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In the setting of flecainide toxicity, supraventricular tachycardia can manifest as a bizarre right or left bundle branch block, sometimes with a northwest axis, and can easily be mistaken for ventricular tachycardia leading to inappropriate therapy. We conducted a comprehensive literature review for cases of flecainide toxicity. We found 21 articles of flecainide toxicity in adult patients in which 22 ECG tracings were published. In patients with flecainide toxicity and QRS duration ≤ 200 ms, the ECGs were more likely to show RBBB, visible P waves (p = 0.03), and shorter QT (p = 0.02) and QTc intervals (p = 0.004). With QRS duration > 200 ms, the ECGs were more likely to show LBBB, loss of P waves, a northwest axis (p = 0.01), and longer QT and QTc intervals. Deaths were reported only in patients with QRS duration >200 ms, and the outcome of death or requirement for mechanical circulatory support was more prevalent in patients with a QRS duration > 200 ms [2/13 (15.4 %) vs. 6/10 (60 %), p = 0.04]. In patients with access to the medication, flecainide toxicity should be suspected with: (1) broad QRS, (2) RBBB morphology with QRS ≤ 200 ms; RBBB or LBBB morphology with QRS ≥ 200 ms (3) HR out of proportion to the degree of hemodynamic instability. The duration of the QRS interval is prognostic, with mortality and the requirement for mechanical circulatory support being more common in patients with a QRS > 200 ms.

Over the past decade, the Department of Veterans Affairs (VA) Pharmacy Benefits Management Services (PBM) has enhanced its formulary management activities and added programs to ensure that the national drug plan continues to meet the pharmacy needs of veterans and to promote safe and appropriate drug therapy in the face of rising medication expenditures. This article describes the broad range of services provided by the VA PBM that work in partnership to deliver a high-quality and sustainable pharmacy benefit for veterans. In support of formulary management, VA PBM pharmacists prepare extensive clinical guidance documents (e.g., drug monographs and criteria for use) that are used by physicians and pharmacists with operational and clinical oversight of the VA national formulary. The VA PBM has utilized various contracting techniques and continually evaluates drug utilization data to identify opportunities for potential savings. Remarkably, since before 2004, the average acquisition cost for a 1-month supply of medication has remained fairly stable at approximately $13-$15. Two new VA PBM programs are the VA Center for Medication Safety (VA MedSAFE) and the Clinical Pharmacy Practice Office (CPPO). VA MedSAFE is a comprehensive pharmacovigilance program focused on the detection, assessment, and prevention of adverse drug events, and CPPO is dedicated to improving safe and appropriate medication use by supporting and expanding clinical pharmacy practice. Moving forward, the VA PBM will consider new initiatives to stay at the forefront of providing quality care while maintaining economic viability., Disclosures: No outside funding supported this research. This work was supported by VA Pharmacy Benefits Management Services (VA PBM), Hines, Illinois, and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. Glassman is co-director of the VA Center for Medication Safety, which is part of the VA PBM. He is also part of the Medical Advisory Panel for the VA PMB. All other authors are employed by the VA PBM. The views expressed in this article are those of the authors, and no official endorsement by the U.S. Department of Veteran Affairs or the U.S. government is intended or should be inferred. Study concept and design were contributed by Valentino, Cunningham, Good, Aspinall, and Sales. Calabrese and Ourth took the lead in data collection, along with Good, Cunningham, Aspinall, Sales, Burk, Moore, Neuhauser, and Golterman. Data interpretation was performed by Burk, Newhauser, and Golterman, along with Glassman, Calabrese, Moore, and Ourth. The manuscript was written by Aspinall and Sales, along with Burk, Newhauser, Golterman, Ourth, and Cunningham. Good, Glassman, and Moore revised the manuscript, along with Calabrese, Valentino, and Aspinall.

Context: There exists a disparity between the views of physicians and the views of their patients on end-of-life decisions. However, the timing of when the end-of-life preferences of physicians and non-medically-trained individuals diverge is currently unknown. The objective of this paper is to characterise how preferences for medical interventions change throughout medical education and residency or fellowship training when confronted with scenarios of critical or terminal illness., Methods: This is a single-centre cross-sectional study that enrolled medical students at Sidney Kimmel Medical College and residents and fellows at Thomas Jefferson University Hospital. Through an online survey we determined the preferences of medical trainees for specific interventions throughout medical training when presented with different clinical scenarios. Interventions were organised into three categories: standard, intermediate and aggressive. We analysed responses to questions regarding different scenarios in separate repeated measures logistic regression models. The probability of declining medical interventions was modelled, and significant predictors of refusal of interventions were identified., Results: Years of training was a significant predictor of declining interventions for several scenarios. When faced with permanent physical disability, increased years of training led to a higher rate of refusal of intermediate (OR = 1.14 [1.02-1.28], p = 0.02) and aggressive interventions (OR = 1.15 [1.03-1.28], p = 0.01). For the scenario of terminal illness with associated physical disability, years of training significantly influenced refusal of intermediate (OR = 1.14 [1.04-1.26], p = 0.006) and aggressive (OR = 1.20 [1.08-1.34], p = 0.001) interventions. For the scenario of permanent cognitive impairment, increased years of training led to a higher rate of refusal of standard (OR = 1.14 [1.01-1.29], p = 0.03), intermediate (OR = 1.30 [1.13-1.50], p < 0.001) and aggressive (OR = 1.38 [1.14-1.66], p = 0.001) interventions., Conclusion: Changes in end-of-life preferences occur throughout medical training. Years of training influenced the likelihood of declining medical interventions when faced with scenarios of terminal illness and physical or cognitive disability., (© 2016 John Wiley & Sons Ltd.)

The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti-obesity drugs.

With the eruption of the obesity pandemic over the past few decades, much research has been devoted to understanding the molecular mechanisms by which the human body regulates energy balance. These studies have revealed several mediators, including gut/pancreatic/adipose hormones and neuropeptides that control both short- and long-term energy balance by regulating appetite and/or metabolism. These endogenous mediators of energy balance have been the focus of many anti-obesity drug-development programs aimed at either amplifying endogenous anorexigenic/lipolytic signaling or blocking endogenous orexigenic/lipogenic signaling. Here, we discuss the efficacy and safety of targeting these pathways for the pharmacologic treatment of obesity.

The Veterans Health Administration (VHA) runs the largest integrated healthcare system in the nation. Formulary management within VHA primarily involves 3 national groups: the Medical Advisory Panel, the Veterans Integrated Service Network Formulary Leaders, and the Pharmacy Benefits Management Strategic Healthcare Group. Together, these groups manage the VHA national drug formulary with a goal of providing a comprehensive, safe, and cost-effective pharmacy benefit for veterans. Traditionally, VHA has relied on cost-minimization analyses in formulary decisions. More recently, VHA has emphasized the use of cost-effectiveness data, especially for newer, costly drugs. In addition to including this data in drug monographs, the VHA has begun requiring formal cost-effectiveness analysis from manufacturers of selected pharmaceuticals. VHA has also requested that clinically relevant information such as quality of life plus mortality benefit be made available from industry so that internal cost analyses can be performed. It is hoped that by setting the expectation that cost-effectiveness will be formally considered in all VHA formulary decisions, the pharmaceutical industry and others will be stimulated to collect and report data that enables these analyses. We believe that if other organizations also place an emphasis on economic evaluations, industry and the public will be more accepting of decisions that incorporate cost considerations.

The Department of Veterans Affairs (VA) Pharmacy Benefits Management Strategic Healthcare Group (VA PBM) oversees the formulary for the entire VA system, which serves more than 4 million veterans and provides more than 108 million prescriptions per year. Since its establishment in 1995, the VA PBM has managed pharmaceuticals and pharmaceutical-related policies, including drug safety and efficacy evaluations, pharmacologic management algorithms, and criteria for drug use. These evidence-based practices promote, optimize, and assist VA providers with the safe and appropriate use of pharmaceuticals while allowing for formulary decisions that can result in substantial cost savings. The VA PBM also has utilized various contracting techniques to standardize generic agents as well as specific drugs and drug classes (eg, antihistamines, angiotensin-converting enzyme inhibitors, alpha-blockers, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [statins]). These methods have enabled the VA to save approximately dollar 1.5 billion since 1996 even as drug expenditures continued to rise from roughly dollar 1 billion in fiscal year (FY) 1996 to more than dollar 3 billion in FY 2003. Furthermore, the VA PBM has established an outcomes research section to undertake quality-improvement and safety initiatives that ultimately monitor and determine the clinical impact of formulary decisions on the VA system nationwide. The experiences of this pharmacy benefits program, including clinical and contracting processes/procedures and their impact on the VA healthcare system, are described.