistically increase cholesterol excretion with a liver X receptor agonist

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.     

Asystole during laryngoscopy of a patient with pleural and pericardial effusions: a case report

A 53-year-old woman presented to the operating room for surgical correction of pericardial and pleural effusions. Her history included stage IV breast cancer, well-controlled hypertension, and diverticulitis. Although her baseline blood pressure, heart rate, and respirations were normal, she was short of breath with diminished breath sounds on the left side of the lungs and required oxygen, 2 L/min via nasal cannula. The nurse anesthesia student, under the direction of the Certified Registered Nurse Anesthetist (CRNA) and anesthesiologist, induced general anesthesia with etomidate, fentanyl, lidocaine, and succinylcholine. During placement of a double-lumen endotracheal tube, the patient became asystolic. The nurse anesthesia student immediately withdrew the laryngoscope, and the patient returned to normal sinus rhythm. A second attempt at laryngoscopy produced asystole as well. Again, the laryngoscope was withdrawn, and the patient returned to normal sinus rhythm. After resuming ventilation with 100% oxygen and administering atropine, 0.4 mg, the next intubation was successful, producing no untoward effects. Reintubation at the end of the case with a single lumen endotracheal tube was uneventful. The patient was transported to the intensive care unit and mechanically ventilated overnight. The next morning, she was extubated with no further anesthetic complications.