A Quality Improvement Initiative to Reduce Unnecessary Rapid Responses Using Early Warning Scores.

OBJECTIVES: The Pediatric Early Warning Score (PEWS) is an evidence-based tool that allows early collaborative assessment and intervention for a rapid response team (RRT) activation. The goal of our quality improvement initiative was to reduce the percentage of unnecessary RRT activations by 50% over 2 years without increasing PICU transfers or compromising patient safety and timely evaluation. METHODS: A PEWS system replaced preexisting vital signs-based pediatric RRT criteria and was modified through plan-do-study-act cycles. Unnecessary RRT activations, total RRT activation rate, transfers to the PICU, total clinical interventions performed per RRT, and missed RRT activation rate were compared between intervention periods. Likert scale surveys were administered to measure satisfaction with each modification. RESULTS: There was a significant decrease in the percentage of unnecessary RRT activations from 33% to 3.5% after the implementation of the PEWS and modified-PEWS systems (P < .05). The RRT activation rate decreased from 22.6 to 13.3 RRT activations per 1000 patient care days after implementation of the PEWS and modified-PEWS systems (P < .05), without changes in PICU transfer rates. Physicians reported that the PEWS system improved nursing communication and accuracy of RRT criteria (P < .05). Nursing reported that the PEWS system improved patient management and clinical autonomy (P < .05). CONCLUSIONS: The PEWS systems have been an effective means of identifying deteriorating pediatric patients and reducing unnecessary RRT activations. The new system fosters collaboration and communication at the bedside to prevent acute deterioration, perform timely interventions, and ultimately improve patient safety and outcomes.

Evaluating the abnormal ossification in tibiotarsi of developing chick embryos exposed to 1.0ppm doses of platinum group metals by spectroscopic techniques.

Platinum group metals (PGMs), i.e., palladium (Pd), platinum (Pt) and rhodium (Rh), are found at pollutant levels in the environment and are known to accumulate in plant and animal tissues. However, little is known about PGM toxicity. Our previous studies showed that chick embryos exposed to PGM concentrations of 1mL of 5.0ppm (LD50) and higher exhibited severe skeletal deformities. This work hypothesized that 1.0ppm doses of PGMs will negatively impact the mineralization process in tibiotarsi. One milliliter of 1.0ppm of Pd(II), Pt(IV), Rh(III) aqueous salt solutions and a PGM-mixture were injected into the air sac on the 7th and 14th day of incubation. Control groups with no-injection and vehicle injections were included. On the 20th day, embryos were sacrificed to analyze the PGM effects on tibiotarsi using four spectroscopic techniques. 1) Micro-Raman imaging: Hyperspectral Raman data were collected on paraffin embedded cross-sections of tibiotarsi, and processed using in-house-written MATLAB codes. Micro-Raman univariate images that were created from the ν1(PO4(3-)) integrated areas revealed anomalous mineral inclusions within the bone marrow for the PGM-mixture treatment. The age of the mineral crystals (ν(CO3(2-))/ν1(PO4(3-))) was statistically lower for all treatments when compared to controls (p≤0.05). 2) FAAS: The percent calcium content of the chemically digested tibiotarsi in the Pd and Pt groups changed by ~45% with respect to the no-injection control (16.1±0.2%). 3) Micro-XRF imaging: Abnormal calcium and phosphorus inclusions were found within the inner longitudinal sections of tibiotarsi for the PGM-mixture treatment. A clear increase in the mineral content was observed for the outer sections of the Pd treatment. 4) ICP-OES: PGM concentrations in tibiotarsi were undetectable (<5ppb). The spectroscopic techniques gave corroborating results, confirmed the hypothesis, and explained the observed pathological (skeletal developmental abnormalities) and histological changes (tibiotarsus ischemia and nuclear fragmentation in chondrocytes).

Translation and adaptation of the life stressor checklist-revised with Colombian women.

We undertook the translation and adaptation of an instrument developed to measure women's lifetime trauma exposure, the Life Stressor Checklist-Revised (LSC-R), in order to determine its utility and cultural appropriateness with Colombian Spanish-speaking women. The LSC-R was forward and backward translated and administered to a sample (N = 217) of community-based women volunteers in Medellín, Colombia. Open-ended questions were included to assess the construct validity and cultural appropriateness of the LSC-R. The LSC-R was found to be valid and easily understood. Trauma exposure was common, but its assessment was not overly distressing to Colombian women.

Measuring stigma in people with lung cancer: psychometric testing of the cataldo lung cancer stigma scale.

PURPOSE/OBJECTIVES: to develop an instrument to measure the stigma perceived by people with lung cancer based on the HIV Stigma Scale. DESIGN: psychometric analysis. SETTING: online survey. SAMPLE: 186 patients with lung cancer. METHODS: an exploratory factor analysis with a common factor model using alpha factor extraction. MAIN RESEARCH VARIABLES: lung cancer stigma, depression, and quality of life. FINDINGS: four factors emerged: stigma and shame, social isolation, discrimination, and smoking. Inspection of unrotated first-factor loadings showed support for a general stigma factor. Construct validity was supported by relationships with related constructs: self-esteem, depression, social support, and social conflict. Coefficient alphas ranging from 0.75-0.97 for the subscales (0.96 for stigma and shame, 0.97 for social isolation, 0.9 for discrimination, and 0.75 for smoking) and 0.98 for the 43-item Cataldo Lung Cancer Stigma Scale (CLCSS) provided evidence of reliability. The final version of the CLCSS was 31 items. Coefficient alpha was recalculated for the total stigma scale (0.96) and the four subscales (0.97 for stigma and shame, 0.96 for social isolation, 0.92 for discrimination, and 0.75 for smoking). CONCLUSIONS: the CLCSS is a reliable and valid measure of health-related stigma in this sample of people with lung cancer. IMPLICATIONS FOR NURSING: the CLCSS can be used to identify the presence and impact of lung cancer stigma and allow for the development of effective stigma interventions for patients with lung cancer.

A cell-sparing electric field stimulation technique for high-throughput screening of voltage-gated ion channels.

The Trans Cell Layer Electrical Field Stimulation (TCL-EFS) system has been developed for high-throughput screening (HTS) of voltage-gated ion channels in microplate format on a Voltage-Ion Probe Reader (VIPR) platform. In this design, a wire electrode is placed above the cell layer of each filter well, and a whole plate perimeter electrode resides beneath the filter layer. This configuration allows the electrodes to be placed away from the cell layer to minimize the near electrode field effects on cell function and dye bleaching observed with other existing designs. Mathematical simulation indicates that the electric field at the cell layer becomes uniform as the top electrode is raised to a position near the surface of the solution in the well. Using the TCL-EFS system and membrane potential fluorescence resonance energy transfer (FRET) dyes, the sensitivity of voltage-gated sodium channels to tetrodotoxin and other channel inhibitors was found to be similar to those determined by established electrophysiological and more conventional VIPR techniques. A good correlation was also observed with the TCL-EFS system for inhibition of Cav2.2 by omega-conotoxin-GVIA and for block of Cav1.2 by known small molecule inhibitors. Thus, the TCLEFS system is suitable for both quantitative analysis and HTS of voltage-gated sodium and calcium channels, without the liabilities of previously reported EFS methodologies.

A high-capacity membrane potential FRET-based assay for NaV1.8 channels.

Clinical treatment of neuropathic pain can be achieved with a number of different drugs, some of which interact with all members of the voltage-gated sodium channel (NaV1) family. However, block of central nervous system and cardiac NaV1 channels can cause dose-limiting side effects, preventing many patients from achieving adequate pain relief. Expression of the tetrodotoxin-resistant NaV1.8 subtype is restricted to small-diameter sensory neurons, and several lines of evidence indicate a role for NaV1.8 in pain processing. Given these features, NaV1.8 subtype-selective blockers are predicted to be efficacious in the treatment of neuropathic pain and to be associated with fewer adverse effects than currently available therapies. To facilitate the identification of NaV1.8-specific inhibitors, we stably expressed the human NaV1.8 channel together with the auxiliary human beta1 subunit (NaV beta1) in human embryonic kidney 293 cells. Heterologously expressed human NaV1.8/NaV beta1 channels display biophysical properties that are similar to those of tetrodotoxin-resistant channels present in mouse dorsal root ganglion neurons. A membrane potential, fluorescence resonance energy transfer-based functional assay on a fluorometric imaging plate reader (FLIPR-Tetra, Molecular Devices, Sunnyvale, CA) platform has been established. This highcapacity assay is sensitive to known state-dependent NaV1 modulators and can be used to identify novel and selective NaV1.8 inhibitors.

Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion.

Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes.

Stichodactyla helianthus peptide, a pharmacological tool for studying Kv3.2 channels.

Voltage-gated potassium (Kv) channels regulate many physiological functions and represent important therapeutic targets in the treatment of several clinical disorders. Although some of these channels have been well-characterized, the study of others, such as Kv3 channels, has been hindered because of limited pharmacological tools. The current study was initiated to identify potent blockers of the Kv3.2 channel. Chinese hamster ovary (CHO)-K1 cells stably expressing human Kv3.2b (CHO-K1.hKv3.2b) were established and characterized. Stichodactyla helianthus peptide (ShK), isolated from S. helianthus venom and a known high-affinity blocker of Kv1.1 and Kv1.3 channels, was found to potently inhibit 86Rb+ efflux from CHO-K1.hKv3.2b (IC50 approximately 0.6 nM). In electrophysiological recordings of Kv3.2b channels expressed in Xenopus laevis oocytes or in planar patch-clamp studies, ShK inhibited hKv3.2b channels with IC50 values of approximately 0.3 and 6 nM, respectively. Despite the presence of Kv3.2 protein in human pancreatic beta cells, ShK has no effect on the Kv current of these cells, suggesting that it is unlikely that homotetrameric Kv3.2 channels contribute significantly to the delayed rectifier current of insulin-secreting cells. In mouse cortical GABAergic fast-spiking interneurons, however, application of ShK produced effects consistent with the blockade of Kv3 channels (i.e., an increase in action potential half-width, a decrease in the amplitude of the action potential after hyperpolarization, and a decrease in maximal firing frequency in response to depolarizing current injections). Taken together, these results indicate that ShK is a potent inhibitor of Kv3.2 channels and may serve as a useful pharmacological probe for studying these channels in native preparations.

Is Internet-based support for dyspnea self-management in patients with chronic obstructive pulmonary disease possible? Results of a pilot study.

BACKGROUND: As of 2003, approximately 67% of US adults have Internet access. The purpose of this study was to determine the feasibility and preliminary efficacy of an Internet-based dyspnea self-management program (iDSMP) for people with chronic obstructive pulmonary disease. A related aim was to compare the differential effects of the iDSMP on 2 different groups: (1) to test a "booster" effect and (2) to evaluate the program as a primary intervention. METHODS: Two groups (n = 16) were evaluated at baseline and at 3 months after completing the iDSMP, which included education, exercise, self-monitoring, and support. Dyspnea, self-efficacy, perception of available support, and exercise behavior were measured. Paired, independent t tests and Mann-Whitney U tests were used. RESULTS: Most subjects (87%) reported that the program increased their access to information and resources for managing dyspnea. Dyspnea with activities of daily living and self-efficacy for managing the symptom showed significant improvements (both P < .01), whereas more modest changes were noted in perceived support and exercise behavior in the overall sample. There were no differences between the 2 groups on these outcomes. CONCLUSIONS: The findings suggest that additional investigations of Internet-based interventions to promote self-management in patients with chronic obstructive pulmonary disease are warranted.

Potent Kv1.3 inhibitors from correolide-modification of the C18 position.

Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation.

Functional assay of voltage-gated sodium channels using membrane potential-sensitive dyes.

The discovery of novel therapeutic agents that act on voltage-gated sodium channels requires the establishment of high-capacity screening assays that can reliably measure the activity of these proteins. Fluorescence resonance energy transfer (FRET) technology using membrane potential-sensitive dyes has been shown to provide a readout of voltage-gated sodium channel activity in stably transfected cell lines. Due to the inherent rapid inactivation of sodium channels, these assays require the presence of a channel activator to prolong channel opening. Because sodium channel activators and test compounds may share related binding sites on the protein, the assay protocol is critical for the proper identification of channel inhibitors. In this study, high throughput, functional assays for the voltage-gated sodium channels, hNa(V)1.5 and hNa(V)1.7, are described. In these assays, channels stably expressed in HEK cells are preincubated with test compound in physiological medium and then exposed to a sodium channel activator that slows channel inactivation. Sodium ion movement through open channels causes membrane depolarization that can be measured with a FRET dye membrane potential-sensing system, providing a large and reproducible signal. Unlike previous assays, the signal obtained in the agonist initiation assay is sensitive to all sodium channel modulators that were tested and can be used in high throughput mode, as well as in support of Medicinal Chemistry efforts for lead optimization.

Supporting cardiac recovery through eHealth technology.

The Internet continues to evolve as a popular and increasingly vital channel for health information and communication among patients, families, and health providers. This article provides an overview of published studies that have described or tested Internet-based resources and interventions designed to support recovery and enhance health outcomes for the cardiac population. Three categories of applications are discussed: (1) peer support communities; (2) information support through automated, tailored patient education; and (3) professionally facilitated education and support programs. The article also address key issues such as barriers to innovation adoption, patient literacy, and the digital divide that must be overcome for successful integration of such interventions into clinical practice. How Internet-based interventions will fit with existing conventional programs and clinical practice structures is not yet clear. However, evidence that supports use of this new communication channel is likely to emerge as more programs are developed and rigorously evaluated.

Damage loss assessment and control of the cereal leaf beetle (Coleoptera: Chrysomelidae) in winter wheat.

Cereal leaf beetle, Oulema melanopus (L.), invaded northern Alabama and Georgia more than a decade ago and since has become an economic pest of winter wheat and other cereal crops in the southeastern United States. A series of trials was conducted beginning in 1995 to determine optimal rate and timing of applications of selected foliar insecticides for managing cereal leaf beetle in soft red winter wheat. These trials, cage studies with larvae, and a manual defoliation experiment were used to provide information on cereal leafbeetle yield loss relationships and to develop economic decision rules for cereal leaf beetle in soft red winter wheat. Malathion, methomyl, carbaryl, and spinosad effectively controlled larval infestations when treatments were applied after most eggs had hatched. Encapsulated endotoxin of Bacillus thuringiensis, methyl parathion, and disulfoton applied at the lowest labeled rates were not effective treatments. Organophosphate insecticides generally were not effective when applied before most eggs had hatched. The most effective treatments were the low rates of lambda cyhalothrin when applied early while adults were still laying eggs and before or near 50% egg hatch. These early applications applied at or before spike emergence virtually eliminated cereal leaf beetle injury. The manual defoliation study demonstrated that defoliation before spike emergence has greater impact on grain yield and yield components than defoliation after spike emergence. Furthermore, flag leaf defoliation causes more damage than injury to lower leaves. Grain test weight and kernel weight were not affected by larval injury in most trials. Regression of larval numbers and yield losses calculated a yield loss of 12.65% or 459 kg/ha per larva per stem, which at current application costs suggested an economic threshold of 0.4 larvae per stem during the spike emergence to anthesis stages.

Internet-based patient education and support interventions: a review of evaluation studies and directions for future research.

The Internet provides patients, families, and health providers with unparalleled opportunities to learn, inform, and communicate with one another. This paper is a review of studies that have evaluated the impact of professionally facilitated Internet-based programs for diverse clinical populations on health outcomes, utilization, and user satisfaction. The findings suggest that some outcomes in certain groups can be moderately improved and that user satisfaction has been generally positive. Given the increasing need to provide timely and effective patient-centered care, a stronger evidence base for eHealth applications must be established before broader deployment of such programs will take place.

Expression of voltage-gated potassium channels in human and rhesus pancreatic islets.

Voltage-gated potassium channels (Kv channels) are involved in repolarization of excitable cells. In pancreatic beta-cells, prolongation of the action potential by block of delayed rectifier potassium channels would be expected to increase intracellular free calcium and to promote insulin release in a glucose-dependent manner. However, the specific Kv channel subtypes responsible for repolarization in beta-cells, most importantly in humans, are not completely resolved. In this study, we have investigated the expression of 26 subtypes from Kv subfamilies in human islet mRNA. The results of the RT-PCR analysis were extended by in situ hybridization and/or immunohistochemical analysis on sections from human or Rhesus pancreas. Cell-specific markers were used to show that Kv2.1, Kv3.2, Kv6.2, and Kv9.3 are expressed in beta-cells, that Kv3.1 and Kv6.1 are expressed in alpha-cells, and that Kv2.2 is expressed in delta-cells. This study suggests that more than one Kv channel subtype might contribute to the beta-cell delayed rectifier current and that this current could be formed by heterotetramers of active and silent subunits.

Substitution of a single residue in Stichodactyla helianthus peptide, ShK-Dap22, reveals a novel pharmacological profile.

ShK, a peptide isolated from Stichodactyla helianthus venom, blocks the voltage-gated potassium channels, K(v)1.1 and K(v)1.3, with similar high affinity. ShK-Dap(22), a synthetic derivative in which a diaminopropionic acid residue has been substituted at position Lys(22), has been reported to be a selective K(v)1.3 inhibitor and to block this channel with equivalent potency as ShK [Kalman et al. (1998) J. Biol. Chem. 273, 32697-32707]. In this study, a large body of evidence is presented which indicates that the potencies of wild-type ShK peptide for both K(v)1.3 and K(v)1.1 channels have been previously underestimated. Therefore, the affinity of ShK-Dap(22) for both channels appears to be ca. 10(2)-10(4)-fold weaker than ShK. ShK-Dap(22) does display ca. 20-fold selectivity for human K(v)1.3 vs K(v)1.1 when measured by the whole-cell voltage clamp method but not in equilibrium binding assays. ShK-Dap(22) has low affinity for K(v)1.2 channels, but heteromultimeric K(v)1.1-K(v)1.2 channels form a receptor with ca. 200-fold higher affinity for ShK-Dap(22) than K(v)1.1 homomultimers. In fact, K(v)1.1-K(v)1.2 channels bind ShK-Dap(22) with only ca. 10-fold less potency than ShK and reveal a novel pharmacology not predicted from the homomultimers of K(v)1.1 or K(v)1.2. The concentrations of ShK-Dap(22) needed to inhibit human T cell activation were ca. 10(3)-fold higher than those of ShK, in good correlation with the relative affinities of these peptides for inhibiting K(v)1.3 channels. All of these data, taken together, suggest that ShK-Dap(22) will not have the same in vivo immunosuppressant efficacy of other K(v)1.3 blockers, such as margatoxin or ShK. Moreover, ShK-Dap(22) may have undesired side effects due to its interaction with heteromultimeric K(v)1.1-K(v)1.2 channels, such as those present in brain and/or peripheral tissues.

Di-substituted cyclohexyl derivatives bind to two identical sites with positive cooperativity on the voltage-gated potassium channel, K(v)1.3.

Di-substituted cyclohexyl (DSC) derivatives inhibit the voltage-gated potassium channel, K(v)1.3, and have immunosuppressant activity (Schmalhofer et al. (2002) Biochemistry 41, 7781-7794). This class of inhibitors displays Hill coefficients of near 2 in functional assays, and trans DSC analogues appear to selectively interact with K(v)1.3 channel conformations related to C-type inactivation. To further understand the details of the DSC inhibitor interaction with potassium channels, trans-1-(N-n-propylcarbamoyloxy)-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclo-hexane (trans-NPCO-DSC) was radiolabeled with tritium, and its binding characteristics to K(v)1.3 channels were determined. Specific binding of [(3)H]-trans-NPCO-DSC to K(v)1.3 channels is a saturable, time-dependent, and fully reversible process. Saturation binding isotherms and competition binding experiments are consistent with the presence of two receptor sites for DSC derivatives on the K(v)1.3 channel that display positive allosteric cooperativity. The high affinity interaction of [(3)H]-trans-NPCO-DSC with K(v)1.3 channels appears to correlate with the rates of C-type inactivation of the channel. These data, taken together, mark the first demonstration of the existence of multiple binding sites for an inhibitor of an ion channel and suggest that the high affinity interaction of trans-NPCO-DSC and similar inhibitors with K(v)1.3 channels could be exploited for the development of selective molecules that target this protein.

Benzamide derivatives as blockers of Kv1.3 ion channel.

The voltage-gated potassium channel, Kv1.3, is present in human T-lymphocytes. Blockade of Kv1.3 results in T-cell depolarization, inhibition of T-cell activation, and attenuation of immune responses in vivo. A class of benzamide Kv1.3 channel inhibitors has been identified. The structure-activity relationship within this class of compounds in two functional assays, Rb_Kv and T-cell proliferation, is presented. In in vitro assays, trans isomers display moderate selectivity for binding to Kv1.3 over other Kv1.x channels present in human brain.

Culturally appropriate family assessment: analysis of the Family Assessment Device in a pediatric Chinese population.

As part of a larger study, we investigated the adaptation of the Family Assessment Device (FAD) to a Chinese population of hospitalized children (N = 313) compared to a sample of families with healthy children (N = 29) in Hong Kong and Chinese Mainland. Confirmatory factor analysis and exploratory factor analysis (EFA) were performed to examine the FAD structure. The results supported the notion of cultural variations in measuring family functioning. Eight factors were found to explain 30.34% of the variance in family functioning. The Cronbach's alphas of families with hospitalized children ranged from 0.29 to 0.74. Similar reliability scores were found in nonhospitalized families. This study indicates that the Chinese FAD has a different factor structure, reliabilities, and mean scores in several subscales compared to U.S. studies. The psychometric properties of the Chinese FAD may be influenced by the fact that the sample was focused on children rather than adults.

Pilot study of an online dyspnea self-management program for COPD.

To address some of the shortcomings to providing timely and convenient education and support to patients with COPD, especially in the management of dyspnea, the Internet was considered a viable medium to deliver a previously tested program at a distance to reach more patients. Older COPD patients were able to participate in the program and most were very satisfied with the program. Changes were noted in dyspnea, support, self-efficacy, and exercise.