Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.

Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.

Differences in demographics and outcomes based on method of consent for a randomised controlled trial on heat loss prevention in the delivery room.

OBJECTIVE: Informed consent is standard in research. International guidelines allow for research without prior consent in emergent situations, such as neonatal resuscitation. Research without prior consent was incorporated in the Vermont Oxford Network Heat Loss Prevention Trial. We evaluated whether significant differences in outcomes exist based on the consent method. DESIGN: Subgroup analysis of infants enrolled in a randomised controlled trial conducted from 2004 to 2010. SETTING: A multicentre trial with 38 participating centres. PARTICIPANTS: Infants born 24-27 weeks of gestation. 3048 infants assessed, 2231 excluded due to fetal congenital anomalies, failure to obtain consent or gestation less than 24 weeks. 817 randomised, 4 withdrew consent, total of 813 analysed. MAIN OUTCOME MEASURE: The difference in mortality between consent groups. RESULTS: No significant differences were found in mortality at 36 weeks (80.2%, 77.4%, p=0.492) or 6 months corrected gestational age (80.7%, 79.7%, p=0.765). Infants enrolled after informed consent were more likely to have mothers who had received antenatal steroids (95.2%, 84.0%, p<0.0001). They also had significantly higher Apgar scores at 1 (5.0, 4.4, p=0.019), 5 (7.3, 6.7, p=0.025) and 10 min (7.5, 6.3, p=0.0003). CONCLUSIONS AND RELEVANCE: Research without prior consent resulted in the inclusion of infants with different baseline characteristics than those enrolled after informed consent. There were no significant differences in mortality. Significantly higher Apgar scores in the informed consent group suggest that some of the sicker infants would have been excluded from enrolment under informed consent. Research without prior consent should be considered in neonatal resuscitation research.

Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors.

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.

Knowledge, attitudes, and behavior toward concussion in adult cyclists.

OBJECTIVE: To determine knowledge, attitudes, and behavior toward concussion in cyclists and to identify predictors of concussion knowledge. METHODS: Cycling organizations sent members a web link to online information about the study and a questionnaire. Anyone aged >16 years, living in New Zealand and engaged in a cycling activity was invited to participate. The 36-item questionnaire included sociodemographics, knowledge about concussion, helmet use, and personal concussion history. Data were collected between 15/05/19 and 30/06/19. A multiple linear regression model identified factors associated with levels of concussion knowledge. RESULTS: The questionnaire was completed by 672 participants aged between 16 and 82 years (x̄ = 48.6 years). Knowledge of concussion was high. However, knowledge that helmets are not able to prevent concussion was low and time to return to sport after injury was variable. Knowledge did not always translate to seeking of medical attention or replacement of helmet behavior. Younger age and having sustained at least one prior concussion were associated with higher levels of concussion knowledge F(df = 3) = 8.81, p < .001. CONCLUSIONS: Knowledge and attitudes toward concussion were positive. However, knowledge gaps and discrepancies between attitudes and behavior were identified. Consistent, clear messages are needed around return to sport timeframes.

Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment.

Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

Parallel Exploratory RCT of Polyethylene Wrap for Heat Loss Prevention in Infants Born at Less than 24 Weeks' Gestation.

BACKGROUND: The treatment effect of occlusive wrap applied immediately after delivery in infants born 24-28 weeks' gestation has been studied, but the effect is not known in infants born at less than 240/7 weeks' gestation. OBJECTIVES: To determine if the use of occlusive wrap applied immediately after birth in infants born at less than 240/7 weeks' gestation results in any differences in outcomes when compared to non-wrapped infants. METHODS: Parallel exploratory randomized controlled trial with a convenience sample of 28 inborn infants born at less than 240/7 weeks' gestation enrolled during the duration of the HeLP trial. Infants were randomized to either the wrap or standard of care (no wrap) group. RESULTS: Twenty-eight infants (wrap n = 14; no wrap n = 14) were randomized and data on all infants was available for intention-to-treat analysis. There were no differences in baseline population characteristics. There was no statistically significant difference in mortality (n = 8/14 wrap, 8/14 no wrap). There was no statistically significant difference in baseline temperature (35.9°C, SD = 1.12, wrap vs. 35.1°C, SD = 1.16, no wrap, p = 0.16) or post-stabilization temperature (36.4°C, SD = 0.84, wrap vs. 36.1°C, SD = 1.2, no wrap, p = 0.56). There was a trend towards increased baseline temperature in the wrap group. CONCLUSION: Application of occlusive wrap to infants born at less than 240/7 weeks' gestation immediately after birth did not reduce mortality or effect baseline or post-stabilization temperature in this small exploratory study. This small sample provides the first estimate of treatment effect for this high-risk population.

Absence of leptin signaling allows fat accretion in cystic fibrosis mice.

Negative energy balance is a prevalent feature of cystic fibrosis (CF). Pancreatic insufficiency, elevated energy expenditure, lung disease, and malnutrition, all characteristic of CF, contribute to the negative energy balance causing low body-growth phenotype. As low body weight and body mass index strongly correlate with poor lung health and survival of patients with CF, improving energy balance is an important clinical goal (e.g., high-fat diet). CF mouse models also exhibit negative energy balance (growth retardation and high energy expenditure), independent from exocrine pancreatic insufficiency, lung disease, and malnutrition. To improve energy balance through increased caloric intake and reduced energy expenditure, we disrupted leptin signaling by crossing the db/db leptin receptor allele with mice carrying the R117H Cftr mutation. Compared with db/db mice, absence of leptin signaling in CF mice (CF db/db) resulted in delayed and moderate hyperphagia with lower de novo lipogenesis and lipid deposition, producing only moderately obese CF mice. Greater body length was found in db/db mice but not in CF db/db, suggesting CF-dependent effect on bone growth. The db/db genotype resulted in lower energy expenditure regardless of Cftr genotype leading to obesity. Despite the db/db genotype, the CF genotype exhibited high respiratory quotient indicating elevated carbohydrate oxidation, thus limiting carbohydrates for lipogenesis. In summary, db/db-linked hyperphagia, elevated lipogenesis, and morbid obesity were partially suppressed by reduced CFTR activity. CF mice still accrued large amounts of adipose tissue in contrast to mice fed a high-fat diet, thus highlighting the importance of dietary carbohydrates and not simply fat for energy balance in CF. NEW & NOTEWORTHY We show that cystic fibrosis (CF) mice are able to accrue fat under conditions of carbohydrate overfeeding, increased lipogenesis, and decreased energy expenditure, although length was unaffected. High-fat diet feeding failed to improve growth in CF mice. Morbid db/db-like obesity was reduced in CF double-mutant mice by reduced CFTR activity.

Inhaled corticosteroids in ventilated preterm neonates: a non-randomized dose-ranging study.

BACKGROUND: Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. METHODS: Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 µg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. RESULTS: The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO2 at a dose of 800 µg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. CONCLUSIONS: Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 µg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. TRIAL REGISTRATION: This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .

Patterns of family management for adolescent and young adult brain tumor survivors.

Little is known about how families systemically incorporate the work of caring for adolescent and young adult (AYA) survivors of childhood brain tumors who often remain dependent on their families well into adulthood. The primary aim of this study was to develop a typology of family management (FM) patterns for AYA survivors. The secondary aims were to compare them with FM patterns previously described for children with chronic health conditions and to validate the patterns using quantitative and qualitative data. Guided by the Family Management Styles Framework, a sequential, mixed-methods design was used to gather quantitative data from 186 mothers (primary caregivers) and 134 AYA survivors. FM patterns (family focused; somewhat family focused; somewhat condition focused; and condition focused) were identified using cluster analysis of data from the Family Management Measure. FM patterns were found to be similar to those for children with chronic health physical conditions and were significantly related to maternal quality of life, survivor quality of life (health-related quality of life [self- and mother proxy report]), cancer-related variables (treatment intensity, medical late effects), and family functioning in theoretically meaningfully ways. Significant demographic characteristics included private insurance and AYA survivors' engagement in school or employment. Qualitative analysis of data from 45 interviews with mothers from the larger sample provided additional support for and elaborated descriptions of FM patterns. Identification of FM patterns moves the science of family caregiving forward by aggregating data into a conceptually based typology, thereby taking into account the complex intersection of the condition, the family, and condition management. (PsycINFO Database Record

Impact of feeding method on diaphragm electrical activity and central apnea in preterm infants (FEAdi study).

BACKGROUND: In preterm infants, it is unknown whether feeding affects neural breathing pattern. OBJECTIVES: By measuring the diaphragm electrical activity (Edi) waveform, we evaluated the effect of enteral feeding and compared the effects of feeding methods on neural breathing pattern and central apnea in very low birth weight preterm infants. METHODS: In a prospective, randomized, crossover study, ten non-ventilated preterm infants with birth weights<1250g and tolerating full feeds were randomized to either bolus feeding (BF) or slow infusion feeding (SF) over 90min, followed by crossover to the other method at the next feed. Edi was continuously measured by a feeding catheter with miniaturized sensors. Five 15-min epochs were chosen [Baseline (BL), first 15min and 90min after BF/SF started] for breath-by-breath analyses of neural breathing pattern, including Edi peak, Edi min (end-expiratory), neural inspiratory and expiratory times, neural respiratory rate, and central apnea. Primary outcome was change in Edi min with feed. Secondary outcomes include change in Edi peak, frequency and duration of central apnea with feeding. RESULTS: Although intrasubject coefficient of variation was not significantly different, individual responses to feeding and feeding method were variable. No significant difference in Edi timing, Edi min, Edi peak, or apnea was observed for the different epochs. CONCLUSIONS: In this study cohort, neural breathing pattern does not appear to be consistently affected by enteral feeding or the feeding method. Compared with BF, SF does not appear to reduce the number or duration of apneas.

Adolescent and Young Adult Survivors of Childhood Brain Tumors: Life After Treatment in Their Own Words.

BACKGROUND: To date, there are few studies that examine the perspectives of older survivors of childhood brain tumors who are living with their families in terms of their sense of self and their role in their families. OBJECTIVE: The aim of this study was to describe how adolescent and young adult survivors of childhood brain tumors describe their health-related quality of life, that is, their physical, emotional, and social functioning. METHODS: This qualitative descriptive study included a purposive sample of 41 adolescent and young adult survivors of a childhood brain tumor who live with their families. Home interviews were conducted using a semistructured interview guide. Directed content analytic techniques were used to analyze data using health-related quality of life as a framework. RESULTS: This group of brain tumor survivors described their everyday lives in terms of their physical health, neurocognitive functioning, emotional health, social functioning, and self-care abilities. Overall, survivors struggle for normalcy in the face of changed functioning due to their cancer and the (late) effects of their treatment. CONCLUSIONS: Neurocognitive issues seemed most compelling in the narratives. The importance of families went beyond the resources, structure, and support for functioning. Their families provided the recognition that they were important beings and their existence mattered to someone. IMPLICATIONS FOR PRACTICE: The value and complexity of care coordination were highlighted by the multifaceted needs of the survivors. Advocacy for appropriate and timely educational, vocational, and social support is critical as part of comprehensive cancer survivorship care.

High-flow nasal cannulae are associated with increased diaphragm activation compared with nasal continuous positive airway pressure in preterm infants.

AIM: High-flow nasal cannulae (HFNC) are increasingly used for respiratory management of preterm infants. However, their ability to provide support compared to nasal continuous positive airway pressure (CPAP) has been questioned. We compared the effect of HFNC versus nasal CPAP on diaphragm electrical activity (EAdi) in preterm infants. METHODS: Preterm infants ≤1500 g were randomised in a crossover design to receive 2 hours of either Infant Flow(®) CPAP (IF-CPAP) at 5-6 cmH2 O or HFNC with the flow rate adjusted to achieve an equivalent pharyngeal pressure. A feeding catheter with miniaturised sensors was inserted for continuous EAdi measurement. RESULTS: The study comprised ten infants. Physiologic parameters and oxygen requirements were not different between the two modes. However, seven infants demonstrated a higher EAdi peak and six showed a higher EAdi tonic on HFNC, even though the mean group data showed no difference between HFNC and IF-CPAP. Neural inspiratory time was significantly longer with HFNC than IF-CPAP (0.55 ± 0.11 versus 0.48 ± 0.06 seconds, p = 0.018). CONCLUSION: In this cohort of preterm infants, the majority exhibited greater diaphragm activation, as assessed by neural breathing patterns, when supported with HFNC than IF-CPAP, suggesting that nasal CPAP may provide more effective respiratory support.

Health-related quality of life of adolescent and young adult survivors of childhood brain tumors.

OBJECTIVE: Our aim was to expand research on predictors of health-related quality of life (HRQOL) for adolescent and young adult survivors of childhood brain tumors who are not living independently by evaluating the mediating role of family functioning in the association of disease severity/treatment late effects with survivor self-report and caregiver-proxy report of physical and emotional HRQOL. METHODS: Mothers (N = 186) and their survivors living at home (N = 126) completed self-report and caregiver-proxy report of physical and emotional HRQOL. Mothers completed family functioning measures of general family functioning, caregiving demands, and caregiver distress. Medical file review and caregiver report were used to evaluate disease severity/treatment late effects. RESULTS: Using structural equation models, family functioning was adjusted for sociodemographic factors. Disease severity/treatment late effects had significant direct effects on self-report and caregiver-proxy report of physical and emotional HRQOL. Family functioning had a significant direct effect on caregiver-proxy report of physical and emotional HRQOL, but these findings were not confirmed for self-report HRQOL. Model-fit indices suggested good fit of the models, but the mediation effect of family functioning was not supported. CONCLUSIONS: Disease severity/treatment late effects explained self-report and caregiver-proxy report of physical and emotional HRQOL for these adolescent and young adult survivors of childhood brain tumors. Family functioning was implicated as an important factor for caregiver-proxy report only. To enhance physical and emotional HRQOL, findings underscore the importance of coordinated, multidisciplinary follow-up care for the survivors who are not living independently and their families to address treatment late effects and support family management.

Randomized trial of occlusive wrap for heat loss prevention in preterm infants.

OBJECTIVE: To determine whether the application of occlusive wrap applied immediately after birth will reduce mortality in very preterm infants. STUDY DESIGN: This was a prospective randomized controlled trial of infants born 24 0/7 to 27 6/7 weeks' gestation who were assigned randomly to occlusive wrap or no wrap. The primary outcome was all cause mortality at discharge or 6 months' corrected age. Secondary outcomes included temperature, Apgar scores, pH, base deficit, blood pressure and glucose, respiratory distress syndrome, bronchopulmonary dysplasia, seizures, patent ductus arteriosus, necrotizing enterocolitis, gastrointestinal perforation, intraventricular hemorrhage, cystic periventricular leukomalacia, pulmonary hemorrhage, retinopathy of prematurity, sepsis, hearing screen, and pneumothorax. RESULTS: Eight hundred one infants were enrolled. There was no difference in baseline population characteristics. There were no significant differences in mortality (OR 1.0, 95% CI 0.7-1.5). Wrap infants had statistically significant greater baseline temperatures (36.3°C wrap vs 35.7°C no wrap, P < .0001) and poststabilization temperatures (36.6°C vs 36.2°C, P < .001) than nonwrap infants. For the secondary outcomes, there was a significant decrease in pulmonary hemorrhage (OR 0.6, 95% CI 0.3-0.9) in the wrap group and a significant lower mean one minute Apgar score (P = .007) in the wrap group. The study was stopped early because continued enrollment would not result in the attainment of a significant difference in the primary outcome. CONCLUSION: Application of occlusive wrap to very preterm infants immediately after birth results in greater mean body temperature but does not reduce mortality.

Competence in caregivers of adolescent and young adult childhood brain tumor survivors.

OBJECTIVE: Caregivers of adolescents and young adults (AYA) with complex medical conditions, including brain tumor survivors, have protracted and often complex roles, yet a gap exists in understanding their perceived competence. The aim of this study is to test a hypothesized model based on the theoretical and empirical literature: better caregiver health, better survivor health, and better family functioning contribute directly to fewer caregiving demands, which in turn contribute to greater caregiver competence. METHOD: Telephone interviews using structured self-report questionnaires were conducted in this cross-sectional study with a sample of 186 caregivers (mothers) of childhood brain tumor survivors aged 14-40 years old who live with at least one parent. Structural equation modeling (SEM) was used to test the hypothesized model. RESULTS: The final SEM model suggests that survivor health and family functioning directly predict caregiver competence. Caregiver health indirectly predicts caregiver competence through caregiver demands and then family functioning. Family income directly predicts family functioning. The model showed adequate fit (CFI = 0.905, TFI = 0.880, and RMSEA = 0.081). Overall, the model accounted for 45% of variance in caregiver competence. CONCLUSIONS: For this sample of caregivers of AYA with medically complex conditions, family functioning and the health of survivors are both important to how they evaluate their skills as caregivers. The results of this study underscore the crucial role of care models that focus on optimizing the health of the survivor, caregiver, and family, along with supporting a family centered approach to their care.

Study protocol for multicentre randomized controlled trial of HeLP (Heat Loss Prevention) in the delivery room.

INTRODUCTION: Immediate postnatal hypothermia is an independent risk factor for death in premature newborns. Three randomized controlled trials (RCTs) and five historical controlled trials show statistically significant differences in admission temperature between infants wrapped in occlusive skin wrap and unwrapped infants. This paper presents a study protocol for The Vermont Oxford Network (VON) Heat Loss Prevention (HeLP) Trial, a multicentre RCT of two interventions (standard of care vs. occlusive wrap) that investigates the effect of polyethylene occlusive wrap applied immediately after birth on mortality in infants born 24 + 0/7 to 27 + 6/7 week gestation. METHODS: Inclusion criteria include: infants 24 + 0/7 to 27 + 6/7 weeks gestational age and a firm decision prior to birth to provide full resuscitative measures. Exclusion criteria comprise infants born with blistering skin conditions or congenital anomalies that are not covered by skin. The primary outcome measure is all-cause mortality until discharge from the hospital or at six months corrected gestational age. The secondary outcome measures include baseline and post-stabilization axillary temperatures, acidosis, hypotension, hypoglycaemia, seizures in the first 12h, patent ductus arteriosus, and respiratory distress syndrome. Long-term follow-up at 18 to 24 months corrected age will be assessed with the combined risk of death and major neurosensory disability as the primary outcome. DISCUSSION: Key covariates and protocol deviations are addressed and steps to monitor these are described. Wrapping may prove an inexpensive and easy method to benefit premature newborns in level I and II nurseries, in both developed and developing countries, as well as large tertiary care centres. REB APPROVAL: Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada-355-2003 University of Alberta, Edmonton, Alberta, Canada-Pro00003810 Vermont Oxford Network, Burlington, Vermont, USA-CHRMS: M04-295.

Development of reference values for the Functional Mobility Assessment.

PURPOSE: To obtain reference values for healthy participants performing the Functional Mobility Assessment (FMA). The FMA is a reliable and valid tool used to examine functional abilities subjectively and objectively in patients with lower-extremity sarcoma in all components of the International Classification of Functioning, Disability, and Health model (body function, activity, and participation). METHODS: Children, adolescents, and young adults who were healthy, representing a sample of convenience (n = 503; 260 females, age 10-21 years), participated in this study. RESULTS: Means and standard deviations for all participants: Timed Up and Down Stairs 6.18 ± 0.8 seconds, Timed Up and Go 3.78 ± 0.6 seconds, 9-minute run/walk 4161 ± 893 feet, and the FMA total 59 ± 3. CONCLUSION: The reference values provided in this study will allow health care professionals to compare the functional abilities of children, adolescents, and young adults with lower extremity sarcoma to age- and gender-matched healthy peers when using the FMA.

Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates.

OBJECTIVE: We designed a multicenter randomized trial to compare 3 approaches to the initial respiratory management of preterm neonates: prophylactic surfactant followed by a period of mechanical ventilation (prophylactic surfactant [PS]); prophylactic surfactant with rapid extubation to bubble nasal continuous positive airway pressure (intubate-surfactant-extubate [ISX]) or initial management with bubble continuous positive airway pressure and selective surfactant treatment (nCPAP). DESIGN/METHODS: Neonates born at 26 0/7 to 29 6/7 weeks' gestation were enrolled at participating Vermont Oxford Network centers and randomly assigned to PS, ISX, or nCPAP groups before delivery. Primary outcome was the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. RESULTS: 648 infants enrolled at 27 centers. The study was halted before the desired sample size was reached because of declining enrollment. When compared with the PS group, the relative risk of BPD or death was 0.78 (95% confidence interval: 0.59-1.03) for the ISX group and 0.83 (95% confidence interval: 0.64-1.09) for the nCPAP group. There were no statistically significant differences in mortality or other complications of prematurity. In the nCPAP group, 48% were managed without intubation and ventilation, and 54% without surfactant treatment. CONCLUSIONS: Preterm neonates were initially managed with either nCPAP or PS with rapid extubation to nCPAP had similar clinical outcomes to those treated with PS followed by a period of mechanical ventilation. An approach that uses early nCPAP leads to a reduction in the number of infants who are intubated and given surfactant.

Characterization of neural breathing pattern in spontaneously breathing preterm infants.

The aim was to characterize the neural breathing pattern in nonintubated preterm infants. The diaphragm electrical activity (EAdi) and heart rate were simultaneously measured repeatedly for 1 h over several days using a modified feeding tube equipped with miniaturized sensors. The EAdi waveform was quantified for phasic and tonic activity, neural timings, and prevalence of recurring patterns, including central apnea. Ten infants with mean age 7 d (range, 3-13 d) were studied. Their birth weight was 1512 g (1158-1800 g) and GA at birth 31 wk (28-36 wk). Neural inspiratory and expiratory times were 278 ms (195-450 ms) and 867 ms (668-1436 ms) and correlated with GA (p < 0.001). Tonic EAdi represented 29.5% of phasic EAdi (16-40%) and was related to GA (r = 0.61, p < 0.001). For the group, 68% of the time was regular phasic breathing (without tonic activity) and 29% of the time with elevated tonic activity. Central apneas >5 s occurred on average 10 times per hour (2-29). Heart rate reductions were correlated to central apnea duration. In conclusion, esophageal recordings of the EAdi waveform demonstrate that neural breathing pattern is variable, with regards to timing, amplitude, and pattern with a distinct amount of tonic diaphragm activity.