Sialyltransferase inhibitors: consideration of molecular shape and charge/hydrophobic interactions.

In order to evaluate the importance of molecular shape of inhibitor molecules and the charge/H-bond and hydrophobic interactions, we synthesized three types of molecules and tested them against a sialyltransferase. The first type of compounds were designed as substrate mimics in which the phosphate in CMP-Neu5NAc was replaced by a non-hydrolysable, uncharged 1,2,3-triazole moiety. The second type of compound contained a 2-deoxy-2,3-dehydro-acetylneuraminic moiety which was linked to cytidine through its carboxylic acid and amide linkers. In the third type of compound the sialyl phosphate was substituted by an aryl sulfonamide which was then linked to cytidine. Inhibition study of these cytidine conjugates against Campylobacter jejuni sialyltransferase Cst 06 showed that the first type of molecules are competitive inhibitors, whereas the other two could only inhibit the enzyme non-competitively. The results indicate that although the binding specificity may be guided by molecular shape and H-bond interaction, the charge and hydrophobic interactions contributed most to the binding affinity.

Learning patient-specific predictive models from clinical data.

We introduce an algorithm for learning patient-specific models from clinical data to predict outcomes. Patient-specific models are influenced by the particular history, symptoms, laboratory results, and other features of the patient case at hand, in contrast to the commonly used population-wide models that are constructed to perform well on average on all future cases. The patient-specific algorithm uses Markov blanket (MB) models, carries out Bayesian model averaging over a set of models to predict the outcome for the patient case at hand, and employs a patient-specific heuristic to locate a set of suitable models to average over. We evaluate the utility of using a local structure representation for the conditional probability distributions in the MB models that captures additional independence relations among the variables compared to the typically used representation that captures only the global structure among the variables. In addition, we compare the performance of Bayesian model averaging to that of model selection. The patient-specific algorithm and its variants were evaluated on two clinical datasets for two outcomes. Our results provide support that the performance of an algorithm for learning patient-specific models can be improved by using a local structure representation for MB models and by performing Bayesian model averaging.

The prevalence and factors associated with QTc prolongation among emergency department patients.

STUDY OBJECTIVE: Previous studies have suggested that QTc prolongation may lead to significant morbidity and mortality. The prevalence of QTc prolongation among emergency department (ED) patients is unknown. The purpose of this study is to determine the prevalence of QTc prolongation among ED patients. METHODS: This was a retrospective review of ED and inpatient data for all patients with an ECG conducted for any reason at a tertiary care university ED during a 3-month period. QTc prolongation was defined as computer-generated QTc intervals greater than or equal to 450 ms for men and greater than or equal to 460 ms for women. RESULTS: Of the 1,558 eligible cases, 544 patients had QTc prolongation (35%; 95% confidence interval [CI] 32% to 37%). The prevalence of QTc intervals greater than or equal to 500 ms was 8% (120/1,558; 95% CI 6% to 9%). The most common comorbidities were structural heart disease, renal failure, and stroke. Forty-four percent (239/544; 95% CI 40% to 48%) of patients with any degree of QTc prolongation were discharged from the ED. Furthermore, 23% (28/120; 95% CI 16% to 32%) of patients with QTc intervals greater than or equal to 500 ms were discharged from the ED, including 16 patients with QTc intervals greater than or equal to 500 ms and QRS durations less than 120 ms (16/60; 27%; 95% CI 16% to 40%). Five percent of the patients with QTc prolongation died in the ED or during hospitalization (27/544; 95% CI 3% to 7%); none had QTc prolongation or torsades de pointes listed as a cause of death. CONCLUSION: QTc prolongation occurred frequently among ED patients who had an ECG study for any reason. Nearly half of all patients with QTc prolongation were discharged from the ED.

Differences in initial severity of illness between black and white emergency department patients hospitalized with heart failure.

BACKGROUND: Black patients hospitalized for heart failure have better reported short-term survival than white patients for unknown reasons. We sought to determine if initial severity of illness differed between black and white emergency department (ED) patients hospitalized for heart failure. METHODS: We analyzed 1,408 black and 7,260 white randomly selected patients in one state hospitalized from an ED during 2003 and 2004 and with a discharge diagnosis of heart failure. We used three validated clinical prediction rules to estimate severity of illness on admission. RESULTS: Black patients were younger than white patients (65.8 +/- 14.8 vs 77.4 +/- 11.5 years, P < .01) and were assigned to lower risk classes by all 3 prediction rules more frequently than white patients (P < .01). The odds ratio (95% CI) for classification of black versus white patients into the lowest risk class within the three rules ranged from 1.16 (1.00-1.33) to 4.30 (3.75-4.94). After adjusting for hospital clustering, the odds ratio (95% CI) for black versus white patient hospital death and complications was 0.75 (0.60-0.95) and, for 30-day death, was 0.34 (0.27-0.48). CONCLUSIONS: Black ED patients hospitalized with heart failure are younger, less severely ill on admission and less likely to experience short-term fatal and nonfatal outcomes than white patients. Our findings suggest a varying opportunity between black and white patients when considering alternative initial treatment strategies and sites of care.

Synthesis of iminoalditol analogues of galactofuranosides and their activities against glycosidases.

Iminoalditol analogues of galactofuranosides were synthesized from 1-C-(2'-oxo-propyl)-1,4-dideoxy-1,4-imino-d-galactosides and different amines by reductive amination, followed by removal of protecting groups. The activity of these compounds against galactosidases and other glycosidases was investigated. The best inhibitor against beta-galactosidase (bovine liver) is a diastereomeric mixture of an iminoalditol (10h), which contains a hydrophobic hexadecyl aglycon (R=C(16)H(33)), whereas no significant inhibitory activity was observed with compounds having a hydrophilic aglycon. Surprisingly, activation of alpha-galactosidase (coffee bean) by 10h was also observed. Because these results were obtained from a mixture of iminoalditols, the inhibition and activation of glycosidases could result from different diastereomers.

Derivation of clinical predictors of failed rescue shock during out-of-hospital ventricular fibrillation.

BACKGROUND: Failed rescue shocks have been shown to decrease the likelihood of survival in the treatment of out-of-hospital ventricular fibrillation (VF). Avoidance of failed shocks may improve survival. OBJECTIVE: We sought to derive clinical predictors that could be used by emergency medical services (EMS) personnel to identify a subset of VF patients whose first rescue shock is likely to fail, making them candidates for a cardiopulmonary resuscitation (CPR)-first strategy. METHODS: After gaining institutional review board approval from all three institutions, we merged data from Los Angeles, Pittsburgh, and Royal Oak into a new cardiac arrest database. We used classification and regression tree (CART) analyses to build the model. We defined a failed first rescue shock as one in which there was no return of spontaneous circulation (ROSC); the postshock electrocardiographic (ECG) rhythm was VF, pulseless electrical activity (PEA), or asystole; or subsequent shocks were delivered (indicating that the first shock had failed). RESULTS: The database contains 5,046 cases, of which 1,777 (35%) had VF as the initial ECG rhythm. Sufficient data were present for 748 cases. Using unwitnessed collapse, a response time of >6 minutes, and absence of bystander CPR (BCPR) on EMS arrival as predictors, 35 of 35 (100%, 95% confidence interval [CI] 100-91.4%) cases had failed first rescue shocks. Second shock failure was predicted in 162 of 164 (99%) cases. CONCLUSIONS: Unwitnessed collapse, response time>6 minutes, and absence of BCPR may be useful in predicting which VF patients are likely to have failed first shocks and would thereby benefit from a CPR-first strategy. Stacked rescue shocks most often fail, and this outcome can also be predicted.

Validation of the Acute Heart Failure Index.

STUDY OBJECTIVE: Validate a clinical prediction rule prognostic of short-term fatal and inpatient nonfatal outcomes for heart failure patients admitted through the emergency department. METHODS: We retrospectively studied a random cohort of 8,384 adult patients admitted to Pennsylvania hospitals in 2003 and 2004 with a diagnosis of heart failure as defined by primary discharge diagnosis codes. We reported the proportions of inpatient death, serious medical complications before discharge, and 30-day death in the patients identified as low risk by the prediction rule. RESULTS: The prediction rule classified 1,609 (19.2%) of the patients as low risk. Within this subgroup, there were 12 (0.7%; 95% confidence interval [CI] 0.3% to 1.2%) inpatient deaths, 28 (1.7%; 95% CI 1.1% to 2.4%) patients survived to hospital discharge after a serious complication, and 47 (2.9%; 95% CI 2.1% to 3.7%) patients died within 30 days of the index hospitalization. CONCLUSION: This prediction rule identifies a group of admitted heart failure patients at low risk of inpatient mortal and nonmortal complications. Our validation findings suggest the rule could assist physicians in making site-of-care decisions for this patient population and aid in analyzing presenting illness burden in study populations.

Comparison of four clinical prediction rules for estimating risk in heart failure.

STUDY OBJECTIVE: We examine the performance of 4 clinical prediction rules prognostic of short-term fatal and hospital-based nonfatal outcomes in heart failure patients. METHODS: We used a retrospective cohort of 33,533 adult patients admitted to Pennsylvania hospitals in 1999 with a diagnosis of heart failure. We stratified patients into risk categories defined by each clinical prediction rule. We assessed prognostic accuracy according to sensitivity and specificity and compared discriminatory power according to area under the receiver operating characteristic (ROC) curves. The outcomes were inpatient death, 30-day mortality, and death or serious medical complications before hospital discharge. RESULTS: The 4 rules each created risk groups of various proportions and frequencies of outcomes. The proportion of patients assigned to the lowest risk group ranged from 13.3% to 73.0%. The rates of inpatient death or complications in the lowest risk group ranged from 6.7% to 9.2%, and 30-day death rates varied from 1.7% to 6.0%. Patients categorized at the highest risk of death or complication demonstrated similar variability. The area under the ROC curve for inpatient death and complications differed only slightly among rules (0.58 to 0.62). The area under the ROC curve for fatal outcomes tended to be higher and differed among rules (0.59 to 0.74) CONCLUSION: Current acute heart failure prediction rules offer varying ability to predict short-term death or serious outcomes. Although each creates a risk gradient, differences in risk-group proportions and outcome frequencies should drive rule selection or use in clinical practice.

A prediction rule to identify low-risk patients with heart failure.

OBJECTIVES: To derive a prediction rule using data available in the emergency department (ED) to identify a group of patients hospitalized for the treatment of heart failure who are at low risk of death and serious complications. METHODS: The authors analyzed data for all 33,533 patients with a primary hospital discharge diagnosis of heart failure in 1999 who were admitted from EDs in Pennsylvania. Candidate predictors were demographic and medical history variables and the most abnormal examination or diagnostic test values measured in the ED (vital signs only) or on the first day of hospitalization. The authors constructed classification trees to identify a subgroup of patients with an observed rate of death or serious medical complications before discharge < 2%; the tree that identified the subgroup with the lowest rate of this outcome and an inpatient mortality rate < 1% was chosen. RESULTS: Within the entire cohort, 4.5% of patients died and 6.8% survived to hospital discharge after experiencing a serious medical complication. The prediction rule used 21 prognostic factors to classify 17.2% of patients as low risk; 19 (0.3%) died and 59 (1.0%) survived to hospital discharge after experiencing a serious medical complication. CONCLUSIONS: This clinical prediction rule identified a group of patients hospitalized from the ED for the treatment of heart failure who were at low risk of adverse inpatient outcomes. Model performance needs to be examined in a cohort of patients with an ED diagnosis of heart failure and treated as outpatients or hospitalized.

Recommendations for treatment of hyponatraemia at endurance events.

This review focuses on possible pathophysiology of exercise-associated hyponatraemia and its implication on evaluation and treatment of collapsed athletes during endurance events. Rehydration guidelines and field care have traditionally been based on the belief that endurance events create a state of significant fluid deficit in athletes, which must be corrected by liberal hydration. Beliefs in the necessity of liberal hydration may have contributed to cases of hyponatraemia. Assumptions that fluid loss accounts for the entire weight loss during exercise and that fluid ingestion is the only source of water gain during exercise may lead to an overestimation of the degree of volume depletion and the amount of fluid needed for replacement. Increasing evidence suggests that hyponatraemic athletes are fluid overloaded; ingestion of large amount of hypotonic fluid in combination with inappropriate or inadequate physiological responses leads to excessive retention of free fluid. Risk factors include hot weather, female sex, slower finishing time, and possibly the use of nonsteroidal anti-inflammatory medications. Symptoms of hyponatraemia can be subtle and can mimic those of other exercise-related illnesses, thereby complicating its diagnosis and leading to possible inappropriate treatment. Most athletes who collapse at the finish line experience exercise-associated collapse, a benign and transient form of postural hypotension that can be treated simply by continued ambulation after finishing or elevation of legs while in a supine position for those who cannot walk. Care providers should consider the use of intravenous hydration with normal saline carefully since it is not needed by most collapsed athletes and may worsen the condition of patients with unsuspected hyponatraemia. Historic information and clinical signs of volume depletion should be elicited prior to its use. Most hyponatraemic athletes will recover uneventfully with careful observation while awaiting spontaneous diuresis. Use of hypertonic saline should be reserved for patients with severe symptoms. Moderate consumption of carbohydrate-electrolyte solution during exercise may allow the maintenance of adequate hydration and the prevention of hyponatraemia.

Angular velocity: a new method to improve prediction of ventricular fibrillation duration.

Ventricular fibrillation (VF) is a leading cause of sudden death. Electrical defibrillation is the primary modality of treatment, but evidence is accumulating that its use in the late stage of VF prior to providing ventilation, chest compressions and the administration of appropriate medication is detrimental. In VF of <5 min duration a 'shock first' strategy is effective. In VF of 5> min duration a 'perfuse first' approach is more effective. Because of the difficulty in determining the duration of VF in the clinical setting we have sought to develop method which analyze 5 s intervals of VF waveform and quickly provide an estimate of duration. Such methods would be useful in directing clinical interventions. Using methods of nonlinear dynamics and fractal geometry we have previously derived a quantitative measure of VF duration, namely the scaling exponent (ScE). In this study we report on a novel method also based on nonlinear dynamics, the angular velocity (AV). By constructing a flat, circular disk-shaped structure in a three-dimensional phase space and measuring the velocity of rotation of the position vector over time, a statistic is developed which rises from 58 rad/s at 1 min to 79 rad/s at 4 min and then decreases in a linear manner to 32 rad/s at 12.5 min. Using ScE and AV probability density estimated, VF of <5 min duration can be identified with 90% sensitivity on the basis of a single 5 s recording of the waveform. The combination of ScE and AV can be used in developing strategies for the treatment of VF during the different clinical phases of VF.

Dynamic nature of electrocardiographic waveform predicts rescue shock outcome in porcine ventricular fibrillation.

STUDY OBJECTIVE: Survival decreases with duration of ventricular fibrillation, and it is possible that failed rescue shocks increase myocardial damage. Structure in the ECG signal during ventricular fibrillation can be quantified by using the scaling exponent, a dimensionless measure that correlates with ventricular fibrillation duration. This study examined whether the scaling exponent could predict rescue shock success and whether unsuccessful rescue shocks altered the structure of the ventricular fibrillation waveform and the responsiveness to subsequent rescue shocks. METHODS: Ventricular fibrillation was electrically induced in 44 anesthetized swine, which were randomly assigned to receive 70-J biphasic rescue shocks at 2, 4, 6, 8, or 10 minutes. If rescue shocks failed, up to 2 subsequent rescue shocks were performed at 2-minute intervals. The scaling exponent was calculated at 1-second intervals from ECG to quantify the organization of the ventricular fibrillation waveform. RESULTS: A total of 92 rescue shocks were delivered, of which 23 successfully converted ventricular fibrillation to an organized rhythm (immediate success). After these 23 rescue shocks, 14 swine sustained organized rhythms for more than 30 seconds (sustained success). Lower scaling exponent values were associated with increased probability of successful rescue shocks. Receiver operating characteristic curves had an area under the curve of 0.86 for immediate rescue shock success and 0.93 for sustained rescue shock success. Failed rescue shocks increased the rate of scaling exponent increase over time but did not appear to affect subsequent rescue shock success when the scaling exponent was taken into account. CONCLUSION: Highly deterministic ventricular fibrillation, reflected by a low scaling exponent, predicted rescue shock success regardless of antecedent failed rescue shocks. In addition, unsuccessful rescue shocks might decrease post-rescue shock ventricular fibrillation waveform organization.

Hyponatremia in runners requiring on-site medical treatment at a single marathon.

STUDY OBJECTIVE: Literature reports indicate an increasing number of cases of hyponatremia in athletes participating in moderate endurance events such as standard marathons. In this study, we evaluated the incidence of hyponatremia in marathon finishers requiring medical treatment on-site and attempted to assess the contribution of fluid type ingested and nonsteroidal antiinflammatory drug (NSAID) use to the development of hyponatremia. METHODS: We examined a prospective, convenience sample of runners requiring intravenous hydration at the final medical tent of a standard marathon course and a comparison group of finishers who did not require intravenous hydration. After giving informed consent, subjects had blood drawn and answered a questionnaire regarding fluid intake on the course and NSAID use before the race. Blood samples were analyzed on-site for serum sodium values as well as other hematologic parameters. RESULTS: Fifty-one subjects requiring intravenous hydration as well as 11 subjects who did not were enrolled. Three subjects (5.6%; 95% CI, 0-11.9%; missing = 8) in the intravenous hydration group had serum sodium less than 130 mEq/L. None of the three runners suffered neurologic or pulmonary consequences and only one required overnight hospital admission for hydration. The small number of hyponatremic subjects precluded the analysis of the role of fluid type or NSAID use in the development of hyponatremia or the development of a model for prediction. CONCLUSION: This study found a 5.6% incidence of hyponatremia in marathon runners requiring medical treatment.