Human-relevant potency threshold (HRPT) for ERα agonism.

The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical's ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical's potency for a specific MoA-its mechanistic potency-is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ERα agonist potencies with the ability of those chemicals to produce ERα-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ERα agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17ß-estradiol or the pharmaceutical estrogen, 17α-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission.

Computer-assisted image processing 12 lead ECG model to diagnose hyperkalemia.

BACKGROUND: We sought to develop an improved 12 lead ECG model to diagnose hyperkalemia by use of traditional and novel parameters. METHODS: We retrospectively analyzed ECGs in consecutive hyperkalemic patients (serum potassium (K)>5.3mEq/L) by blinded investigators with normokalemic ECGs as internal controls. Potassium levels were modeled using general linear mixed models followed by refit with standardized variables. Optimum sensitivity and specificity were determined using cut point analysis of ROC-AUC. RESULTS: The training set included 236 ECGs (84 patients) and validation set 97 ECGs (23 patients). Predicted K=(5.2354)+(0.03434*descending T slope)+(-0.2329*T width)+(-0.9652*reciprocal of new QRS width>100msec). ROC-AUC in the validation set was 0.78 (95% CI 0.69-0.88). Maximum specificity of the model was 84% for K>5.91 with sensitivity of 63%. CONCLUSION: ECG model incorporating T-wave width, descending T-wave slope and new QRS prolongation improved hyperkalemia diagnosis over traditional ECG analysis.

Comparison of a self-inflating bulb syringe and a colorimetric CO2 indicator with capnography and radiography to detect the misdirection of naso/orogastric tubes into the airway of critically ill adult patients.

OBJECTIVE: The objective of this study was to develop a mechanism of discovering misdirection into the airway of naso/orogastric (NG) tubes before they reach their full depth of placement in adults. METHODS: A prospective, observational study was performed in humans, evaluating both the self-inflating bulb syringe (SIBS) and a colorimetric CO2 detector. A prospective convenience sample of 257 NG tube placements was studied in 199 patients in medical ICUs of a tertiary care medical center. Findings were compared to a "standard" (ie, end tidal CO2 results of a capnograph and the results of a chest radiograph performed at the completion of the tube placement). RESULTS: On the first tube placement attempt in any patient, the SIBS had a sensitivity of 91.5% and a specificity of 87.0% in detecting nonesophageal placement, while the colorimetric device exhibited 99.4% sensitivity and 91.3% specificity. On subsequent insertions, the SIBS showed 95.7% sensitivity and 100% specificity, while the colorimetric device exhibited 97.8% sensitivity and 100% specificity. The colorimetric device was eight times more expensive than the SIBS. CONCLUSIONS: The SIBS and the colorimetric CO2 detector are very good at detecting NG tube malpositioning into the airway, although the colorimetric device is slightly more sensitive and specific. Neither method adds substantial time or difficulty to the insertion process. The colorimetric device is substantially more expensive. The decision as to which method to use may be based on local institutional factors, such as expense.

Spatial re-organization of myogenic regulatory sequences temporally controls gene expression.

During skeletal muscle differentiation, the activation of some tissue-specific genes occurs immediately while others are delayed. The molecular basis controlling temporal gene regulation is poorly understood. We show that the regulatory sequences, but not other regions of genes expressed at late times of myogenesis, are in close physical proximity in differentiating embryonic tissue and in differentiating culture cells, despite these genes being located on different chromosomes. Formation of these inter-chromosomal interactions requires the lineage-determinant MyoD and functional Brg1, the ATPase subunit of SWI/SNF chromatin remodeling enzymes. Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated. The data indicate that the spatial organization of late genes contributes to temporal regulation of myogenic transcription by restricting late gene expression during the early stages of myogenesis.

The bundle "plus": the effect of a multidisciplinary team approach to eradicate central line-associated bloodstream infections.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) have decreased significantly over the last decade. Further reductions in CLABSI rates should be possible. We describe a multidisciplinary approach to the reduction of CLABSIs. METHODS: This was an observational study of critically ill patients requiring central venous catheters in 8 intensive care units in a tertiary medical center. We implemented a catheter bundle that included hand hygiene, education of providers, chlorhexidine skin preparation, use of maximum barrier precautions, a dedicated line cart, checklist, avoidance of the femoral vein for catheter insertion, chlorhexidine-impregnated dressings, use of anti-infective catheters, and daily consideration of the need for the catheter. Additional measures included root cause analyses of all CLABSIs, creation of a best practice atlas for internal jugular catheters, and enhanced education on blood culture collection. Data were analyzed using the Poisson test and regression. RESULTS: CLABSI, catheter use, and microbiology were tracked from 2004 to 2012. There was a 92% reduction in CLABSIs (95% lower confidence limit: 67.4% reduction, P < 0.0001). Central venous catheter use decreased significantly from 2008 to 2012 (P = 0.032, -151 catheters per year, 95% confidence limits: -277 to -25), whereas peripherally inserted central catheter use increased (P = 0.005, 89 catheters per year, 95% confidence limits: 50 to 127). There was no apparent association between unit-specific Acute Physiology And Chronic Health Evaluation III/IV scores and CLABSI. Three units have not had a CLABSI in more than a year. The most common organism isolated was coagulase-negative staphylococcus. Since the implementation of minocycline/rifampin catheters, no cases of methicillin-resistant Staphylococcus aureus CLABSI have occurred. CONCLUSIONS: The implementation of a standard catheter bundle combined with chlorhexidine dressings, minocycline/rifampin catheters, and other behavioral changes was associated with a sustained reduction in CLABSIs.

Prevalence and test characteristics of national health safety network ventilator-associated events.

OBJECTIVES: The primary aim of the study was to measure the test characteristics of the National Health Safety Network ventilator-associated event/ventilator-associated condition constructs for detecting ventilator-associated pneumonia. Its secondary aims were to report the clinical features of patients with National Health Safety Network ventilator-associated event/ventilator-associated condition, measure costs of surveillance, and its susceptibility to manipulation. DESIGN: Prospective cohort study. SETTING: Two inpatient campuses of an academic medical center. PATIENTS: Eight thousand four hundred eight mechanically ventilated adults discharged from an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The National Health Safety Network ventilator-associated event/ventilator-associated condition constructs detected less than a third of ventilator-associated pneumonia cases with a sensitivity of 0.325 and a positive predictive value of 0.07. Most National Health Safety Network ventilator-associated event/ventilator-associated condition cases (93%) did not have ventilator-associated pneumonia or other hospital-acquired complications; 71% met the definition for acute respiratory distress syndrome. Similarly, most patients with National Health Safety Network probable ventilator-associated pneumonia did not have ventilator-associated pneumonia because radiographic criteria were not met. National Health Safety Network ventilator-associated event/ventilator-associated condition rates were reduced 93% by an unsophisticated manipulation of ventilator management protocols. CONCLUSIONS: The National Health Safety Network ventilator-associated event/ventilator-associated condition constructs failed to detect many patients who had ventilator-associated pneumonia, detected many cases that did not have a hospital complication, and were susceptible to manipulation. National Health Safety Network ventilator-associated event/ventilator-associated condition surveillance did not perform as well as ventilator-associated pneumonia surveillance and had several undesirable characteristics.

A multicenter study of ICU telemedicine reengineering of adult critical care.

BACKGROUND: Few studies have evaluated both the overall effect of ICU telemedicine programs and the effect of individual components of the intervention on clinical outcomes. METHODS: The effects of nonrandomized ICU telemedicine interventions on crude and adjusted mortality and length of stay (LOS) were measured. Additionally, individual intervention components related to process and setting of care were evaluated for their association with mortality and LOS. RESULTS: Overall, 118,990 adult patients (11,558 control subjects, 107,432 intervention group patients) from 56 ICUs in 32 hospitals from 19 US health-care systems were included. After statistical adjustment, hospital (hazard ratio [HR]=0.84; 95% CI, 0.78-0.89; P<.001) and ICU (HR=0.74; 95% CI, 0.68-0.79; P<.001) mortality in the ICU telemedicine intervention group was significantly better than that of control subjects. Moreover, adjusted hospital LOS was reduced, on average, by 0.5 (95% CI, 0.4-0.5), 1.0 (95% CI, 0.7-1.3), and 3.6 (95% CI, 2.3-4.8) days, and adjusted ICU LOS was reduced by 1.1 (95% CI, 0.8-1.4), 2.5 (95% CI, 1.6-3.4), and 4.5 (95% CI, 1.5-7.2) days among those who stayed in the ICU for ≥7, ≥14, and ≥30 days, respectively. Individual components of the interventions that were associated with lower mortality, reduced LOS, or both included (1) intensivist case review within 1 h of admission, (2) timely use of performance data, (3) adherence to ICU best practices, and (4) quicker alert response times. CONCLUSIONS: ICU telemedicine interventions, specifically interventions that increase early intensivist case involvement, improve adherence to ICU best practices, reduce response times to alarms, and encourage the use of performance data, were associated with lower mortality and LOS.

Effect of linker length and composition on heterobivalent ligand-mediated receptor cross-talk between the A1 adenosine and ß2 adrenergic receptors.

Heterobivalent ligands that possess pharmacophores designed to interact with both the A1 adenosine receptor (A1 AR) and the ß2 adrenergic receptor (ß2 AR) were prepared. More specifically, these ligands contain an adenosine moiety that is linked via its N(6) -position to the amino group of the saligenin-substituted ethanolamine moiety present in the well-known ß2 AR agonist, salbutamol. The affinities of these ligands were determined at both receptors and found to vary with linker length and composition. With all compounds, affinity and functional potencies were found to have selectivity for the A1 AR over the ß2 AR. In all cases, cAMP accumulation (a ß2 AR-mediated response) was mainly observed when the A1 AR was blocked or its function decreased by pertussis toxin or chronic agonist treatment. This suggests that heterobivalent compounds for receptors that mediate opposite responses might be useful for elucidating the mechanisms of receptor cross-talk and how this interaction, in terms of responsiveness, may change under pathophysiological conditions.

Potency matters: thresholds govern endocrine activity.

Whether thresholds exist for endocrine active substances and for endocrine disrupting effects of exogenous chemicals has been posed as a question for regulatory policy by the European Union. This question arises from a concern that the endocrine system is too complex to allow estimations of safe levels of exposure to any chemical with potential endocrine activity, and a belief that any such chemical can augment, retard, or disrupt the normal background activity of endogenous hormones. However, vital signaling functions of the endocrine system require it to continuously discriminate the biological information conveyed by potent endogenous hormones from a more concentrated background of structurally similar, endogenous molecules with low hormonal potential. This obligatory ability to discriminate important hormonal signals from background noise can be used to define thresholds for induction of hormonal effects, without which normal physiological functions would be impossible. From such thresholds, safe levels of exposure can be estimated. This brief review highlights how the fundamental principles governing hormonal effects - affinity, efficacy, potency, and mass action - dictate the existence of thresholds and why these principles also define the potential that exogenous chemicals might have to interfere with normal endocrine functioning.