Search

Abstract Background The purpose of this study was to examine the career decision-making process of International Medical Graduates (IMGs). There are two main types of IMGs who apply for licensure in Canada. Canadian International Medical Graduates (CIMGs) were Canadian citizens before leaving to study medicine in a foreign country, in comparison to those non-CIMGs who had studied medicine in a foreign country before immigrating to Canada. Given that their motivations for becoming a doctor in Canada may differ, it is important to examine how they decided to become a doctor for each group separately. Methods A total of 46 IMGs participated in a semi-structured interview - 20 were CIMGs and 26 were non-CIMGs. Results An iterative process of content analysis was conducted to categorize responses from five open-ended questions according to the Ego Identity Statuses theory of career decision-making. Event contingency analysis identified a significant difference between CIMGs and non-CIMGs, Fisher’s exact test (1) = 18.79, p Conclusion About half of the Canadian citizens who had studied medicine in a foreign country had explored different careers before making a commitment to medicine, and half had not. No IMGs, however, who studied medicine in another country before immigrating to Canada, had explored various career opportunities before selecting medicine.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O 2 /support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O 2 /support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Background: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO 2 ) data contain signatures that improve sepsis risk prediction over HR or demographics alone., Methods: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500 g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10 m: mean, standard deviation, skewness, kurtosis of HR and SpO 2 , and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO 2 features alone for comparison with HR-SpO 2 models., Results: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO 2 model performed better than models using either HR or SpO 2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance., Conclusions: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO 2 features provides the best dynamic risk prediction., Impact: Heart rate characteristics aid early detection of late-onset sepsis, but respiratory data contain signatures of illness due to infection. Predictive models using both heart rate and respiratory data may improve early sepsis detection. A cardiorespiratory early warning score, analyzing heart rate from electrocardiogram or pulse oximetry with SpO 2 , predicts late-onset sepsis within 24 h across multiple NICUs and detects sepsis better than heart rate characteristics or demographics alone. Demographics risk-stratify, but predictive modeling with both HR and SpO 2 features provides the best dynamic risk prediction. The results increase understanding of physiologic signatures of neonatal sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Acute respiratory failure requiring the initiation of invasive mechanical ventilation remains commonplace in the pediatric intensive care unit (PICU). Early recognition of patients at risk for respiratory failure may provide clinicians with the opportunity to intervene and potentially improve outcomes. Through the development of a random forest model to identify patients at risk for requiring unplanned intubation, we tested the hypothesis that subtle signatures of illness are present in physiological and biochemical time series of PICU patients in the early stages of respiratory decompensation. We included 116 unplanned intubation events as recorded in the National Emergency Airway Registry for Children in 92 PICU admissions over a 29-month period at our institution. We observed that children have a physiologic signature of illness preceding unplanned intubation in the PICU. Generally, it comprises younger age, and abnormalities in electrolyte, hematologic and vital sign parameters. Additionally, given the heterogeneity of the PICU patient population, we found differences in the presentation among the major patient groups - medical, cardiac surgical, and non-cardiac surgical. At four hours prior to the event, our random forest model demonstrated an area under the receiver operating characteristic curve of 0.766 (0.738 for medical, 0.755 for cardiac surgical, and 0.797 for non-cardiac surgical patients). The multivariable statistical models that captured the physiological and biochemical dynamics leading up to the event of urgent unplanned intubation in a PICU can be repurposed for bedside risk prediction., Competing Interests: Authors LPM and MTC were employed by company Nihon Kohden Digital Health Solutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Spaeder, Moorman, Moorman, Adu-Darko, Keim-Malpass, Lake and Clark.)

To seek new signatures of illness in heart rate and oxygen saturation vital signs from Neonatal Intensive Care Unit (NICU) patients, we implemented highly comparative time-series analysis to discover features of all-cause mortality in the next 7 days. We collected 0.5 Hz heart rate and oxygen saturation vital signs of infants in the University of Virginia NICU from 2009 to 2019. We applied 4998 algorithmic operations from 11 mathematical families to random daily 10 min segments from 5957 NICU infants, 205 of whom died. We clustered the results and selected a representative from each, and examined multivariable logistic regression models. 3555 operations were usable; 20 cluster medoids held more than 81% of the information, and a multivariable model had AUC 0.83. New algorithms outperformed others: moving threshold, successive increases, surprise, and random walk. We computed provenance of the computations and constructed a software library with links to the data. We conclude that highly comparative time-series analysis revealed new vital sign measures to identify NICU patients at the highest risk of death in the next week., (© 2022. The Author(s).)

Background: Neonatal intensive care unit (NICU) patients are at increased risk for autism spectrum disorder (ASD). Autonomic nervous system aberrancy has been described in children with ASD, and we aimed to identify heart rate (HR) patterns in NICU patients associated with eventual ASD diagnosis., Methods: This retrospective cohort study included NICU patients from 2009 to 2016 with archived HR data and follow-up beyond age 3 years. Medical records provided clinical variables and ASD diagnosis. HR data were compared in infants with and without ASD., Results: Of the 2371 patients, 88 had ASD, and 689,016 h of data were analyzed. HR skewness (HRskw) was significantly different between ASD and control infants. Preterm infants at early postmenstrual ages (PMAs) had negative HRskw reflecting decelerations, which increased with maturation. From 34 to 42 weeks PMA, positive HRskw toward accelerations was higher in males with ASD. In 931 males with at least 4 days of HR data, overall ASD prevalence was 5%, whereas 11% in the top 5th HRskw percentile had ASD., Conclusion: High HRskw in NICU males, perhaps representing autonomic imbalance, was associated with increased ASD risk. Further study is needed to determine whether HR analysis identifies highest-risk infants who might benefit from earlier screening and therapies., Impact: In a large retrospective single-center cohort of NICU patients, we found that high positive skewness of heart rate toward more accelerations was significantly associated with increased risk of eventual autism spectrum disorder diagnosis in male infants but not in females. Existing literature describes differences in heart rate characteristics in children, adolescents, and adults with autism spectrum disorders, but the finding from our study in NICU infants is novel. Heart rate analysis during the NICU stay might identify, among an inherently high-risk population, those infants with especially high risk of ASD who might benefit from earlier screening and therapies., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Continuous heart rate (HR) and oxygenation (SpO 2 ) metrics can be useful for predicting adverse events in very low birth weight (VLBW) infants. To optimize the utility of these tools, inter-site variability must be taken into account., Methods: For VLBW infants at three neonatal intensive care units (NICUs), we analyzed the mean, standard deviation, skewness, kurtosis, and cross-correlation of electrocardiogram HR, pulse oximeter pulse rate, and SpO 2 . The number and durations of bradycardia and desaturation events were also measured. Twenty-two metrics were calculated hourly, and mean daily values were compared between sites., Results: We analyzed data from 1168 VLBW infants from birth through day 42 (35,238 infant-days). HR and SpO 2 metrics were similar at the three NICUs, with mean HR rising by ~10 beats/min over the first 2 weeks and mean SpO 2 remaining stable ~94% over time. The number of bradycardia events was higher at one site, and the duration of desaturations was longer at another site., Conclusions: Mean HR and SpO 2 were generally similar among VLBW infants at three NICUs from birth through 6 weeks of age, but bradycardia and desaturation events differed in the first 2 weeks after birth. This highlights the importance of developing predictive analytics tools at multiple sites., Impact: HR and SpO 2 analytics can be useful for predicting adverse events in VLBW infants in the NICU, but inter-site differences must be taken into account in developing predictive algorithms. Although mean HR and SpO 2 patterns were similar in VLBW infants at three NICUs, inter-site differences in the number of bradycardia events and duration of desaturation events were found. Inter-site differences in bradycardia and desaturation events among VLBW infants should be considered in the development of predictive algorithms., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

To demonstrate how heart rate fragmentation gives novel insights into non-autonomic mechanisms of beat-to-beat variability in cycle length, and predicts survival of cardiology clinic patients, over and above traditional clinical risk factors and measures of heart rate variability. Approach: We studied 2893 patients seen by cardiologists with clinical data including 24-hour Holter monitoring. Novel measures of heart rate fragmentation alongside canonical time and frequency domain measures of heart rate variability, as well as an existing local dynamics score were calculated. A proportional hazards model was utilized to relate the results to survival. Main results: The novel heart rate fragmentation measures were validated and characterized with respect to the effects of age, ectopy and atrial fibrillation. Correlations between parameters were determined. Critically, heart rate fragmentation results could not be accounted for by undersampling respiratory sinus arrhythmia. Increased heart rate fragmentation was associated with poorer survival (p ≪ 0.01 in the univariate model). In multivariable analyses, increased heart rate fragmentation and more abnormal local dynamics (p 0.045), along with increased clinical risk factors (age (p ≪ 0.01), tobacco use (p ≪ 0.01) and history of heart failure (p 0.019)) and lower low- to high-frequency ratio (p 0.022) were all independent predictors of 2-year mortality. Significance: Analysis of continuous ECG data with heart rate fragmentation indices yields information regarding non-autonomic control of beat-to-beat variability in cycle length that is independent of and additive to established parameters for investigating heart rate variability, and predicts mortality in concert with measures of local dynamics, frequency content of heart rate, and clinical risk factors., (© The Author(s) 2020.)

Objective: Trajectories of physiomarkers over time can be useful to define phenotypes of disease progression and as predictors of clinical outcomes. The aim of this study was to identify phenotypes of the time course of late-onset sepsis in premature infants in Neonatal Intensive Care Units., Methods: We examined the trajectories of a validated continuous physiomarker, abnormal heart rate characteristics, using functional data analysis and clustering techniques., Participants: We analyzed continuous heart rate characteristics data from 2989 very low birth weight infants (<1500 grams) from nine NICUs from 2004-2010., Result: Despite the relative homogeneity of the patients, we found extreme variability in the physiomarker trajectories. We identified phenotypes that were indicative of seven and 30 day mortality beyond that predicted by individual heart rate characteristics values or baseline demographic information., Conclusion: Time courses of a heart rate characteristics physiomarker reveal snapshots of illness patterns, some of which were more deadly than others., (© The Author(s) 2020.)

Background: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI., Methods: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests., Results: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis., Conclusions: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.

Objectives: Early detection of subacute potentially catastrophic illnesses using available data is a clinical imperative, and scores that report risk of imminent events in real time abound. Patients deteriorate for a variety of reasons, and it is unlikely that a single predictor such as an abnormal National Early Warning Score will detect all of them equally well. The objective of this study was to test the idea that the diversity of reasons for clinical deterioration leading to ICU transfer mandates multiple targeted predictive models., Design: Individual chart review to determine the clinical reason for ICU transfer; determination of relative risks of individual vital signs, laboratory tests and cardiorespiratory monitoring measures for prediction of each clinical reason for ICU transfer; and logistic regression modeling for the outcome of ICU transfer for a specific clinical reason., Setting: Cardiac medical-surgical ward; tertiary care academic hospital., Patients: Eight-thousand one-hundred eleven adult patients, 457 of whom were transferred to an ICU for clinical deterioration., Interventions: None., Measurements and Main Results: We calculated the contributing relative risks of individual vital signs, laboratory tests and cardiorespiratory monitoring measures for prediction of each clinical reason for ICU transfer, and used logistic regression modeling to calculate receiver operating characteristic areas and relative risks for the outcome of ICU transfer for a specific clinical reason. The reasons for clinical deterioration leading to ICU transfer were varied, as were their predictors. For example, the three most common reasons-respiratory instability, infection and suspected sepsis, and heart failure requiring escalated therapy-had distinct signatures of illness. Statistical models trained to target-specific reasons for ICU transfer performed better than one model targeting combined events., Conclusions: A single predictive model for clinical deterioration does not perform as well as having multiple models trained for the individual specific clinical events leading to ICU transfer., Competing Interests: Dr. Moorman is Chief Medical Officer and shareholder and Dr. Clark is Chief Scientific Officer and shareholder in Advanced Medical Predictive Devices, Diagnostics, and Displays, Charlottesville, VA. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Early recognition of patients at risk for sepsis is paramount to improve clinical outcomes. We hypothesized that subtle signatures of illness are present in physiological and biochemical time series of pediatric-intensive care unit (PICU) patients in the early stages of sepsis., Methods: We developed multivariate models in a retrospective observational cohort to predict the clinical diagnosis of sepsis in children. We focused on age as a predictor and asked whether random forest models, with their potential for multiple cut points, had better performance than logistic regression., Results: One thousand seven hundred and eleven admissions for 1425 patients admitted to a mixed cardiac and medical/surgical PICU were included. We identified, through individual chart review, 187 sepsis diagnoses that were not within 14 days of a prior sepsis diagnosis. Multivariate models predicted sepsis in the next 24 h: cross-validated C-statistic for logistic regression and random forest were 0.74 (95% confidence interval (CI): 0.71-0.77) and 0.76 (95% CI: 0.73-0.79), respectively., Conclusions: Statistical models based on physiological and biochemical data already available in the PICU identify high-risk patients up to 24 h prior to the clinical diagnosis of sepsis. The random forest model was superior to logistic regression in capturing the context of age.

Background: Preterm very low birth weight (VLBW) infants experience physiologic maturation and transitions off therapies from 32 to 35 weeks postmenstrual age (PMA), which may impact episodic bradycardia and oxygen desaturation. We sought to characterize bradycardias and desaturations from 32 to 35 weeks PMA and test whether events at 32 weeks PMA are associated with NICU length of stay., Methods: For 265 VLBW infants from 32 to 35 weeks PMA, we quantified the number and duration of bradycardias (HR <100 for ≥4 s) and desaturations (SpO 2 <80% for ≥10 s) and compared events around discontinuation of CPAP, caffeine, and supplemental oxygen. We modeled associations between clinical variables, bradycardias and desaturations at 32 weeks PMA, and discharge PMA., Results: Desaturations decreased from 60 to 41 per day at 32 and 35 weeks, respectively (p < 0.01). Duration of desaturations and number and duration of bradycardias decreased to a smaller extent (p < 0.05), and there was a non-significant trend toward increased desaturations after stopping CPAP and caffeine. Controlling for clinical variables, longer duration of bradycardias and desaturations at 32 weeks PMA was associated with later discharge PMA., Conclusion: Delayed recovery from bradycardias and desaturations at 32 weeks PMA, perhaps reflecting less physiologic resilience, is associated with prolonged NICU stay for VLBW infants.

Background: Bradycardia and oxygen desaturation episodes are common among preterm very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU), and their association with adverse outcomes such as bronchopulmonary dysplasia (BPD) is unclear., Methods: For 502 VLBW infants we quantified bradycardias (HR < 100 for ≥ 4 s) and desaturations (SpO 2  < 80% for ≥ 10 s), combined bradycardia and desaturation (BD) events, and percent time in events in the first 4 weeks after birth (32 infant-years of data). We tested logistic regression models of clinical risks (including a respiratory acuity score incorporating FiO 2 and level of respiratory support) to estimate the risks of BPD or death and secondary outcomes. We then tested the additive value of the bradycardia and desaturation metrics for outcomes prediction., Results: BPD occurred in 187 infants (37%). The clinical risk model had ROC area for BPD of 0.874. Measures of desaturation, but not bradycardia, significantly added to the predictive model. Desaturation metrics also added to clinical risks for prediction of severe intraventricular hemorrhage, retinopathy of prematurity and prolonged length of stay in the NICU., Conclusions: Oxygen desaturations in the first month of the NICU course are associated with risk of BPD and other morbidities in VLBW infants.

Objective: There are limited evidence-based published heart rate ranges for premature neonates. We determined heart rate ranges in premature neonates based on gestational and post-menstrual age., Study Design: Retrospective observational study of premature neonates admitted to the neonatal intensive care unit at the University of Virginia between January 2009 and October 2015. We included gestational ages between 23 0/7 weeks and 34 6/7 weeks. We stratified data by gestational and post-menstrual age groups., Results: Over two billion heart rate values in 1703 neonates were included in our study. We established percentile-based reference ranges based on gestational and post-menstrual age. Our results demonstrate a slight increase in the initial weeks after birth, followed by a gradual decline with age. The baseline heart rate is lower with advancing gestational age., Conclusions: Knowing heart rate reference ranges in the premature neonatal population can be helpful in the bedside assessment of the neonate.

Background: Charted vital signs and laboratory results represent intermittent samples of a patient's dynamic physiologic state and have been used to calculate early warning scores to identify patients at risk of clinical deterioration. We hypothesized that the addition of cardiorespiratory dynamics measured from continuous electrocardiography (ECG) monitoring to intermittently sampled data improves the predictive validity of models trained to detect clinical deterioration prior to intensive care unit (ICU) transfer or unanticipated death., Methods and Findings: We analyzed 63 patient-years of ECG data from 8,105 acute care patient admissions at a tertiary care academic medical center. We developed models to predict deterioration resulting in ICU transfer or unanticipated death within the next 24 hours using either vital signs, laboratory results, or cardiorespiratory dynamics from continuous ECG monitoring and also evaluated models using all available data sources. We calculated the predictive validity (C-statistic), the net reclassification improvement, and the probability of achieving the difference in likelihood ratio χ2 for the additional degrees of freedom. The primary outcome occurred 755 times in 586 admissions (7%). We analyzed 395 clinical deteriorations with continuous ECG data in the 24 hours prior to an event. Using only continuous ECG measures resulted in a C-statistic of 0.65, similar to models using only laboratory results and vital signs (0.63 and 0.69 respectively). Addition of continuous ECG measures to models using conventional measurements improved the C-statistic by 0.01 and 0.07; a model integrating all data sources had a C-statistic of 0.73 with categorical net reclassification improvement of 0.09 for a change of 1 decile in risk. The difference in likelihood ratio χ2 between integrated models with and without cardiorespiratory dynamics was 2158 (p value: <0.001)., Conclusions: Cardiorespiratory dynamics from continuous ECG monitoring detect clinical deterioration in acute care patients and improve performance of conventional models that use only laboratory results and vital signs.

Background: Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment., Methods: For 1,065 very-low-birth-weight (VLBW) infants in two neonatal intensive care units (NICUs), mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO 2 ) were analyzed hourly (131 infant-years' data). Cross-correlation (cotrending) between two vital signs was measured allowing a lag of ± 30 s. Cases of LOS and NEC were identified retrospectively (n = 186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24 h., Results: The best single illness predictor within and between institutions was cross-correlation of HR-SpO 2 . The best combined model (mean SpO 2 , SDHR, and cross-correlation of HR-SpO 2 ,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement: 0.205; 95% confidence interval (CI): 0.113, 0.328)., Conclusion: Despite minor inter-institutional differences in vital sign patterns of VLBW infants, cross-correlation of HR-SpO 2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC.

Apnea is nearly universal among very low birth weight (VLBW) infants, and the associated bradycardia and desaturation may have detrimental consequences. We describe here very long (>60 s) central apnea events (VLAs) with bradycardia and desaturation, discovered using a computerized detection system applied to our database of over 100 infant years of electronic signals. Eighty-six VLAs occurred in 29 out of 335 VLBW infants. Eighteen of the 29 infants had a clinical event or condition possibly related to the VLA. Most VLAs occurred while infants were on nasal continuous positive airway pressure, supplemental oxygen, and caffeine. Apnea alarms on the bedside monitor activated in 66% of events, on average 28 s after cessation of breathing. Bradycardia alarms activated late, on average 64 s after cessation of breathing. Before VLAs oxygen saturation was unusually high, and during VLAs oxygen saturation and heart rate fell unusually slowly. We give measures of the relative severity of VLAs and theoretical calculations that describe the rate of decrease of oxygen saturation. A clinical conclusion is that very long apnea (VLA) events with bradycardia and desaturation are not rare. Apnea alarms failed to activate for about one-third of VLAs. It appears that neonatal intensive care unit (NICU) personnel respond quickly to bradycardia alarms but not consistently to apnea alarms. We speculate that more reliable apnea detection systems would improve patient safety in the NICU. A physiological conclusion is that the slow decrease of oxygen saturation is consistent with a physiological model based on assumed high values of initial oxygen saturation., (Copyright © 2015 the American Physiological Society.)

Objective: Brain injury in preterm infants may lead to an inflammatory response and central nervous system dysfunction reflected by abnormal heart rate characteristics (HRC). We hypothesized that a continuously monitored HRC index reflecting reduced HR variability and decelerations correlates with abnormal neuroimaging and outcomes in extremely low birth weight infants (ELBW)., Study Design: We analyzed the average HRC index within 28 days after birth (aHRC28) and head ultrasound (HUS) in 384 ELBW infants. In 50 infants with brain magnetic resonance imaging (MRI) and 70 infants with Bayley neurodevelopmental testing at 1 year of age, we analyzed the relationship between aHRC28, MRI abnormalities and low Bayley scores., Result: aHRC28 was higher in infants with severe HUS abnormalities (2.65±1.27 for Grade III-IV intraventricular hemorrhage (IVH) or cystic periventricular leukomalacia (cPVL) versus 1.72±0.95 for normal or Grade I-II IVH, P<0.001). Higher aHRC28 was also associated with white matter damage on MRI and death or Bayley motor or mental developmental index <70. Associations persisted after adjusting for gestational age, birth weight and septicemia. For every one point increase in aHRC28, the odds ratio of death or Bayley score <70 was 2.45 (95% CI 1.46, 4.05, P<0.001)., Conclusion: A continuously monitored HRC index provides an objective, noninvasive measure associated with abnormal brain imaging and adverse neurologic outcomes in ELBW infants.

Background: Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality., Methods: This is a secondary analysis of clinical and HRC data from 2,989 VLBW infants enrolled in a randomized clinical trial of HRC monitoring in nine NICUs from 2004 to 2010., Results: LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and nondisplay groups. Mortality within 30 d of LOS was lower in the HRC display as compared with the nondisplay group (11.8 vs. 19.6%; relative risk: 0.61; 95% confidence interval: 0.43, 0.87; P < 0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed., Conclusion: Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.

Objective: Earlier diagnosis and treatment of necrotizing enterocolitis (NEC) in preterm infants, before clinical deterioration, might improve outcomes. A monitor that measures abnormal heart rate characteristics (HRC) of decreased variability and transient decelerations was developed as an early warning system for sepsis. As NEC shares pathophysiologic features with sepsis, we tested the hypothesis that abnormal HRC occur before clinical diagnosis of NEC., Study Design: Retrospective review of Bells stage II to III NEC cases among infants <34 weeks gestation enrolled in a prospective randomized clinical trial of HRC monitoring at three neonatal intensive care units., Result: Of 97 infants with NEC and HRC data, 33 underwent surgical intervention within 1 week of diagnosis. The baseline HRC index from 1 to 3 days before diagnosis was higher in patients who developed surgical vs medical NEC (2.06±1.98 vs 1.22±1.10, P=0.009). The HRC index increased significantly 16 h before the clinical diagnosis of surgical NEC and 6 h before medical NEC. At the time of clinical diagnosis, the HRC index was higher in patients with surgical vs medical NEC (3.3±2.2 vs 1.9±1.7, P<0.001)., Conclusion: Abnormal HRC occur before clinical diagnosis of NEC, suggesting that continuous HRC monitoring may facilitate earlier detection and treatment.

Background: Implantable cardioverter-defibrillators (ICDs), the first line of therapy for preventing sudden cardiac death in high-risk patients, deliver appropriate shocks for termination of ventricular tachycardia (VT)/ventricular fibrillation. A common shortcoming of ICDs is imperfect rhythm discrimination, resulting in the delivery of inappropriate shocks for atrial fibrillation (AF). An underexplored area for rhythm discrimination is the difference in dynamic properties between AF and VT/ventricular fibrillation. We hypothesized that the higher entropy of rapid cardiac rhythms preceding ICD shocks distinguishes AF from VT/ventricular fibrillation., Methods and Results: In a multicenter, prospective, observational study of patients with primary prevention ICDs, 119 patients received shocks from ICDs with stored, retrievable intracardiac electrograms. Blinded adjudication revealed shocks were delivered for VT/ventricular fibrillation (62%), AF (23%), and supraventricular tachycardia (15%). Entropy estimation of only 9 ventricular intervals before ICD shocks accurately distinguished AF (receiver operating characteristic curve area, 0.98; 95% confidence intervals, 0.93-1.0) and outperformed contemporary ICD rhythm discrimination algorithms., Conclusions: This new strategy for AF discrimination based on entropy estimation expands on simpler concepts of variability, performs well at fast heart rates, and has potential for broad clinical application.

Background: Infants admitted to the neonatal intensive care unit (NICU), and especially those born with very low birth weight (VLBW; <1,500 g), are at risk for respiratory decompensation requiring endotracheal intubation and mechanical ventilation. Intubation and mechanical ventilation are associated with increased morbidity, particularly in urgent unplanned cases., Methods: We tested the hypothesis that the systemic response associated with respiratory decompensation can be detected from physiological monitoring and that statistical models of bedside monitoring data can identify infants at increased risk of urgent unplanned intubation. We studied 287 VLBW infants consecutively admitted to our NICU and found 96 events in 51 patients, excluding intubations occurring within 12 h of a previous extubation., Results: In order of importance in a multivariable statistical model, we found that the characteristics of reduced O(2) saturation, especially as heart rate was falling; increased heart rate correlation with respiratory rate; and the amount of apnea were all significant independent predictors. The predictive model, validated internally by bootstrap, had a receiver-operating characteristic area of 0.84 ± 0.04., Conclusion: We propose that predictive monitoring in the NICU for urgent unplanned intubation may improve outcomes by allowing clinicians to intervene noninvasively before intubation is required.

In healthy neonates, connections between the heart and lungs through brain stem chemosensory pathways and the autonomic nervous system result in cardiorespiratory synchronization. This interdependence between cardiac and respiratory dynamics can be difficult to measure because of intermittent signal quality in intensive care settings and variability of heart and breathing rates. We employed a phase-based measure suggested by Schäfer and coworkers (Schäfer C, Rosenblum MG, Kurths J, Abel HH. Nature 392: 239-240, 1998) to obtain a breath-by-breath analysis of cardiorespiratory interaction. This measure of cardiorespiratory interaction does not distinguish between cardiac control of respiration associated with cardioventilatory coupling and respiratory influences on the heart rate associated with respiratory sinus arrhythmia. We calculated, in sliding 4-min windows, the probability density of heartbeats as a function of the concurrent phase of the respiratory cycle. Probability density functions whose Shannon entropy had a <0.1% chance of occurring from random numbers were classified as exhibiting interaction. In this way, we analyzed 18 infant-years of data from 1,202 patients in the Neonatal Intensive Care Unit at University of Virginia. We found evidence of interaction in 3.3 patient-years of data (18%). Cardiorespiratory interaction increased several-fold with postnatal development, but, surprisingly, the rate of increase was not affected by gestational age at birth. We find evidence for moderate correspondence between this measure of cardiorespiratory interaction and cardioventilatory coupling and no evidence for respiratory sinus arrhythmia, leading to the need for further investigation of the underlying mechanism. Such continuous measures of physiological interaction may serve to gauge developmental maturity in neonatal intensive care patients and prove useful in decisions about incipient illness and about hospital discharge.

Introduction: Biomarkers and physiomarkers may be useful adjunct tests for sepsis detection in neonatal intensive care unit (NICU) patients. We studied whether measuring plasma cytokines at the time of suspected sepsis could identify patients with bacteremia in centers in which patients were undergoing continuous physiomarker screening using a heart rate characteristics (HRC) index monitor., Results: Six cytokines were higher in Gram-negative bacteremia (GNB) than in Gram-positive bacteremia or candidemia (GPBC). A cytokine score using thresholds for granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α had 100% sensitivity and 69% positive predictive value (PPV) for GNB. A single cytokine marker, IL-6 < 130 pg/ml, had 100% sensitivity and 52% PPV for sepsis ruled out (SRO). The average HRC index was abnormal in this cohort of patients with clinical suspicion of sepsis and did not discriminate between the final sepsis designations., Discussion: In summary, in NICU patients with suspected late-onset sepsis, plasma cytokines can identify those with SRO and those with GNB, potentially aiding in decisions regarding therapy., Methods: Seven cytokines were measured in 226 plasma samples from patients >3 d old with sepsis suspected based on clinical signs, abnormal HRC index, or both. Cases were classified as SRO, clinical sepsis (CS), GPBC, or GNB.

Background: In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD., Methodology/principal Findings: We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one ≥90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-γ, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p<0.0001), and decreased concentrations of angiostatic ligands CXCL9 (p<0.0001), CXCL10 (p = 0.002), and CXCL11 (p = 0.0002), and interferon-γ (p = 0.0004)., Conclusions/significance: Plasma chemokine concentrations are associated with the presence and extent of spontaneously visible coronary artery collaterals and may be mechanistically involved in their recruitment.

Entropy estimation is useful but difficult in short time series. For example, automated detection of atrial fibrillation (AF) in very short heart beat interval time series would be useful in patients with cardiac implantable electronic devices that record only from the ventricle. Such devices require efficient algorithms, and the clinical situation demands accuracy. Toward these ends, we optimized the sample entropy measure, which reports the probability that short templates will match with others within the series. We developed general methods for the rational selection of the template length m and the tolerance matching r. The major innovation was to allow r to vary so that sufficient matches are found for confident entropy estimation, with conversion of the final probability to a density by dividing by the matching region volume, 2r(m). The optimized sample entropy estimate and the mean heart beat interval each contributed to accurate detection of AF in as few as 12 heartbeats. The final algorithm, called the coefficient of sample entropy (COSEn), was developed using the canonical MIT-BIH database and validated in a new and much larger set of consecutive Holter monitor recordings from the University of Virginia. In patients over the age of 40 yr old, COSEn has high degrees of accuracy in distinguishing AF from normal sinus rhythm in 12-beat calculations performed hourly. The most common errors are atrial or ventricular ectopy, which increase entropy despite sinus rhythm, and atrial flutter, which can have low or high entropy states depending on dynamics of atrioventricular conduction.

Atrial Fibrillation Centers (AFCs) are becoming increasingly common and are often developed at institutions to provide comprehensive evaluation and management for patients with atrial fibrillation (AF) including catheter and surgical ablation. Studies have shown that women and racial minority patients are less likely to be offered aggressive or invasive therapies. The University of Virginia (UVA) AFC was opened in 2004. We analyzed data collected during initial visits to our AFC from 2004-2008 to determine the gender and racial characteristics of a tertiary AFC population. Multivariable regression analysis was used to compare clinical characteristics. There were a total of 1664 consecutive initial patient visits. Cardiologists referred 61% and primary care physicians referred 37% of patients. Twice as many men were referred as women (570 vs. 1094; P<0.0001). Women were older (68.0±11.9 vs. 62.4±13.0 years; P<0.0001) and more symptomatic with palpitations (80% vs. 73%; P=0.008), but otherwise were not substantially different from men. Our referring physicians treated the majority of both men and women with anticoagulant and rate-controlling medications. African American patients accounted for 2.8% of AFC initial visits. In contrast, they accounted for 7.4% of patients seen for a primary diagnosis of AF at all other UVA outpatient clinics (P<0.0001). In conclusion, the demographics of a tertiary AFC are different than those of the general population. Women and racial minority patients are underrepresented, and the women have few comorbidities and symptoms than the known epidemiology would lead us to expect.

Background: Sepsis in very low birth weight (VLBW) infants has been associated with an increased risk of adverse developmental outcome. We have identified abnormal heart rate characteristics (HRCs) that are predictive of impending sepsis, and we have developed a summary measure of an infant's abnormal HRCs during the neonatal hospitalization that we refer to as the cumulative HRC score (cHRC)., Objective: In this study, we tested the hypothesis that increasing cHRC is associated with an increasing risk of adverse neurodevelopmental outcome in VLBW infants., Method: Data were collected on 65 VLBW infants whose HRCs were monitored while in the neonatal intensive care unit and who were examined at 12 to 18 months adjusted age. Using the Bayley Scale of Infant Development-II, we identified delays in early cognitive function (i.e., Mental Developmental Index <70) and psychomotor development (i.e., Psychomotor Developmental Index <70). Cerebral palsy (CP) was diagnosed using a standard neurological examination., Result: Increasing cHRC score was associated with an increased risk of CP (odds ratio per 1 standard deviation increase in cHRC: 2.6, 95% confidence limits: 1.42, 5.1) and delayed early cognitive development [odds ratio: 2.3 (1.3; 4.3)]. These associations remain statistically significant when adjusted for major cranial ultrasound abnormality. There was an association of increasing cHRC and delayed psychomotor development, which did not reach statistical significance [odds ratio: 1.7 (1.0, 3.0)]., Conclusion: Among VLBW infants, the cumulative frequency of abnormal HRCs, which can be assessed non-invasively in the neonatal intensive care unit, is associated with an increased risk of adverse neurodevelopmental outcome.

Heart rate variability (HRV) falls in humans with sepsis, but the mechanism is not well understood. We utilized a mouse model of endotoxemia to test the hypothesis that cytokines play a role in abnormal HRV during sepsis. Adult male C57BL/6 mice underwent surgical implantation of probes to continuously monitor electrocardiogram and temperature or blood pressure via radiotelemetry. Administration of high-dose LPS (Escherichia coli LPS, 10 mg/kg, n = 10) caused a biphasic response characterized by an early decrease in temperature and heart rate at 1 h in some mice, followed by a prolonged period of depressed HRV in all mice. Further studies showed that LPS doses as low as 0.01 mg/kg evoked a significant decrease in HRV. With high-dose LPS, the initial drops in temperature and HR were temporally correlated with peak expression of TNFalpha 1 h post-LPS, whereas maximal depression in HRV coincided with peak levels of multiple other cytokines 3-9 h post-LPS. Neither hypotension nor hypothermia explained the HRV response. Pretreatment with dexamethasone prior to LPS significantly blunted expression of 7 of the 10 cytokines studied and shortened the duration of depressed HRV by about half. Interestingly, dexamethasone treatment alone caused a dramatic increase in both low- and high-frequency HRV. Administration of recombinant TNFalpha caused a biphasic response in HR and HRV similar to that caused by LPS. Understanding the role of cytokines in abnormal HRV during sepsis could lead to improved strategies for detecting life-threatening nosocomial infections in intensive care unit patients.

Purpose: To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway., Experimental Design: Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one to two prior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression, response duration, and stabilization of disease of > or = 26 weeks. Correlative studies were done on tumor tissue, including EGFR expression and mutation analysis., Results: One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median time to progression was 11 weeks (95% confidence interval, 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy., Conclusions: The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.

To test the hypothesis that heart rate characteristic (HRC) monitoring adds information to clinical signs of illness in diagnosing neonatal sepsis, we prospectively recorded clinical data and the HRC index in 76 episodes of proven sepsis and 80 episodes of clinical sepsis in 337 infants in the University of Virginia NICU more than 7 d old. We devised an illness severity score based on clinical findings and tests relevant to sepsis. Point scores were derived from coefficients of multivariable regression models, and we internally validated a total score. We determined relationships of the HRC index with individual clinical signs, laboratory tests, and the total score. We found highly significant correlations of the clinical score and individual clinical signs with the HRC index. The clinical score and HRC index added independent information in predicting sepsis, and were similar in clinical and proven sepsis. The clinical score and the HRC index rose before sepsis, and the HRC index rose first. We conclude that clinical signs of illness and HRC monitoring add independent information to one another in the diagnosis of neonatal sepsis.

Messenger RNA levels of phospholemman (PLM), a member of the FXYD family of small single-span membrane proteins with putative ion-transport regulatory properties, were increased in postmyocardial infarction (MI) rat myocytes. We tested the hypothesis that the previously observed reduction in Na+-K+-ATPase activity in MI rat myocytes was due to PLM overexpression. In rat hearts harvested 3 and 7 days post-MI, PLM protein expression was increased by two- and fourfold, respectively. To simulate increased PLM expression post-MI, PLM was overexpressed in normal adult rat myocytes by adenovirus-mediated gene transfer. PLM overexpression did not affect the relative level of phosphorylation on serine68 of PLM. Na+-K+-ATPase activity was measured as ouabain-sensitive Na+-K+ pump current (Ip). Compared with control myocytes overexpressing green fluorescent protein alone, Ip measured in myocytes overexpressing PLM was significantly (P < 0.0001) lower at similar membrane voltages, pipette Na+ ([Na+]pip) and extracellular K+ ([K+]o) concentrations. From -70 to +60 mV, neither [Na+]pip nor [K+]o required to attain half-maximal Ip was significantly different between control and PLM myocytes. This phenotype of decreased V(max) without appreciable changes in K(m) for Na+ and K+ in PLM-overexpressed myocytes was similar to that observed in MI rat myocytes. Inhibition of Ip by PLM overexpression was not due to decreased Na+-K+-ATPase expression because there were no changes in either protein or messenger RNA levels of either alpha1- or alpha2-isoforms of Na+-K+-ATPase. In native rat cardiac myocytes, PLM coimmunoprecipitated with alpha-subunits of Na+-K+-ATPase. Inhibition of Na+-K+-ATPase by PLM overexpression, in addition to previously reported decrease in Na+-K+-ATPase expression, may explain altered V(max) but not K(m) of Na+-K+-ATPase in postinfarction rat myocytes.

Sample entropy and approximate entropy are measures that have been successfully utilized to study the deterministic dynamics of heart rate (HR). A complementary stochastic point of view and a heuristic argument using the Central Limit Theorem suggests that the Gaussianity of HR is a complementary measure of the physiological complexity of the underlying signal transduction processes. Renyi entropy (or q-entropy) is a widely used measure of Gaussianity in many applications. Particularly important members of this family are differential (or Shannon) entropy (q = 1) and quadratic entropy (q = 2). We introduce the concepts of differential and conditional Renyi entropy rate and, in conjunction with Burg's theorem, develop a measure of the Gaussianity of a linear random process. Robust algorithms for estimating these quantities are presented along with estimates of their standard errors.

While heart rate variability has been measured in many clinical settings and has offered insights into how HR is controlled, rarely has it offered unique information that has led to changes in patient management. We review our experience in developing continuous HR characteristics monitoring to aid in the early diagnosis of sepsis in premature infants in the neonatal intensive care unit. A predictive algorithm, developed at one center and validated at another, has led to diagnosis and treatment of this subacute and potentially catastrophic illness prior to appearance of symptoms of severe illness.

Continuous electronic fetal heart rate (FHR) monitoring during labor is motivated by the clinical experience that fetal distress causes loss of FHR variation and the occurrence of decelerations late during uterine contraction. This practice is of uncertain clinical benefit, perhaps because the interpretation is qualitative. We have developed new quantitative measures and analyzed cardiotocograph records from 148 consecutive patients, 44 of whom had at least one "nonreassuring" epoch. In multivariate regression models, measures of deceleration and variability were significantly associated with the obstetrician's diagnosis (receiver operating characteristic area 0.84, p < 0.05). This approach may be useful clinically.

Estimating the risk of in-hospital mortality in the newborn intensive care unit can provide important information for health-care providers, and illness severity scores have been devised to provide mortality risk estimates. Calculation of illness severity scores is time-consuming, and the information used to predict mortality is collected only for the first 12 to 24 h of life. A noninvasive continuous measure that uses information collected throughout the hospitalization and that requires no data entry could be less costly and more informative. We have previously shown that the abnormal heart rate characteristics (HRC) of reduced variability and transient decelerations accompany neonatal illness such as late-onset sepsis. We hypothesized that more frequent and severe abnormal HRC are associated with an increased risk of death. We tested this hypothesis in two ways. Using data on infants older than 7 d of age, we first determined the association of the HRC index with death in the next week. Second, we devised a cumulative HRC score and determined its association with in-hospital death. There were 37 deaths in the 685 patients. The major findings were 1) the HRC index showed highly significant association with death in the succeeding 7 d (receiver-operating characteristic area > 0.7, p < 0.001), and 2) the cumulative HRC was highly significantly associated with neonatal in-hospital mortality (receiver-operating characteristic area > 0.80, p < 0.001). In both analyses, HRC added information to birth weight, gestational age, and postnatal age (p < 0.01). The HRC index provides independent information about the risk of neonatal death in the upcoming 7 d, and the cumulative HRC is an estimate of the risk of in-hospital neonatal mortality.

We introduce the sample asymmetry analysis (SAA) and illustrate its utility for assessment of heart rate characteristics occurring early in the course of neonatal sepsis and systemic inflammatory response syndrome (SIRS). Conceptually, SAA describes changes in the shape of the histogram of RR intervals that are caused by reduced accelerations and/or transient decelerations of heart rate. Unlike other measures of heart rate variability, SAA allows separate quantification of the contribution of accelerations and decelerations. The application of SAA is exemplified by a study comparing 50 infants, who experienced a total of 75 episodes of sepsis and SIRS, with 50 control infants. The two groups were matched by birth weight and gestational age. RR intervals were recorded for all infants throughout their course in the Neonatal Intensive Care Unit. The sample asymmetry of the RR intervals increased in the 3-4 d preceding sepsis and SIRS, with the steepest increase in the last 24 h, from a baseline value of 3.3 (SD = 1.6) to 4.2 (SD = 2.3), p = 0.02. After treatment and recovery, sample asymmetry returned to its baseline value of 3.3 (SD = 1.3). The difference between sample asymmetry in health and before sepsis and SIRS was mainly due to fewer accelerations than to decelerations. Compared with healthy infants, infants who experienced sepsis had similar sample asymmetry in health, and elevated values before sepsis and SIRS (p = 0.002). We conclude that SAA is a useful new mathematical technique for detecting the abnormal heart rate characteristics that precede neonatal sepsis and SIRS.

Late-onset neonatal sepsis is a significant cause of morbidity and mortality, and early detection could prove beneficial. Previously, we found that abnormal heart rate characteristics (HRC) of reduced variability and transient decelerations occurred early in the course of neonatal sepsis and sepsis-like illness in infants in a single neonatal intensive care unit (NICU). We hypothesized that this finding can be generalized to other NICUs. We prospectively collected clinical data and continuously measured RR intervals in all infants in two NICUs who stayed for >7 d. We defined episodes of sepsis and sepsis-like illness as acute clinical deteriorations that prompted physicians to obtain blood cultures and start antibiotics. A predictive statistical model yielding an HRC index was developed on a derivation cohort of 316 neonates in the University of Virginia NICU and then applied to the validation cohort of 317 neonates in the Wake Forest University NICU. In the derivation cohort, there were 155 episodes of sepsis and sepsis-like illness in 101 infants, and in the validation cohort, there were 118 episodes in 93 infants. In the validation cohort, the HRC index 1) showed highly significant association with impending sepsis and sepsis-like illness (receiver operator characteristic area 0.75, p < 0.001) and 2) added significantly to the demographic information of birth weight, gestational age, and days of postnatal age in predicting sepsis and sepsis-like illness (p < 0.001). Continuous HRC monitoring is a generally valid and potentially useful noninvasive tool in the early diagnosis of neonatal sepsis and sepsis-like illness.

Background: Tamoxifen has been the endocrine treatment of choice for patients with breast cancer. The development of selective aromatase inhibitors has offered an alternative management approach for patients in whom a hormonal approach is indicated., Methods: The authors reviewed reports in which aromatase inhibitors were compared with tamoxifen for the treatment of metastatic disease, as well as information pertinent to their use as adjuvant therapy., Results: Both nonsteroidal (anastrozole and letrozole) and steroidal (exemestane) aromatase inhibitors for metastatic disease appear to provide superior efficacy and a better toxicity profile in first- and second-line treatment of metastatic disease than tamoxifen. Early results from the ATAC trial suggest anastrozole is superior to tamoxifen for disease-free survival, particularly in receptor-positive patients, and in reducing the incidence of contralateral breast cancer., Conclusions: Aromatase inhibitors have important roles in optimal management of postmenopausal patients with hormone-responsive metastases in both the adjuvant and advanced-disease settings.

Abnormal heart rate characteristics of reduced variability and transient decelerations are present early in the course of neonatal sepsis. To investigate the dynamics, we calculated sample entropy, a similar but less biased measure than the popular approximate entropy. Both calculate the probability that epochs of window length m that are similar within a tolerance r remain similar at the next point. We studied 89 consecutive admissions to a tertiary care neonatal intensive care unit, among whom there were 21 episodes of sepsis, and we performed numerical simulations. We addressed the fundamental issues of optimal selection of m and r and the impact of missing data. The major findings are that entropy falls before clinical signs of neonatal sepsis and that missing points are well tolerated. The major mechanism, surprisingly, is unrelated to the regularity of the data: entropy estimates inevitably fall in any record with spikes. We propose more informed selection of parameters and reexamination of studies where approximate entropy was interpreted solely as a regularity measure.

Microbiological surveys of post-processing can handling equipment were conducted in three low-acid food canneries to identify the source and numbers of mesophilic anaerobic sporeformers isolated from post-processing spoilage of cans packed at those canneries. Significant numbers of spores of these organisms were found on various equipment and can tracks. The spores were also isolated from the can cooling waters in two of the canneries and in numbers higher than have been reported previously. No correlation was noted between mesophilic anaerobic spore counts and total aerobic counts in samples obtained from the surveys. Clostridium botulinum was not isolated from any of the survey samples. A medium useful in the isolation of mesophilic anaerobic sporeformers is described.

Over a period of 4 years, 770 low-acid canned food spoilage incidents were investigated to determine the cause of spoilage. In 27 of these, the cause was attributed to the growth of bacteria of the Clostridium genus that had entered the cans as a result of post-processing leakage. No correlations were found that might explain the occurrence of this mesophilic anaerobic type of spoilage. It appears to be a random event, probably linked to cannery insanitation. A variety of species was found, consisting of both proteolytic and non-proteolytic types. Clostridium botulinum was not isolated from any of the canned foods examined, nor were any of the samples found to contain botulinal toxin. Container leak test methodology and principles are discussed.

Deibel, R. H. (American Meat Institute Foundation, Chicago, Ill.), Donald E. Lake, and C. F. Niven, Jr. Physiology of the enterococci as related to their taxonomy. J. Bacteriol. 86:1275-1282. 1963-Studies on a collection of enterococci isolated from diverse sources have confirmed the existence of two distinct species, namely, Streptococcus faecalis and Streptococcus faecium. In contrast with S. faecium, S. faecalis characteristically ferments melezitose, sorbitol, glycerol (anaerobically), citrate, and gluconate; fails to ferment arabinose and melibiose; has strong reducing capacities as demonstrated by prompt reduction of litmus in milk or tetrazolium in an agar medium; initiates growth on an agar medium containing 0.04% potassium tellurite; does not require folic acid for growth; and does not produce strong greening in blood agar. S. liquefaciens and S. zymogenes differ from S. faecalis only in their proteolytic capacities and, therefore, deserve only varietal status. Some S. faecalis and S. faecium strains are proteolytic when tested on agar media. S. durans differs from S. faecium only in its inability to ferment arabinose and mannitol, and the failure of most strains to ferment sucrose. Therefore, it should be considered as a variety of S. faecium. It is recommended that the term "enterococcus" be used only when referring to S. faecalis and S. faecium, and their respective varieties.