[show abstract][hide abstract] ABSTRACT: Introduction:The aim of this analysis was to examine the performance of the Myasthenia Gravis–specific Activities of Daily Living scale (MG-ADL) during a multicenter scale validation study.Methods:Consecutive MG patients were assessed with several MG outcome measures, including the MG-ADL. Statistical tests included descriptive analysis, Pearson correlation, and sensitivity/specificity.Results:Eighty-seven patients completed the MG-ADL, MG Composite (MGC), and MG 15-item Quality of Life scale (MG-QOL15) on the first visit, and 76 returned for the second visit. At the first visit, there was a strong positive correlation between MG-ADL and MGC (r = 0.85, P < 0.0001) and MG-QOL15 (r = 0.76, P < 0.0001). Correlation of the delta MG-ADL score and physician impression of change between the visits was strong (r = 0.70, P < 0.0001). A 2-point improvement in the MG-ADL best predicted clinical improvement. Test–retest analysis demonstrated a high reliability coefficient.Conclusions:The MG-ADL correlates strongly with newer, validated MG outcome measures. A 2-point improvement in the MG-ADL indicates clinical improvement. The MG-ADL is useful as a research tool and in routine clinical management. Muscle Nerve, 2011
[show abstract][hide abstract] ABSTRACT: Ventilator-associated pneumonia is a complication of mechanical ventilation that is associated with increased length of stay, morbidity, mortality, and costs. Evidence-based guidelines to reduce the risk of ventilator-associated pneumonia recommend use of 30º to 45º backrest elevation. Despite recommendations, patients continue to be cared for in positions with a lower backrest elevation. Hemodynamic stability may be a factor in the lack of adherence, yet few data exist to confirm this hypothesis.
To determine the relationship between backrest elevation and hemodynamic instability among patients in a thoracic cardiovascular intensive care unit.
A sample of 100 patients was studied. Patients were randomly selected by time of day. A protractor was used to measure patients' backrest elevation. Mean blood pressure, time of day, and fluid and vasopressor use also were recorded.
Lower backrest elevation was associated with use of vasopressors (P = .001). Patients who received hemodynamic support also had a lower backrest elevation than did patients not receiving these therapies (mean, 19º vs 26º ; P = .01). Patients with a mean blood pressure of 64 mm Hg or less had a mean backrest elevation of 17º versus 24º for patients with a mean blood pressure greater than 65 mm Hg (P = .01). Back-rest elevations did not differ between shifts.
That backrest elevation is associated with lower mean blood pressure and vasopressor use suggests that nurses are not adhering to recommended levels of backrest elevation so as to maintain hemodynamic stability. Further studies are needed to elucidate reasons for lack of adherence to recommended levels of backrest elevation.
American Journal of Critical Care 09/2011; 20(5):395-9. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Targeted therapies have often given disappointing results when used as single agents in solid tumors, suggesting the importance of devising rational combinations of targeted drugs. We hypothesized that construction of such combinations could be guided by identification of growth and survival pathways whose activity or expression become upregulated in response to single-agent drug treatment. We mapped alterations in signaling pathways assessed by gene array and protein phosphorylation to identify compensatory signal transduction pathways in prostate cancer xenografts treated with a MAP/ERK kinase (MEK) inhibitor PD325901. In addition to numerous components of the extracellular signal-regulated kinase (ERK) signaling pathway, components of the IKK, hedgehog, and phosphoinositide 3-kinase/Akt/mTOR pathways were upregulated following treatment with PD325901. Combinations of PD325901 with inhibitors of any one of these upregulated pathways provided synergistically greater growth inhibition of in vitro cell growth and survival than the individual drugs alone. Thus, the identification of compensatory signal transduction pathways paves the way for rational combinatorial therapies for the effective treatment of prostate cancer.
Molecular Cancer Therapeutics 06/2011; 10(9):1581-90. · 5.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose-toxicity curve.
Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori.
We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known.
We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design.
A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders.
The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials.
[show abstract][hide abstract] ABSTRACT: Much of the statistical methodology underlying the experimental design of phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose-toxicity curve. This is a reasonable assumption for single-agent trials in which the administration of greater doses of the agent can be expected to produce dose-limiting toxicities in increasing proportions of patients. When studying multiple agents, the assumption may not hold because the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two-dimensional dose-finding method for multiple-agent trials that simplifies to the continual reassessment method (CRM), introduced by O'Quigley, Pepe, and Fisher (1990, Biometrics 46, 33-48), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose-toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders.
[show abstract][hide abstract] ABSTRACT: We discuss extensions of model-based designs, such as the continual reassessment method, for use in dose-finding studies. Rather than work with a single model to carry out the design and analysis of a dose-finding study we indicate how the use of several models can greatly increase flexibility. We can appeal to established results on Bayesian model choice and this device makes the inferential problem essentially straightforward. The greater flexibility enables us to take on board many different kinds of added complexity. Examples include extended models to deal with subject heterogeneity, extended models to take account of different treatment schedules and extended models to tackle the problem of partial ordering.
Statistics in Medicine 02/2011; 30(17):2062-9. · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: As blood products are being used more judiciously, registered nurses need to develop practices to facilitate the effective administration of these products. The study results suggest both the syringe push method and the continuous infusion method of normal saline provide adequate line patency during packed red blood cell infusions through peripheral catheters.
Medsurg nursing: official journal of the Academy of Medical-Surgical Nurses 01/2011; 20(3):134-8.
[show abstract][hide abstract] ABSTRACT: RalA expression in human prostate cancer is associated with cell migration and is necessary for bone metastasis. However, the downstream effectors of RalA that mediate these functions remain unclear. Here we examined cell migration after small interfering RNA-mediated depletion of Ral effectors Ral binding protein 1 (RalBP1/RLIP), exocyst complex component 2 (Sec5), and phospholipase D1 (PLD1) and found that RalBP1 and RalA depletion inhibited cell migration to a similar extent. Stable lentivirus short hairpin interfering RNA-mediated depletion of RalA and RalBP1 in PC3 human prostate cancer cells inhibited bone metastasis after intracardiac inoculation. Depletion of RalBP1 diminished orthotopic tumor growth of PC3 cells and inhibited spontaneous metastasis from this site. Interestingly, the expression of wild-type or RalA mutants deficient in RalBP1 binding was effective at rescuing the reduced metastatic capacity of RalA-depleted PC3 cells, suggesting that RalA depletion does not reduce this solely by diminished interaction with RalBP1. To determine whether the role of RalBP1 in metastasis is relevant beyond prostate cancer, we studied the requirement of RalBP1 expression in an experimental metastasis model of human bladder cancer, a tumor type with high RalBP1 expression. Depletion of RalBP1 in UMUC3 cells resulted in decreased lung colonization while having a minimal effect on subcutaneous tumor growth. Our studies are the first to suggest that the expression of RalBP1 is necessary for human cancer cell metastasis. Furthermore, we show that the requirement for RalA expression for manifestation of this phenotype is not entirely dependent on a RalA-RalBP1 interaction.
Neoplasia (New York, N.Y.) 12/2010; 12(12):1003-12. · 5.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: The MG-QOL15 is helpful in informing the clinician about the patient's perception of the extent of and dissatisfaction with myasthenia gravis (MG)-related dysfunction. The aims of this study were to determine the usefulness of the MG-QOL15 for following individuals with MG and to guide clinical researchers who plan to use the MG-QOL15. We assessed sensitivity and specificity for detecting clinical change and evaluated test-retest reliability. Sensitivities and specificities of various cut-points of change in scores are presented. Also presented are means and standard deviations of MG-QOL15 scores for all patients and for subgroups of patients. The test-retest reliability coefficient was 98.6%. The MG-QOL15 has an acceptable longitudinal construct validity. We consider this instrument to be most useful for informing the clinician about the patient's perception and tolerance of MG-related dysfunction. More objective measures, such as the MG Composite, should also be used to follow disease severity.
[show abstract][hide abstract] ABSTRACT: Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor alpha (ERalpha) is certainly involved, nonreceptor mediated effects of estradiol (E(2)) may also play an important role in facilitating breast tumor development. A "reductionist" strategy allowed us to examine the role of ERalpha independent effects of E(2) on mammary tumor development in ERalpha knockout (ERKO) mice bearing the Wnt-1 oncogene. Exogenous E(2) "clamped" at early follicular and midluteal phase levels (i.e., 80 and 240 pg/ml) accelerated tumor formation in a dose-related fashion in ERKO/Wnt-1 animals (p = 0.0002). Reduction of endogenous E(2) by oophorectomy (p < 0.001) or an aromatase inhibitor (AI) (p = 0.055) in intact ERKO/Wnt-1 animals delayed tumorigenesis as further evidence for an ER-independent effect. The effects of residual ERalpha or beta were not involved since enhancement of tumor formation could not be blocked by the antiestrogen fulvestrant. 17alpha-OH-E(2), a metabolizable but ER-impeded analogue of E(2) stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER-independent actions of E(2) can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block E(2) synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER-mediated effects.
International Journal of Cancer 10/2010; 127(8):1748-57. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: This quantitative study was designed to identify the needs of family members of neuroscience patients. An adaptation of the Critical Care Family Needs Inventory was used to identify the top 10 needs of neuroscience families. Results were compared on the basis of whether the admission was planned or emergent. Needs were further examined on the basis of a family's perception of patient prognosis and communication with physicians and nurses. Most needs were recognized as being either important or very important with the need for information about the patient's care receiving the highest rating. Significant differences were noted between family members who expected their loved one to return to normal or with a slight decrease in activity versus those who expected their loved one to have a moderate to complete inability to perform normal activities. Communication with nurses was rated excellent or good significantly more often than communication with physicians.
Journal of Neuroscience Nursing 10/2010; 42(5):274-9. · 0.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: RalA and RalB are monomeric G proteins that are 83% identical in amino acid sequence but have paralogue-specific effects on cell proliferation, metastasis, and apoptosis. Using in vitro kinase assays and phosphosite-specific antibodies, here we show phosphorylation of RalB by protein kinase C (PKC) and RalA by protein kinase A. We used mass spectrometry and site-directed mutagenesis to identify S198 as the primary PKC phosphorylation site in RalB. Phorbol ester [phorbol 12-myristate 13-acetate (PMA)] treatment of human bladder carcinoma cells induced S198 phosphorylation of stably expressed FLAG-RalB as well as endogenous RalB. PMA treatment caused RalB translocation from the plasma membrane to perinuclear regions in a S198 phosphorylation-dependent manner. Using RNA interference depletion of RalB followed by rescue with wild-type RalB or RalB(S198A) as well as overexpression of wild-type RalB or RalB(S198A) with and without PMA stimulation, we show that phosphorylation of RalB at S198 is necessary for actin cytoskeletal organization, anchorage-independent growth, cell migration, and experimental lung metastasis of T24 or UMUC3 human bladder cancer cells. In addition, UMUC3 cells transfected with a constitutively active RalB(G23V) exhibited enhanced subcutaneous tumor growth, whereas those transfected with phospho-deficient RalB(G23V-S198A) were indistinguishable from control cells. Our data show that RalA and RalB are phosphorylated by different kinases, and RalB phosphorylation is necessary for in vitro cellular functions and in vivo tumor growth and metastasis.
Cancer Research 10/2010; 70(21):8760-9. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previously we determined that S81 is the highest stoichiometric phosphorylation on the androgen receptor (AR) in response to hormone. To explore the role of this phosphorylation on growth, we stably expressed wild-type and S81A mutant AR in LHS and LAPC4 cells. The cells with increased wild-type AR expression grow faster compared with parental cells and S81A mutant-expressing cells, indicating that loss of S81 phosphorylation limits cell growth. To explore how S81 regulates cell growth, we tested whether S81 phosphorylation regulates AR transcriptional activity. LHS cells stably expressing wild-type and S81A mutant AR showed differences in the regulation of endogenous AR target genes, suggesting that S81 phosphorylation regulates promoter selectivity. We next sought to identify the S81 kinase using ion trap mass spectrometry to analyze AR-associated proteins in immunoprecipitates from cells. We observed cyclin-dependent kinase (CDK)9 association with the AR. CDK9 phosphorylates the AR on S81 in vitro. Phosphorylation is specific to S81 because CDK9 did not phosphorylate the AR on other serine phosphorylation sites. Overexpression of CDK9 with its cognate cyclin, Cyclin T, increased S81 phosphorylation levels in cells. Small interfering RNA knockdown of CDK9 protein levels decreased hormone-induced S81 phosphorylation. Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced S81 phosphorylation further, suggesting that CDK9 regulates S81 phosphorylation. Pharmacological inhibition of CDK9 also resulted in decreased AR transcription in LNCaP cells. Collectively these results suggest that CDK9 phosphorylation of AR S81 is an important step in regulating AR transcriptional activity and prostate cancer cell growth.
[show abstract][hide abstract] ABSTRACT: The Burns Wean Assessment Program is a 26-factor weaning assessment worksheet and scoring instrument used to reduce practice variability in the clinical management of patients receiving mechanical ventilation. The instrument has been tested in patients in a medical-surgical intensive care unit, but further testing in different populations of adult patients is needed.
To determine the relationship between Burns Wean Assessment Program scores and outcomes of weaning trials in patients treated with mechanical ventilation for 3 or more days.
For 5 years in 5 adult critical care units (surgical, medical, neurological, thoracic-cardiovascular, and coronary care), advanced practice nurses collected scores within 24 hours of a weaning attempt. All patients were managed similarly by using a multidisciplinary pathway, the Burns Wean Assessment Program checklist, protocols for weaning trials, and sedation guidelines.
Of 1889 weaning attempts, 1669 (88%) were successful, and 220 (12%) were unsuccessful. Weaning outcomes did not differ according to sex, but significantly more trials were successful in younger patients than in older patients (P = .002) and in patients in different units (P = .01). Regardless of unit, patients with Burns Wean Assessment Program scores greater than 50 were significantly more likely to be weaned successfully (P = .001) than were patients with lower scores.
Systematic tracking of the factors and scores on the Burns Wean Assessment Program may be helpful in care planning and management and in determining weaning potential.
American Journal of Critical Care 09/2010; 19(5):431-9. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: To study the concurrent and construct validity and test-retest reliability in the practice setting of an outcome measure for myasthenia gravis (MG).
Eleven centers participated in the validation study of the Myasthenia Gravis Composite (MGC) scale. Patients with MG were evaluated at 2 consecutive visits. Concurrent and construct validities of the MGC were assessed by evaluating MGC scores in the context of other MG-specific outcome measures. We used numerous potential indicators of clinical improvement to assess the sensitivity and specificity of the MGC for detecting clinical improvement. Test-retest reliability was performed on patients at the University of Virginia.
A total of 175 patients with MG were enrolled at 11 sites from July 1, 2008, to January 31, 2009. A total of 151 patients were seen in follow-up. Total MGC scores showed excellent concurrent validity with other MG-specific scales. Analyses of sensitivities and specificities of the MGC revealed that a 3-point improvement in total MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC also appears to represent a meaningful improvement to most patients, as indicated by improved 15-item myasthenia gravis quality of life scale (MG-QOL15) scores. The psychometric properties were no better for an individualized subscore made up of the 2 functional domains that the patient identified as most important to treat. The test-retest reliability coefficient of the MGC was 98%, with a lower 95% confidence interval of 97%, indicating excellent test-retest reliability.
The Myasthenia Gravis Composite is a reliable and valid instrument for measuring clinical status of patients with myasthenia gravis in the practice setting and in clinical trials.
[show abstract][hide abstract] ABSTRACT: Two recent randomized, controlled trials failed to demonstrate a benefit of mycophenolate mofetil (MMF) over prednisone in the treatment of myasthenia gravis (MG). We reviewed our experience with MMF in MG to determine whether these trials may have been unsuccessful because of their short duration and the unpredicted benefit of prednisone. We reviewed outcomes and prednisone dosage for all our acetylcholine-receptor (AChR)-antibody positive MG patients treated with MMF alone or with prednisone for at least 3 months. The percentage of patients with a desirable outcome (MG-specific Manual Muscle Test score <4 or Myasthenia Gravis Foundation of America post-invention status of minimal manifestations or better) began to increase after 6 months; 80% of those followed for >24 months had a desirable outcome. Prednisone dose decreased after 12 months; after 25 months, 54.5% of patients took no prednisone and 75% took <7.5 mg/day. This retrospective analysis provides class IV evidence that MMF begins to improve AChR-positive MG after 6 months, both with prednisone and as monotherapy.
[show abstract][hide abstract] ABSTRACT: During the last twenty years there have been considerable methodological developments in the design and analysis of Phase 1, Phase 2 and Phase 1/2 dose-finding studies. Many of these developments are related to the continual reassessment method (CRM), first introduced by O'Quigley, Pepe and Fisher (1990). CRM models have proven themselves to be of practical use and, in this discussion, we investigate the basic approach, some connections to other methods, some generalizations, as well as further applications of the model. We obtain some new results which can provide guidance in practice.
[show abstract][hide abstract] ABSTRACT: Health-related quality of life (HRQOL) estimates can play an important role in patient care by providing information about the patient's perception of impairment and disability and the degree to which the patient tolerates disease manifestations. The 15-item myasthenia gravis quality of life scale (MG-QOL15) is an HRQOL evaluative instrument specific to patients with myasthenia gravis (MG) that was designed to be easy to administer and interpret. In this multicenter study we demonstrate the construct validity of the MG-QOL15 in the practice setting. To assess the construct validity, score distributions were examined for test items in different MG patient groups that represent the clinical spectrum of the disease. For example, patients in remission more frequently scored test items as normal than did patients in other groups. Patients with lower (better) MG composite scores also more frequently scored items as normal than did patients with higher (worse) scores. There was also appropriate correlation between the MG-QOL15 and the other MG-specific scales studied. The study findings shed light on what troubles MG patients. The MG-QOL15 has construct validity in the clinical practice setting and represents an efficient and valuable tool for assessing HRQOL for patients with MG.
[show abstract][hide abstract] ABSTRACT: Hyperglycemia is associated with worse outcome in patients with acute stroke.
We conducted a prospective, randomized, multicenter, 3-arm trial (tight control [target 70 to 110 mg/dL], loose control [target 70 to 200 mg/dL], and control usual care [70 to 300 mg/dL]) to assess the feasibility and safety of 2 insulin infusion protocol targets in patients with acute ischemic stroke. The planned sample was 72 subjects.
A total of 74 subjects were enrolled. Seventy-two (97%) had data available for the primary analyses and 73 (99%) had 3-month clinical outcome data. Median age was 67 years, median National Institutes of Health Stroke Scale score was 8, median glucose was 163 mg/dL, and median time to randomization was 10.7 hours. Fifty-nine percent of patients were diabetic, 35% received thrombolysis, and 14% of subjects died within 3 months. The loose control and usual care groups had median glucose concentrations of 151 mg/dL. The tight control group had a median glucose concentration of 111 mg/dL. The loose control group spent 90% of the first 24 hours in target and the tight group 44% of time in target. There was only one symptomatic patient with hypoglycemia in the loose control group (4%) and zero in the tight control group. The overall rates of hypoglycemia (<55 mg/dL) were 4% in control, 4% in loose, and 30% in tight. Exploratory efficacy analysis was conducted.
Insulin infusion for patients with acute ischemic stroke is feasible and safe using the insulin infusion protocol in the Glucose Regulation in Acute Stroke Patients (GRASP) trial. Exploratory efficacy analysis supports further comparative study.