"Seeing the Patient Is the Joy:" A Focus Group Analysis of Burnout in Outpatient Providers.

Background And Objectives: The increased demand on providers from health care systems combined with the complex and difficult practice of medicine contributes to provider stress and burnout. In order to develop effective, sustainable interventions for provider burnout, it is important to understand the lived experiences of providers and their perceptions of its causative factors. We describe focus group findings that explore provider perceptions and offer suggestions for future actions.

Extending Our Understanding of Burnout and Its Associated Factors: Providers and Staff in Primary Care Clinics.

Burnout has been identified as an occupational hazard in the helping professions for many years and is often overlooked, as health-care systems strive to improve cost and quality. The Maslach Burnout Inventory (MBI) and the Areas of Worklife Survey (AWS) are tools for assessing burnout prevalence and its associated factors. We describe how we used them in outpatient clinics to assess burnout for multiple job types.

A Bayesian dose-finding trial with adaptive dose expansion to flexibly assess efficacy and safety of an investigational drug.

Background: Adaptive dose-ranging trials are more efficient than traditional approaches and may be designed to explicitly address the goals and decisions inherent in learn-phase drug development. We report the design, implementation, and outcome of an innovative Bayesian, response-adaptive, dose-ranging trial of an investigational drug in patients with diabetes, incorporating a dose expansion approach to flexibly address both efficacy and safety.

Purpose: The design was developed to assess whether one or more doses of an investigational drug demonstrated superior efficacy to an active control while maintaining an acceptable safety profile.

Molecular classification of Crohn's disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells.

Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases.

Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-Cyanoguanidine bioisosteres possessing in vivo bladder selectivity.

A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vivo. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally.

Oxytocin and vasopressin constrict rat isolated uterine resistance arteries by activating vasopressin V1A receptors.

Both oxytocin and vasopressin cause potent and long-lasting vasoconstriction of uterine arteries from several species, including humans, and the resulting tissue ischemia is thought to be involved in the pathogenesis of primary dysmenorrhea. We have studied the effects of oxytocin and vasopressin in isolated resistance arteries (diameter, 90-120 microm) from non-pregnant rat uteri using two potent and selective receptor antagonists, SR 49059, a selective vasopressin V1A antagonist, and atosiban, a selective oxytocin antagonist. Uterine arteries with intact endothelium were mounted in a microvessel chamber, and pressurized to 75 mm Hg to allow the development of myogenic tone.

Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and In vivo bladder instability in rat.

The effects of the ATP-dependent potassium channel agonists ZD6169, celikalim, and WAY-133537 on bladder contractile function were examined in vitro on isolated bladder strips and in vivo on spontaneous bladder contractions. All three compounds produced a concentration-dependent relaxation of isolated rat detrusor strips (IC50 values = 0.93, 0.

Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice.

Mutations in the HERG gene are linked to the LQT2 form of the inherited long-QT syndrome. Transgenic mice were generated expressing high myocardial levels of a particularly severe form of LQT2-associated HERG mutation (G628S). Hearts from G628S mice appeared normal except for a modest enlargement seen only in females.

Characterization of muscarinic receptors mediating the contraction of the urinary detrusor muscle in cynomolgus monkeys and guinea pigs.

We have characterized in vitro the muscarinic receptors mediating the contraction of the detrusor muscle in Cynomolgus monkeys and guinea pigs using carbachol as the agonist and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M3-selective), methoctramine (M2-selective) and pirenzepine (M1-selective) as the antagonists. Carbachol induced a concentration-dependent contraction of the detrusor muscle of monkey and guinea pig yielding similar pD2 values of 6.67+/-0.

Voltage-dependent inhibition of the ATP-sensitive K+ current by the class Ia agent disopyramide in cat ventricular myocytes.

The inhibition of the adenosine triphosphate-sensitive K+ (KATP) current by disopyramide, a class Ia antiarrhythmic drug, was studied using whole cell voltage clamp in cat ventricular myocytes at 37 degrees C and was compared to that seen with quinidine, a prototypical class Ia drug. The inhibition of the levcromakalim-induced KATP current was concentration dependent, with Ki, at -20 mV, of 4.9 +/- 0.

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique.

Cellular electrophysiology of WAY-123,398, a new class III antiarrhythmic agent: specificity of IK block and lack of reverse use dependence in cat ventricular myocytes.

Objective: The objectives were (a) to evaluate the effects of WAY-123,398, a new class III antiarrhythmic agent, on the action potential of canine Purkinje fibres in comparison with dofetilide, E-4031, and dl-sotalol, and (b) to characterise the mechanism of the class III action by studying its effects on several ionic currents in isolated cat myocytes.

Methods: Transmembrane potentials in Purkinje fibres were studied with standard microelectrodes filled with 3M KCl. Myocytes were isolated by enzymatic disaggregation with collagenase and current recordings were obtained by voltage clamp with either the nystatin perforated patch technique or the usual whole cell configuration.

Effects of WAY-123,398, a new class III antiarrhythmic agent, on cardiac refractoriness and ventricular fibrillation threshold in anesthetized dogs: a comparison with UK-68798, E-4031, and dl-sotalol.

Previous studies in isolated ventricular myocytes showed that WAY-123,398 is a selective blocker of the delayed rectifier K+ current (IK). In this report, we studied the electrophysiological and hemodynamic effects of WAY-123,398 in open-chest anesthetized dogs. WAY-123,398 prolonged atrial and ventricular refractoriness without affecting conduction; WAY-123,398 was as effective as UK-68798, E-4031, and dl-sotalol, but less potent than UK-68798 and E-4031.

Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides.

The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization.

Synthesis and selective class III antiarrhythmic activity of novel N-heteroaralkyl-substituted 1-(aryloxy)-2-propanolamine and related propylamine derivatives.

The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None of these compounds showed any class I activity.

Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil.

We tested the hypothesis that a selective increase in membrane current, as contrasted with the decreases in currents caused by most antiarrhythmic agents, would be an effective antiarrhythmic intervention. We studied models of early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and abnormal automaticity in single canine ventricular myocytes using intracellular microelectrodes or patch electrodes. EADs were induced by injected current, Bay K 8644 (0.

Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs.

The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.

Mechanisms of termination of reentrant atrial arrhythmias by class I and class III antiarrhythmic agents.

We studied atrial flutter due to circus movement in chronically instrumented conscious dogs to identify the mechanism by which class I and class III antiarrhythmic drugs terminate reentrant excitation. We used a crossover experimental design administering five class I agents and one class III agent, by intravenous bolus followed by intravenous infusion. The class I agents other than lidocaine were almost uniformly effective in terminating the arrhythmia (disopyramide in six of seven dogs, propafenone in six of six, flecainide in seven of seven, and SC-40230 in seven of seven).

Some recent concepts concerning the mechanisms of action of antiarrhythmic drugs.

The administration of antiarrhythmic drugs is determined largely on the basis of empiricism, and the experience of individual physicians and the results of clinical studies are probably the two major factors determining the approach to treatment. Although much effort has been expended in learning the mechanisms of action of antiarrhythmic drugs, the applicability to clinical treatment of the knowledge attained has been limited. Nonetheless, recent advances in our understanding of the biology of the cardiac cell, of the factors that predispose to arrhythmias and of drug-receptor interactions, have not only provided new insights into the mechanisms whereby specific drugs exert their effects, but promise to provide means for designing and testing compounds whose actions will be more specific and more predictable than is presently the case.

Reduction of Vmax by QX-314 and benzocaine in neonatal and adult canine cardiac Purkinje fibers.

The authors have previously shown that the use-dependent action of lidocaine on the Vmax of canine Purkinje fibers and on intraventricular conduction in the in situ heart undergoes significant developmental changes. In this study, they use standard microelectrode techniques to test whether these age-related differences are due to the charged, more hydrophilic form or to the uncharged, more lipophilic form of a local anesthetic. QX-314, a permanently charged lidocaine derivative, depressed Vmax to a significantly greater extent in adult than in neonatal Purkinje fibers.

Cardiac electrophysiologic effects of R 54718.

We studied the cellular electrophysiologic effects of a lidocaine derivative, R-54718, that has been found effective in treating arrhythmias in experimental animals and in human subjects. R-54718 depresses Vmax, action potential amplitude, and conduction and accelerates repolarization of the canine Purkinje fiber action potential, with an effective concentration range 2 or 3 orders of magnitude lower than that of most class I antiarrhythmic drugs. Its action on Vmax shows no use dependence.

The effects of doxorubicin on ventricular tachycardia.

Doxorubicin, in concentrations that have no effect on fast or slow response action potentials, has been shown to suppress ouabain-induced delayed afterdepolarizations. In this study, we used standard microelectrode techniques to determine the effects of doxorubicin on isolated canine Purkinje fibers. We studied automaticity induced at normal and low membrane potentials, conduction in normal and K+-depolarized Purkinje fibers, and triggered activity induced by ouabain and by experimental myocardial infarction.