Effects of Selection for Mass-Independent Maximal Metabolic Rate on Food Consumption.

Metabolic rates potentially regulate the pace of important physiological and life-history traits. Natural selection has shaped the evolution of metabolic rates and the physiology that supports them, including digestibility and the rate of food consumption. Understanding the relationship between metabolic rates and energy internalization is central to understanding how resources are allocated among competing physiological functions. We investigated how artificial selection on mass-independent basal metabolic rate (BMR) and mass-independent aerobic maximal metabolic rate (MMR) affected food consumption and apparent digestibility in mice. Evolved changes in mass-corrected BMR-but not mass-corrected MMR-corresponded with changes in food consumption. This result is consistent with previous work showing that BMR constitutes a large portion of an animal's daily energy budget and thus that BMR might provide a better indicator of daily food requirements than MMR. In contrast, digestive efficiencies did not differ among selection treatments and did not evolve in these mice. This study provides insights into how evolution of metabolic rates may affect food consumption and overall energy use.

Decreasing birth asphyxia: utility of statistical process control in a low-resource setting.

The neonatal period is a critical time for survival of the child. A disproportionate amount of neonatal deaths occur in low-resource countries and are attributable to perinatal events, especially birth asphyxia. This project aimed to reduce the incidence of birth asphyxia by 20% by June 2014 through training in neonatal resuscitation and improving the availability of resuscitation equipment in the delivery room in the National Hospital Abuja, Nigeria. A prospective, longitudinal study using statistical process control analytical methods was done enrolling babies delivered at the National Hospital Abuja. Low Apgar scores or birth asphyxia (defined a priori as any score <7 at 1, 5 and/or at 10 min) was assessed. To ensure reliability and validity of Apgar scoring, trainings on scoring were held for labour and delivery staff. Interventions included provision of additional equipment and trainings on neonatal resuscitation. Apgar scores were aggregated weekly over 25 months. Control charts with three SE confidence limits were used to monitor the proportion of scores ≤7. The baseline incidence of low Apgar scores, as defined a priori, was 33%, 17% and 10% while postintervention the incidence was 18%, 17% and 6% at 1, 5 and 10 min, respectively-a reduction of 45% and 40% in the 1-min and 10-min low Apgar scores. Increased communication, additional resuscitation equipment and training of delivery personnel on neonatal resuscitation are associated with reductions in measures of birth asphyxia. These improvements have been sustained and efforts are ongoing to spread our interventions to other special care delivery units/nursery in adjoining states. Our study demonstrates the feasibility and utility of using improvement science methods to assess and improve perinatal outcome in low-resource settings.

State-based perinatal quality collaboratives: Pursuing improvements in perinatal health outcomes for all mothers and newborns.

State-based perinatal quality collaboratives (SPQC) have become increasingly widespread in the United States. Whereas the first was launched in 1997, today over 40 states have SPQCs that are actively working or are in development. Despite great variability in the structure and function of SPQCs among states, many have seen their efforts lead to significant improvements in the care of mothers and newborns. Clinical topics targeted by SPQCs have included nosocomial infection in newborns, human milk use, neonatal abstinence syndrome, early term deliveries without a medical indication, maternal hemorrhage, and maternal hypertension, among others. While each SPQC uses approaches suited to its own context, several themes are common to the goals of all SPQCs, including developing obstetric and neonatal partnerships; including families as partners; striving for participation by all providers; utilizing rigorous quality improvement science; maintaining close partnerships with public health departments; and seeking population-level improvements in health outcomes.

Speeding up Growth: Selection for Mass-Independent Maximal Metabolic Rate Alters Growth Rates.

Investigations into relationships between life-history traits, such as growth rate and energy metabolism, typically focus on basal metabolic rate (BMR). In contrast, investigators rarely examine maximal metabolic rate (MMR) as a relevant metric of energy metabolism, even though it indicates the maximal capacity to metabolize energy aerobically, and hence it might also be important in trade-offs. We studied the relationship between energy metabolism and growth in mice (Mus musculus domesticus Linnaeus) selected for high mass-independent metabolic rates. Selection for high mass-independent MMR increased maximal growth rate, increased body mass at 20 weeks of age, and generally altered growth patterns in both male and female mice. In contrast, there was little evidence that the correlated response in mass-adjusted BMR altered growth patterns. The relationship between mass-adjusted MMR and growth rate indicates that MMR is an important mediator of life histories. Studies investigating associations between energy metabolism and life histories should consider MMR because it is potentially as important in understanding life history as BMR.

Metabolic rates associated with membrane fatty acids in mice selected for increased maximal metabolic rate.

Aerobic metabolism of vertebrates is linked to membrane fatty acid (FA) composition. Although the membrane pacemaker hypothesis posits that desaturation of FAs accounts for variation in resting or basal metabolic rate (BMR), little is known about the FA profiles that underpin variation in maximal metabolic rate (MMR). We examined membrane FA composition of liver and skeletal muscle in mice after seven generations of selection for increased MMR. In both liver and skeletal muscle, unsaturation index did not differ between control and high-MMR mice. We also examined membrane FA composition at the individual-level of variation. In liver, 18:0, 20:3 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In gastrocnemius muscle, 18:2 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In addition, muscle 16:1 n-7, 18:1 n-9, and 22:5 n-3 FAs were significant predictors of BMR, whereas no liver FAs were significant predictors of BMR. Our findings indicate that (i) individual variation in MMR and BMR appears to be linked to membrane FA composition in the skeletal muscle and liver, and (ii) FAs that differ between selected and control lines are involved in pathways that can affect MMR or BMR.

Muscle activation patterns and motor anatomy of Anna's hummingbirds Calypte anna and zebra finches Taeniopygia guttata.

Flying animals exhibit profound transformations in anatomy, physiology, and neural architecture. Although much is known about adaptations in the avian skeleton and musculature, less is known about neuroanatomy and motor unit integration for bird flight. Hummingbirds are among the most maneuverable and specialized of vertebrate fliers, and two unusual neuromuscular features have been previously reported: (1) the pectoralis major has a unique distribution pattern of motor end plates (MEPs) compared with all other birds and (2) electromyograms (EMGs) from the hummingbird's pectoral muscles, the pectoralis major and the supracoracoideus, show activation bursts composed of one or a few spikes that appear to have a very consistent pattern. Here, we place these findings in a broader context by comparing the MEPs, EMGs, and organization of the spinal motor neuron pools of flight muscles of Anna's hummingbird Calypte anna, zebra finches Taeniopygia guttata, and, for MEPs, several other species. The previously shown MEP pattern of the hummingbird pectoralis major is not shared with its closest taxonomic relative, the swift, and appears to be unique to hummingbirds. MEP arrangements in previously undocumented wing muscles show patterns that differ somewhat from other avian muscles. In the parallel-fibered strap muscles of the shoulder, MEP patterns appear to relate to muscle length, with the smallest muscles having fibers that span the entire muscle. MEP patterns in pennate distal wing muscles were the same regardless of size, with tightly clustered bands in the middle portion of the muscle, not evenly distributed bands over the muscle's entire length. Muscle activations were examined during slow forward flight in both species, during hovering in hummingbirds, and during slow ascents in zebra finches. The EMG bursts of a wing muscle, the pronator superficialis, were highly variable in peak number, size, and distribution across wingbeats for both species. In the pectoralis major, although the individual EMG bursts were much shorter in duration in hummingbirds relative to zebra finches, the variables describing the normalized amplitude and area of the activation bursts were otherwise indistinguishable between taxa during these flight modes. However, the degree of variation in the time intervals between EMG peaks was much lower in hummingbirds, which is a plausible explanation for the "patterned" EMG signals reported previously.

Selection for increased mass-independent maximal metabolic rate suppresses innate but not adaptive immune function.

Both appropriate metabolic rates and sufficient immune function are essential for survival. Consequently, eco-immunologists have hypothesized that animals may experience trade-offs between metabolic rates and immune function. Previous work has focused on how basal metabolic rate (BMR) may trade-off with immune function, but maximal metabolic rate (MMR), the upper limit to aerobic activity, might also trade-off with immune function. We used mice artificially selected for high mass-independent MMR to test for trade-offs with immune function. We assessed (i) innate immune function by quantifying cytokine production in response to injection with lipopolysaccharide and (ii) adaptive immune function by measuring antibody production in response to injection with keyhole limpet haemocyanin. Selection for high mass-independent MMR suppressed innate immune function, but not adaptive immune function. However, analyses at the individual level also indicate a negative correlation between MMR and adaptive immune function. By contrast BMR did not affect immune function. Evolutionarily, natural selection may favour increasing MMR to enhance aerobic performance and endurance, but the benefits of high MMR may be offset by impaired immune function. This result could be important in understanding the selective factors acting on the evolution of metabolic rates.

The investment case for preventing NICU-associated infections.

BACKGROUND: Nosocomial [hospital-associated or neonatal intensive care unit (NICU)-associated] infections occur in as many as 10 to 36% of very low-birth-weight infants cared for in NICUs. OBJECTIVE: To determine the potentially avoidable, incremental costs of care associated with NICU-associated bloodstream infections. STUDY DESIGN: This retrospective study included all NICU admissions of infants weighing 401 to 1500 g at birth in the greater Cincinnati region from January 1, 2005, through December 31, 2007. Nonphysician costs of care were compared between infants who developed at least one bacterial bloodstream infection prior to NICU discharge or death and infants who did not. Costs were adjusted for clinical and demographic characteristics that are present in the first 3 days of life and are known associates of infection. RESULTS: Among 900 study infants with no congenital anomaly and no major surgery, 82 (9.1%) developed at least one bacterial bloodstream infection. On average, the cost of NICU care was $16,800 greater per infant who experienced NICU-associated bloodstream infection. CONCLUSION: Potentially avoidable costs of care associated with bloodstream infection can be used to justify investments in the reliable implementation of evidence-based interventions designed to prevent these infections.

Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy.

OBJECTIVE: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. DESIGN AND PATIENTS: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. RESULTS: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. CONCLUSIONS: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

Changes in the indications for scheduled births to reduce nonmedically indicated deliveries occurring before 39 weeks of gestation.

OBJECTIVE: To estimate the change in indications for scheduled deliveries during the Ohio Perinatal Quality Collaborative's initiative to decrease scheduled deliveries for nonmedical indications before 39 weeks of gestation. METHODS: Documented indications for scheduled deliveries between 36 0/7 and 38 6/7 weeks were categorized as: strong medically accepted reasons for delivery; intermediate acceptability; and unnecessary before 39 weeks. We describe each of these indication categories as a proportion of all deliveries in the participating hospitals between October 2008 and December 2009. RESULTS: The percentage of scheduled deliveries that were unnecessary before 39 weeks or had intermediate indications decreased over time (P=.03). There were 145 fewer with intermediate reasons and 265 fewer that were unnecessary when the first 4 months of the project were compared with the last 4 months. Strong medical indications as a percentage of all deliveries did not change significantly over time (P=.99). CONCLUSION: Our quality collaborative reduced scheduled deliveries of medically unnecessary and intermediate indications for delivery at 36 0/7 and 38 6/7 weeks. However, scheduled deliveries with strong medical indication did not change significantly over time. LEVEL OF EVIDENCE: III.

Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease.

OBJECTIVES: Variations in chronic illness care are common in our health care system and may lead to suboptimal outcomes. Specifically, inconsistent use and suboptimal medication dosing have been demonstrated in the care of patients with inflammatory bowel disease (IBD). Quality improvement (QI) efforts have improved outcomes in conditions such as asthma and diabetes mellitus, but have not been well studied in IBD. We hypothesized that QI efforts would lead to improved outcomes in our pediatric IBD population. METHODS: A QI team was formed within our IBD center in 2005. By 2007, we began prospectively capturing physician global assessment (PGA) and patient-reported global assessment. Significant QI interventions included creating evidence-based medication guidelines, joining a national QI collaborative, initiation of preclinic planning, and monitoring serum 25-hydroxyvitamin D. RESULTS: From 2007 to 2010, 505 patients have been followed at our IBD center. During this time, the frequency of patients in clinical remission increased from 59% to 76% (P < 0.05), the frequency of patients who report that their global assessment is >7 increased from 69% to 80% (P < 0.05), and the frequency of patients with a Short Pediatric Crohn's Disease Activity Index (sPCDAI) <15 increased from 60% to 77% (P < 0.05). The frequency of repeat steroid use decreased from 17% to 10% (P < 0.05). We observed an association between the use of a vitamin D supplement (P = 0.02), serum 25-hydroxyvitamin D (P < 0.05), and quiescent disease activity. CONCLUSIONS: Our results show that significant improvements in patient outcomes are associated with QI efforts that do not rely on new medication or therapies.

In their own words: adolescent views on ADHD and their evolving role managing medication.

OBJECTIVE: Up to 90% of adolescents with attention deficit hyperactivity disorder (ADHD) remain functionally impaired, yet less than half continue to take medication. The objective of this study was to gain a detailed understanding of how adolescents with ADHD contribute to medication treatment decisions. METHODS: Forty-four adolescents with ADHD aged 13 to 18 years old participated in 1 of 7 focus groups. An experienced facilitator used a semi-structured focus group guide to prompt discussion which was audio-recorded and transcribed verbatim. We coded transcripts using an inductive approach. Thematic saturation was reached after the seventh focus group. RESULTS: Adolescents assumed increased responsibility for managing medication as they matured and developed insight into the functional impact of ADHD and medication on their lives. Insights were often formed by contrasting time spent on and off medication. ADHD impacted functioning in the following domains: academics, social interactions and relationships, creativity, and driving skills. Select domains were relevant for some adolescents but not others. Adolescents described different roles that they played in managing medication as well as strategies they used to exert autonomy over medication use. Side effects were common and contributed to negative feelings toward medication. Some adolescents had begun to use medication selectively. Many expressed uncertainty about future use of medication. CONCLUSIONS: Adolescents assume an increasing role in managing medication for ADHD. Well-structured and coordinated trials stopping medication and measuring outcomes relevant to adolescents, parents, teachers, doctors, and/or other stakeholders may help ensure a developmentally appropriate transition from family to self-management of ADHD.

Using improvement science to increase accuracy and reliability of gestational age documentation.

Our aim was to improve the reliability of recording gestational age (GA) in the mother's obstetric record, as this record is used for clinical management, research databases, and eventual transmission to the Ohio Department of Health birth certificates. We performed a prospective cohort study, including all hospital births. We began quality improvement interventions in October 2009. Improvement test cycles were targeted to four working groups, including nursing staff, community obstetric providers, and the process itself. Test cycle results were evaluated to determine which successful interventions could spread further. Rates of process outcome measurements were compared by statistical process control and univariate analysis pre- and postintervention. During the preintervention period, the median daily GA reliability was 25%. To date, over 30 small sample size tests of change have been completed. Of 8795 births studied, significant improvement in GA accuracy/completeness was detected (median postintervention = 78%, p < 0.01). Increased communication of and completion of the prenatal record, in addition to GA recording in high-risk groups, such as premature infants, were also achieved (all p < 0.01). GA reliability can be increased using standardized improvement science methods. Better communication of GA will enable better clinical decisions and foster population-based perinatal research.

Metabolomics of aerobic metabolism in mice selected for increased maximal metabolic rate.

Maximal aerobic metabolic rate (MMR) is an important physiological and ecological variable that sets an upper limit to sustained, vigorous activity. How the oxygen cascade from the external environment to the mitochondria may affect MMR has been the subject of much interest, but little is known about the metabolic profiles that underpin variation in MMR. We tested how seven generations of artificial selection for high mass-independent MMR affected metabolite profiles of two skeletal muscles (gastrocnemius and plantaris) and the liver. MMR was 12.3% higher in mass selected for high MMR than in controls. Basal metabolic rate was 3.5% higher in selected mice than in controls. Artificial selection did not lead to detectable changes in the metabolic profiles from plantaris muscle, but in the liver amino acids and tricarboxylic acid cycle (TCA cycle) metabolites were lower in high-MMR mice than in controls. In gastrocnemius, amino acids and TCA cycle metabolites were higher in high-MMR mice than in controls, indicating elevated amino acid and energy metabolism. Moreover, in gastrocnemius free fatty acids and triacylglycerol fatty acids were lower in high-MMR mice than in controls. Because selection for high MMR was associated with changes in the resting metabolic profile of both liver and gastrocnemius, the result suggests a possible mechanistic link between resting metabolism and MMR. In addition, it is well established that diet and exercise affect the composition of fatty acids in muscle. The differences that we found between control lines and lines selected for high MMR demonstrate that the composition of fatty acids in muscle is also affected by genetic factors.

Spontaneous late preterm births: what can be done to improve outcomes?

Despite the increase in indicated late preterm births, spontaneous preterm labor and preterm premature rupture of the fetal membranes are the most common antecedent diagnoses leading to births between 34-0/7 and 36-6/7 weeks of gestation. Regional and institutional variation in the rates of late spontaneous preterm birth suggests that there may be opportunities to reduce the number of these births. This article summarizes the factors contributing to late spontaneous preterm birth and offers suggestions to improve care for these mothers and infants.

What we have here is a failure to communicate: obstacles to optimal care for preterm birth.

Obstetricians and pediatricians share the common goal of a healthy beginning for every baby, mother, and family. This article asserts that miscommunication between the specialties, fostered by separate definitions, metrics, and outcomes, is an impediment to optimal care. Solutions are suggested for improving communication and outcomes.

Cytokines and neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVE: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. STUDY DESIGN: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1ß; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. RESULTS: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-ß, soluble IL rα, macrophage inflammatory protein 1ß) were found to be altered on days 0-4 in infants who developed CP. CONCLUSIONS: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

Predictive value of an early amplitude integrated electroencephalogram and neurologic examination.

OBJECTIVE: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia. DESIGN: Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months. RESULTS: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19). CONCLUSIONS: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

Ohio statewide quality-improvement collaborative to reduce late-onset sepsis in preterm infants.

OBJECTIVE: We aimed to reduce late-onset bacterial infections in infants born at 22 to 29 weeks' gestation by using collaborative quality-improvement methods to implement evidence-based catheter care. We hypothesized that these methods would result in a 50% reduction in nosocomial infection. PATIENTS AND METHODS: We conducted an interrupted time-series study among 24 Ohio NICUs. The intervention began in September 2008 and continued through December 2009. Sites used the Institute for Healthcare Improvement Breakthrough Series quality-improvement model to facilitate implementation of evidence-based catheter care. Data were collected monthly for all catheter insertions and for at least 10 observations of indwelling catheter care. NICUs also submitted monthly data on catheter-days, patient-days, and episodes of infection. Data were analyzed by using statistical process control methods. RESULTS: During the intervention, NICUs submitted information on 1916 infants. Of the 242 infections reported, 69% were catheter associated. Compliance with catheter-insertion components was >90% by April 2009. Compliance with components of evidence-based indwelling catheter care reached 80.4% by December 2009. There was a significant reduction in the proportion of infants with at least 1 late-onset infection from a baseline of 18.2% to 14.3%. CONCLUSIONS: There was a 20% reduction in the incidence of late-onset infection after the intervention, but the magnitude was less than hypothesized, perhaps because compliance with components of evidence-based care of indwelling catheters remained <90%. Because nearly one-third of infections were not catheter associated, improvement may require attention to other aspects of care such as skin integrity and nutrition.

Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial.

It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.