Exploring the role of the Kölliker-Fuse nucleus in breathing variability by mathematical modelling.

The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnoea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apnoeas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupnoeic as well as RTT-like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT-like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late-expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing. KEY POINTS: The Kölliker-Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation. Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modelling to explore different dynamical regimes of KF activity and their compatibility with experimental observations. By analysing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT-like respiratory patterns and proposes potential KF local circuit organizations. Two models are presented that simulate both normal breathing and RTT-like breathing patterns. These models provide testable hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.

The role of Kölliker-Fuse nucleus in breathing variability.

The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apneas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupneic as well as RTT-like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT-like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late-expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing. Key points: The Kölliker-Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation. Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modeling to explore different dynamical regimes of KF activity and their compatibility with experimental observations. By analyzing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT-like respiratory patterns and proposes potential KF local circuit organizations. Two models are presented that simulate both normal breathing and RTT-like breathing patterns. These models provide plausible hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.

Early Childhood Education: Health, Equity, and Economics.

Many low-income and minority children in the United States and globally are at risk of poor educational trajectories and, consequently, diminished life courses, because their households and neighborhoods lack resources to adequately support learning and development prior to formal schooling. This review summarizes evidence on center-based early childhood education (ECE) for three- and four-year-olds as a means of assuring school readiness in cognitive and socioemotional skills. While the details of ECE programs merit further research, it is clear that ECE can benefit children, especially those most disadvantaged, with additional societal benefits and positive long-run economic returns. Universal ECE is not a cure-all, and its success requires ongoing alignment with subsequent education and attention to child household and community conditions. Because resource deprivation is concentrated in low-income and minority communities, publicly funded universal ECE can also be a powerful instrument for the promotion of social equity.

Frontal plane dynamics of the centre of mass during quadrupedal locomotion on a split-belt treadmill.

Our previous study of cat locomotion demonstrated that lateral displacements of the centre of mass (COM) were strikingly similar to those of human walking and resembled the behaviour of an inverted pendulum (Park et al. 2019 J. Exp. Biol.222, 14. (doi:10.1242/jeb.198648)). Here, we tested the hypothesis that frontal plane dynamics of quadrupedal locomotion are consistent with an inverted pendulum model. We developed a simple mathematical model of balance control in the frontal plane based on an inverted pendulum and compared model behaviour with that of four cats locomoting on a split-belt treadmill. The model accurately reproduced the lateral oscillations of cats' COM vertical projection. We inferred the effects of experimental perturbations on the limits of dynamic stability using data from different split-belt speed ratios with and without ipsilateral paw anaesthesia. We found that the effect of paw anaesthesia could be explained by the induced bias in the perceived position of the COM, and the magnitude of this bias depends on the belt speed difference. Altogether, our findings suggest that the balance control system is actively involved in cat locomotion to provide dynamic stability in the frontal plane, and that paw cutaneous receptors contribute to the representation of the COM position in the nervous system.

Installation and commissioning of the ion source systems for the new spallation neutron source 2.5 MeV injector.

The U.S. Spallation Neutron Source (SNS) is a state-of-the-art neutron scattering facility delivering the world's most intense pulsed neutron beams to a wide array of instruments, which are used to conduct investigations in many fields of engineering, physics, chemistry, material science, and biology. Neutrons are produced by spallation of liquid Hg by the bombardment of short (∼1 µs), intense (∼35 A) pulses of protons delivered at 60 Hz by an accumulator ring which is fed by a high-intensity, 1 GeV, H- LINAC (linear accelerator). This facility has operated nearly continuously since 2006 but has recently undergone a 4-month maintenance period, which featured a complete replacement of the 2.5 MeV injector feeding the LINAC. The new injector was developed at ORNL in an off-line beam test facility and consists of an ion source, low energy beam transport, and a Radio Frequency Quadrupole (RFQ). This report first describes the installed configuration of the new injector detailing the ion source system. The first beam current, RFQ transmission, emittance, and energy measurements from the injector installed on the SNS are reported. These data not only show a significant performance improvement for our existing facility but will also make accessible the higher beam current requirements for future SNS upgrade projects: the proton power upgrade and second target station.

Associations of antenatal maternal psychological distress with infant birth and development outcomes: Results from a South African birth cohort.

BACKGROUND: Antenatal maternal psychological distress is common in low and middle-income countries (LMIC), but there is a dearth of research on its effect on birth and developmental outcomes in these settings, particularly in Sub-Saharan Africa. This study set out to identify risk factors for antenatal maternal psychological distress and determine whether antenatal maternal psychological distress was associated with infant birth and developmental outcomes, using data from the Drakenstein Child Health Study (DCHS), a birth cohort study in South Africa. METHODS: Pregnant women were enrolled in the DCHS from primary care antenatal clinics. Antenatal maternal psychological distress was measured using the Self-Reporting Questionnaire 20-item (SRQ-20). A range of psychosocial measures, including maternal childhood trauma, depression, and posttraumatic stress disorder (PTSD) were administered. Birth outcomes, including premature birth, weight-for-age z-score and head circumference-for-age z-score, were measured using revised Fenton growth charts. The Bayley III Scales of Infant and Toddler Development was administered at 6 months of age to assess infant development outcomes, including cognitive, language, and motor domains in a subset of n=231. Associations of maternal antenatal psychological distress with psychosocial measures, and with infant birth and developmental outcomes were examined using linear regression models. RESULTS: 961 women were included in this analysis, with 197 (21%) reporting scores indicating the presence of psychological distress. Antenatal psychological distress was associated with maternal childhood trauma, antenatal depression, and PTSD, and inversely associated with partner support. No association was observed between antenatal maternal psychological distress and preterm birth or early developmental outcomes, but antenatal maternal psychological distress was associated with a smaller head circumference at birth (coefficient=-0.30, 95% CI: -0.49; -0.10). CONCLUSION: Antenatal maternal psychological distress is common in LMIC settings and was found to be associated with key psychosocial measures during pregnancy, as well as with adverse birth outcomes, in our study population. These associations highlight the potential value of screening for antenatal maternal psychological distress as well as of developing targeted interventions.

Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science.

Over a decade ago, the Society for Prevention Research endorsed the first standards of evidence for research in preventive interventions. The growing recognition of the need to use limited resources to make sound investments in prevention led the Board of Directors to charge a new task force to set standards for research in analysis of the economic impact of preventive interventions. This article reports the findings of this group's deliberations, proposes standards for economic analyses, and identifies opportunities for future prevention science. Through examples, policymakers' need and use of economic analysis are described. Standards are proposed for framing economic analysis, estimating costs of prevention programs, estimating benefits of prevention programs, implementing summary metrics, handling uncertainty in estimates, and reporting findings. Topics for research in economic analysis are identified. The SPR Board of Directors endorses the "Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science."

Early Childhood Education to Promote Health Equity: A Community Guide Economic Review.

CONTEXT: A recent Community Guide systematic review found that early childhood education (ECE) programs improve educational, social, and health-related outcomes and advance health equity because many are designed to increase enrollment for high-risk children. This follow-up economic review examines how the economic benefits of center-based ECE programs compare with their costs. EVIDENCE ACQUISITION: Kay and Pennucci from the Washington State Institute for Public Policy, whose meta-analysis formed the basis of the Community Guide effectiveness review, conducted a benefit-cost analysis of ECE programs for low-income children in Washington State. We performed an electronic database search using both effectiveness and economic key words to identify additional cost-benefit studies published through May 2015. Kay and Pennucci also provided us with national-level benefit-cost estimates for state and district and federal Head Start programs. EVIDENCE SYNTHESIS: The median benefit-to-cost ratio from 11 estimates of earnings gains, the major benefit driver for 3 types of ECE programs (ie, state and district, federal Head Start, and model programs), was 3.39:1 (interquartile interval [IQI] = 2.48-4.39). The overall median benefit-to-cost ratio from 7 estimates of total benefits, based on all benefit components including earnings gains, was 4.19:1 (IQI = 2.62-8.60), indicating that for every dollar invested in the program, there was a return of $4.19 in total benefits. CONCLUSIONS: ECE programs promote both equity and economic efficiency. Evidence indicates there is positive social return on investment in ECE irrespective of the type of ECE program. The adoption of a societal perspective is crucial to understand all costs and benefits of ECE programs regardless of who pays for the costs or receives the benefits.

Maternal and infant factors had a significant impact on birthweight and longitudinal growth in a South African birth cohort.

AIM: This birth cohort study investigated longitudinal infant growth and associated factors in a multiethnic population living in a low-resource district surrounding the town of Paarl in South Africa. METHODS: Between March 2012 and October 2014, all mothers attending their second trimester antenatal visit at Paarl Hospital were approached for enrolment. Mother-infant pairs were followed from birth until 12 months of age. Comprehensive socio-demographic, nutritional and psychosocial data were collected at birth, two, six and 12 months. Infant anthropometry was analysed as z-scores for weight and height. Linear regression was used to investigate predictors of birthweight, and linear mixed-effects models were used to investigate predictors of infant growth. RESULTS: Longitudinal anthropometric data from 792 infants were included: 53% were Black African, 47% were mixed race, and 15% were born preterm. Stunting occurred in 13% of infants at 12 months. Maternal height, antenatal alcohol and tobacco use, ethnicity and socioeconomic status were significant predictors of birthweight. In the adjusted mixed-effects model, birthweight was a significant predictor of growth during the first year of life. CONCLUSION: Birthweight was an important predictor of growth trajectory during infancy. Birthweight and growth were influenced by several important modifiable factors.

Antenatal and early life tobacco smoke exposure in an African birth cohort study.

BACKGROUND: Exposure to tobacco smoke in African infants has not been well studied, despite the high burden of childhood respiratory disease in these communities. OBJECTIVE: To investigate the prevalence of antenatal and early life tobacco smoke exposure and associations with infant birth outcomes in an African birth cohort, the Drakenstein Child Health Study. METHODS: Self-report questionnaires assessing maternal and household smoking were administered. Maternal and infant urine cotinine testing was conducted antenatally, at birth and at 6-10 weeks of life to measure tobacco smoke exposure. Multivariate regression models explored the associations between exposure to smoke and infant birth outcomes. RESULTS: Of 789 pregnant women included, 250 (32%) were active smokers on cotinine testing. At birth and at 6-10 weeks of life, respectively 135/241 (56%) and 154/291 (53%) infants had urine cotinine levels indicating tobacco smoke exposure. Household smoking was prevalent and was associated with positive infant cotinine test results. Antenatal maternal smoking was associated with decreased infant birthweight-for-age Z-score (0.3, 95%CI 0.1-0.5). CONCLUSION: Antenatal and early life tobacco smoke exposure is highly prevalent in this community, and may impact on birth outcomes and subsequent child health. Smoking cessation interventions are urgently needed to reduce tobacco smoke exposure in African communities.

Early Childhood Education to Promote Health Equity: A Community Guide Systematic Review.

CONTEXT: Children in low-income and racial and ethnic minority families often experience delays in development by 3 years of age and may benefit from center-based early childhood education. DESIGN: A meta-analysis on the effects of early childhood education by Kay and Pennucci best met Community Guide criteria and forms the basis of this review. RESULTS: There were increases in intervention compared with control children in standardized test scores (median = 0.29 SD) and high school graduation (median = 0.20 SD) and decreases in grade retention (median = 0.23 SD) and special education assignment (median = 0.28 SD). There were decreases in crime (median = 0.23 SD) and teen births (median = 0.46 SD) and increases in emotional self-regulation (median = 0.21 SD) and emotional development (median = 0.04 SD). All effects were favorable, but not all were statistically significant. Effects were also long-lasting. CONCLUSIONS: Because many programs are designed to increase enrollment for high-risk students and communities, they are likely to advance health equity.

Investigating the psychosocial determinants of child health in Africa: The Drakenstein Child Health Study.

BACKGROUND: Early life psychobiological and psychosocial factors play a key role in influencing child health outcomes. Longitudinal studies may help elucidate the relevant risk and resilience profiles, and the underlying mechanisms that impact on child health, but there is a paucity of birth cohort data from low and middle-income countries (LMIC). We describe the rationale for and present baseline findings from the psychosocial component of the Drakenstein Child Health Study (DCHS). METHODS: We review the psychosocial measures used in the DCHS, a multidisciplinary birth cohort study in a peri-urban area in South Africa, and provide initial data on psychological distress, depression, substance use, and exposure to traumatic stressors and intimate partner violence (IPV). These and other measures will be assessed longitudinally in mothers in order to investigate associations with child neurodevelopmental and health outcomes. RESULTS: Baseline psychosocial data is presented for mothers (n=634) and fathers (n=75) who have completed antenatal assessments to date. The sample of pregnant mothers is characterized by multiple psychosocial risk factors, including a high prevalence of psychological distress and depression, high levels of substance use, and high exposure to traumatic stressors and IPV. DISCUSSION: These data are consistent with prior South African studies which have documented a high prevalence of a multitude of risk factors during pregnancy. Further longitudinal assessment of mothers and children may clarify the underlying psychobiological and psychosocial mechanisms which impact on child health, and so inform clinical and public health interventions appropriate to the South African and other LMIC contexts.

Investigating the early-life determinants of illness in Africa: the Drakenstein Child Health Study.

Respiratory disease is the predominant cause of illness in children globally. We describe a unique multidisciplinary South African birth cohort, the Drakenstein Child Health Study (DCHS), to investigate the incidence, risk factors, aetiology and long-term impact of early lower respiratory tract infection (LRTI) on child health. Pregnant women from a poor, peri-urban community with high exposure to infectious diseases and environmental risk factors are enrolled with 1000 mother-child pairs followed for at least 5 years. Biomedical, environmental, psychosocial and demographic risk factors are longitudinally measured. Environmental exposures are measured using monitors placed at home visits. Lung function is measured in children at 6 weeks, annually and during LRTI episodes. Microbiological investigations including microbiome and multiplex PCR measures are done longitudinally and at LRTI episodes. The DCHS is a unique African birth cohort study that uses sophisticated measures to comprehensively investigate the early-life determinants of child health in an impoverished area of the world.

Coagulation factor and hemostatic protein content of canine plasma after storage of whole blood at ambient temperature.

BACKGROUND: Standard practice in canine blood banking is to produce fresh frozen plasma (FFP) by separating and freezing plasma produced from blood within 8 hours of collection. Within canine blood donation programs, this can limit the number of units collected. HYPOTHESIS/OBJECTIVES: The aim was to compare the coagulation factor and hemostatic protein content (CF&HPC) of plasma produced from blood stored at ambient temperature for 8, 12, and 24 hours. Another aim was to compare the CF&HPC between Greyhound types and other breeds. ANIMALS: None. METHODS: In vitro study. A convenience sample of 58 units of canine blood from a blood donor pool was processed to prepare and freeze plasma 8, 12, or 24 hours following collection. RESULTS: Regardless of time of processing, the units contained therapeutic CF&HPC. Frozen plasma prepared after 24 hours had significantly higher factor VIII (P = .014) and factor X (P = .03) when compared with the frozen plasma prepared at 8 hours. Factor X (P < .01), fibrinogen (P < .01), and vWF (P = .04) were significantly lower in plasma collected from Greyhound types than in plasma collected from other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: Storing whole blood for up to 24 hours is a suitable method for producing FFP. Lower values for some coagulation factors and hemostatic proteins in plasma produced from Greyhound types would not preclude these dogs as FFP donors.

Effectiveness of early educational intervention.

Early educational intervention has been proposed to partially offset the impacts of poverty and inadequate learning environments on child development and school success. A broad range of early educational interventions are found to produce meaningful, lasting effects on cognitive, social, and schooling outcomes. However, all interventions are not equally effective. Two major U.S. programs perform relatively poorly. Research provides some guidance regarding the features of highly effective programs, but much remains to be learned. New experimental studies of key program features would have a high payoff.

Novel method of measuring the mental workload of anaesthetists during clinical practice.

BACKGROUND: Cognitive overload has been recognized as a significant cause of error in industries such as aviation and measuring mental workload has become a key method of improving safety. The aim of this study was to pilot the use of a new method of measuring mental workload in the operating theatre using a previously published methodology. METHODS: The mental workload of the anaesthetists was assessed by measuring their response times to a wireless vibrotactile device and the NASA TLX subjective workload score during routine surgical procedures. Primary task workload was inferred from the phase of anaesthesia. RESULTS: Significantly increased response time was associated with the induction phase of anaesthesia compared with maintenance/emergence, non-consultant grade, and during more complex cases. Increased response was also associated with self-reported mental load, physical load, and frustration. These findings are consistent with periods of increased mental workload and with the findings of other studies using similar techniques. CONCLUSIONS: These findings confirm the importance of mental workload to the performance of anaesthetists and suggest that increased mental workload is likely to be a common problem in clinical practice. Although further studies are required, the method described may be useful for the measurement of the mental workload of anaesthetists.

Early childhood development and social mobility.

Steven Barnett and Clive Belfield examine the effects of preschool education on social mobility in the United States. They note that under current policy three- and four-year-old children from economically and educationally disadvantaged families have higher preschool attendance rates than other children. But current programs fail to enroll even half of poor three- and four-year-olds. Hispanics and children of mothers who drop out of school also participate at relatively low rates. The programs also do little to improve learning and development. The most effective programs, they explain, are intensive interventions such as the model Abecedarian and Perry Preschool programs, which feature highly qualified teachers and small group sizes. State preschool programs with the highest standards rank next, followed by Head Start and the average state program, which produce effects ranging from one-tenth to one-quarter of those of the best programs. Typical child care and family support programs rank last. Barnett and Belfield point out that preschool programs raise academic skills on average, but do not appear to have notably different effects for different groups of children, and so do not strongly enhance social mobility. In such areas as crime, welfare, and teen parenting, however, preschool seems more able to break links between parental behaviors and child outcomes. Increased investment in preschool, conclude Barnett and Belfield, could raise social mobility. Program expansions targeted to disadvantaged children would help them move up the ladder, as would a more universal set of policies from which disadvantaged children gained disproportionately. Increasing the educational effectiveness of early childhood programs would provide for greater gains in social mobility than increasing participation rates alone. The authors observe that if future expansions of preschool programs end up serving all children, not just the poorest, society as a whole would gain. Benefits would exceed costs and there would be more economic growth, but relative gains for disadvantaged children would be smaller than absolute gains because there would be some (smaller) benefits to other children.