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Correlated, spontaneous neural activity is known to play a necessary role in visual development, but the higher-order statistical structure of these coherent, amorphous patterns has only begun to emerge in the past decade. Several computational studies have demonstrated how this endogenous activity can be used to train a developing visual system. Models that generate spontaneous activity analogous to retinal waves have shown that these waves can serve as stimuli for efficient coding models of V1. This general strategy in development has one clear advantage: The same learning algorithm can be used both before and after eye-opening. This same insight can be applied to understanding LGN/V1 spontaneous activity. Although lateral geniculate nucleus (LGN) activity has been less discussed in the literature than retinal waves, here we argue that the waves found in the LGN have a number of properties that fill the role of a training pattern. We make the case that the role of "innate learning" with spontaneous activity is not only possible, but likely in later stages of visual development, and worth pursuing further using an efficient coding paradigm., Competing Interests: The 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., (Copyright © 2021 Behpour,Field and Albert.)

A number of neuroimaging techniques have been employed to understand how visual information is transformed along the visual pathway. Although each technique has spatial and temporal limitations, they can each provide important insights into the visual code. While the BOLD signal of fMRI can be quite informative, the visual code is not static and this can be obscured by fMRI's poor temporal resolution. In this study, we leveraged the high temporal resolution of EEG to develop an encoding technique based on the distribution of responses generated by a population of real-world scenes. This approach maps neural signals to each pixel within a given image and reveals location-specific transformations of the visual code, providing a spatiotemporal signature for the image at each electrode. Our analyses of the mapping results revealed that scenes undergo a series of nonuniform transformations that prioritize different spatial frequencies at different regions of scenes over time. This mapping technique offers a potential avenue for future studies to explore how dynamic feedforward and recurrent processes inform and refine high-level representations of our visual world., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate socioeconomic inequalities in cause-specific stillbirth and neonatal mortality to identify key areas of focus for future intervention strategies to achieve government ambitions to reduce mortality rates., Design: Retrospective cohort study., Setting: England, Wales, Scotland and the UK Crown Dependencies., Participants: All singleton births between 1 January 2014 and 31 December 2015 at ≥24 weeks' gestation., Main Outcome Measure: Cause-specific stillbirth or neonatal death (0-27 days after birth) per 10 000 births by deprivation quintile., Results: Data on 5694 stillbirths (38.1 per 10 000 total births) and 2368 neonatal deaths (15.9 per 10 000 live births) were obtained from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK). Women from the most deprived areas were 1.68 (95% CI 1.56 to 1.81) times more likely to experience a stillbirth and 1.67 (95% CI 1.48 to 1.87) times more likely to experience a neonatal death than those from the least deprived areas, equating to an excess of 690 stillbirths and 231 neonatal deaths per year associated with deprivation. Small for gestational age (SGA) unexplained antepartum stillbirth was the greatest contributor to excess stillbirths accounting for 33% of the deprivation gap in stillbirths. Congenital anomalies accounted for the majority (59%) of the deprivation gap in neonatal deaths, followed by preterm birth not SGA (24-27 weeks, 27%)., Conclusions: Cause-specific mortality rates at a national level allow identification of key areas of focus for future intervention strategies to reduce mortality. Despite a reduction in the deprivation gap for stillbirths and neonatal deaths, public health interventions should primarily focus on socioeconomic determinants of SGA stillbirth and congenital anomalies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Our understanding of information processing by the mammalian visual system has come through a variety of techniques ranging from psychophysics and fMRI to single unit recording and EEG. Each technique provides unique insights into the processing framework of the early visual system. Here, we focus on the nature of the information that is carried by steady state visual evoked potentials (SSVEPs). To study the information provided by SSVEPs, we presented human participants with a population of natural scenes and measured the relative SSVEP response. Rather than focus on particular features of this signal, we focused on the full state-space of possible responses and investigated how the evoked responses are mapped onto this space. Our results show that it is possible to map the relatively high-dimensional signal carried by SSVEPs onto a 2-dimensional space with little loss. We also show that a simple biologically plausible model can account for a high proportion of the explainable variance (~73%) in that space. Finally, we describe a technique for measuring the mutual information that is available about images from SSVEPs. The techniques introduced here represent a new approach to understanding the nature of the information carried by SSVEPs. Crucially, this approach is general and can provide a means of comparing results across different neural recording methods. Altogether, our study sheds light on the encoding principles of early vision and provides a much needed reference point for understanding subsequent transformations of the early visual response space to deeper knowledge structures that link different visual environments., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions., Approach and Results: In a cohort of patients with metabolic and peripheral artery disease, platelet activity was enhanced, and inhibition with oral antiplatelet agents was impaired compared with platelets from control subjects, suggesting a difference in platelet phenotype caused by the disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O 2 ) had increased expression of some proteins that augment platelet activation compared with platelets in normoxic conditions (21% O 2 ). Using a murine model of critical limb ischemia, platelet activity was increased even 2 weeks postsurgery compared with sham surgery mice. This effect was partly inhibited in platelet-specific ERK5 (extracellular regulated protein kinase 5) knockout mice., Conclusions: These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses because of changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should, therefore, be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of antiplatelet therapy., (© 2018 American Heart Association, Inc.)

Objectives: To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity., Study Design: Geographical, prospective population-based cohort study of 1139 infants born LMPT (32 0/7 to 36 6/7 weeks' gestation) and 1255 infants born at term (37 0/7 to 42 6/7 weeks' gestation). Parent questionnaires were obtained to identify impaired cognitive and language development, behavioral problems, delayed social-emotional competence, autistic features, and clinically significant eating difficulties at 24 months corrected age for 638 (57%) children born LMPT and 765 (62%) children born at term., Results: Latent class analysis revealed 2 profiles of development among the term group: optimal (84%) and a profile of social, emotional, and behavioral impairments termed "nonoptimal" (16%). These 2 profiles were also identified among the LMPT group (optimal: 67%; nonoptimal: 26%). In the LMPT group, a third profile was identified (7%) that was similar to the phenotype previously identified in infants born very preterm. Nonwhite ethnicity, socioeconomic risk, and not receiving breast milk at hospital discharge were risk factors for nonoptimal outcomes in both groups. Male sex, greater gestational age, and pre-eclampsia were only associated with the preterm phenotype., Conclusions: Among children born LMPT with parent-reported cognitive or behavioral impairments, most had problems similar to the profile of difficulties observed in children born at term. A smaller proportion of children born LMPT had impairments consistent with the "very preterm phenotype" which are likely to have arisen through a preterm pathway. These results suggest that prematurity may affect development through several etiologic pathways in the late and moderately preterm population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Platelet factor 4 (PF4) is a megakaryocyte-/platelet-derived chemokine with diverse functions as a regulator of vascular and immune biology. PF4 has a central role in vessel injury responses, innate immune cell responses, and T-helper cell differentiation. We have now discovered that PF4 has a direct role in B cell differentiation in the bone marrow. Mice lacking PF4 (PF4 -/- mice) had fewer developing B cells in the bone marrow beginning after the pre-pro-B cell stage of differentiation. In vitro, PF4 increased the differentiation of hematopoietic progenitors to B cell lineage cells, indicating that PF4 has a direct effect on B cell differentiation. STAT5 activation is essential in early B cell development and PF4 increased the phosphorylation of STAT5. Taken together, these data demonstrate that PF4 has an important role in increasing B cell differentiation in the bone marrow environment.

In this article, we explore two forms of selectivity in sensory neurons. The first we call classic selectivity, referring to the stimulus that optimally stimulates a neuron. If a neuron is linear, then this stimulus can be determined by measuring the response to an orthonormal basis set (the receptive field). The second type of selectivity we call hyperselectivity; it is either implicitly or explicitly a component of several models including sparse coding, gain control, and some linear-nonlinear models. Hyperselectivity is unrelated to the stimulus that maximizes the response. Rather, it refers to the drop-off in response around that optimal stimulus. We contrast various models that produce hyperselectivity by comparing the way each model curves the iso-response surfaces of each neuron. We demonstrate that traditional sparse coding produces such curvature and increases with increasing degrees of overcompleteness. We demonstrate that this curvature produces a systematic misestimation of the optimal stimulus when the neuron's receptive field is measured with spots or gratings. We also show that this curvature allows for two apparently paradoxical results. First, it allows a neuron to be very narrowly tuned (hyperselective) to a broadband stimulus. Second, it allows neurons to break the Gabor-Heisenberg limit in their localization in space and frequency. Finally, we argue that although gain-control models, some linear-nonlinear models, and sparse coding have much in common, we believe that this approach to hyperselectivity provides a deeper understanding of why these nonlinearities are present in the early visual system.

MicroRNAs (miRNAs) are major regulators of cell responses, particularly in stressed cell states and host immune responses. Some miRNAs have a role in pathogen defense, including regulation of immune responses to Plasmodium parasite infection. Using a nonlethal mouse model of blood stage malaria infection, we have found that miR-451 -/- mice infected with Plasmodium yoelii XNL cleared infection at a faster rate than did wild-type (WT) mice. MiR-451 -/- mice had an increased leukocyte response to infection, with the protective phenotype primarily driven by CD4 + T cells. WT and miR-451 -/- CD4 + T cells had similar activation responses, but miR-451 -/- CD4 + cells had significantly increased proliferation, both in vitro and in vivo. Myc is a miR-451 target with a central role in cell cycle progression and cell proliferation. CD4 + T cells from miR-451 -/- mice had increased postactivation Myc expression. RNA-Seq analysis of CD4 + cells demonstrated over 5000 differentially expressed genes in miR-451 -/- mice postinfection, many of which are directly or indirectly Myc regulated. This study demonstrates that miR-451 regulates T cell proliferative responses in part via a Myc-dependent mechanism.

Thrombosis-associated pathologies, such as myocardial infarction and stroke, are major causes of morbidity and mortality worldwide. Because platelets are necessary for hemostasis and thrombosis, platelet directed therapies must balance inhibiting platelet function with bleeding risk. Glutamate receptor interacting protein 1 (GRIP1) is a large scaffolding protein that localizes and organizes interacting proteins in other cells, such as neurons. We have investigated the role of GRIP1 in platelet function to determine its role as a molecular scaffold in thrombus formation. Platelet-specific GRIP1-/- mice were used to determine the role of GRIP1 in platelets. GRIP1-/- mice had normal platelet counts, but a prolonged bleeding time and delayed thrombus formation in a FeCl3-induced vessel injury model. In vitro stimulation of WT and GRIP1-/- platelets with multiple agonists showed no difference in platelet activation. However, in vivo platelet rolling velocity after endothelial stimulation was significantly greater in GRIP1-/- platelets compared to WT platelets, indicating a potential platelet adhesion defect. Mass spectrometry analysis of GRIP1 platelet immunoprecipitation revealed enrichment of GRIP1 binding to GPIb-IX complex proteins. Western blots confirmed the mass spectrometry findings that GRIP1 interacts with GPIbα, GPIbβ, and 14-3-3. Additionally, in resting GRIP1-/- platelets, GPIbα and 14-3-3 have increased interaction compared to WT platelets. GRIP1 interactions with the GPIb-IX binding complex are necessary for normal platelet adhesion to a stimulated endothelium., Competing Interests: The authors have declared that no competing interests exist.

From the earliest stages of sensory processing, neurons show inherent non-linearities: the response to a complex stimulus is not a sum of the responses to a set of constituent basis stimuli. These non-linearities come in a number of forms and have been explained in terms of a number of functional goals. The family of spatial non-linearities have included interactions that occur both within and outside of the classical receptive field. They include, saturation, cross orientation inhibition, contrast normalization, end-stopping and a variety of non-classical effects. In addition, neurons show a number of facilitatory and invariance related effects such as those exhibited by complex cells (integration across position). Here, we describe an approach that attempts to explain many of the non-linearities under a single geometric framework. In line with Zetzsche and colleagues (e.g., Zetzsche et al., 1999) we propose that many of the principal non-linearities can be described by a geometry where the neural response space has a simple curvature. In this paper, we focus on the geometry that produces both increased selectivity (curving outward) and increased tolerance (curving inward). We demonstrate that overcomplete sparse coding with both low-dimensional synthetic data and high-dimensional natural scene data can result in curvature that is responsible for a variety of different known non-classical effects including end-stopping and gain control. We believe that this approach provides a more fundamental explanation of these non-linearities and does not require that one postulate a variety of explanations (e.g., that gain must be controlled or the ends of lines must be detected). In its standard form, sparse coding does not however, produce invariance/tolerance represented by inward curvature. We speculate on some of the requirements needed to produce such curvature., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Very preterm (<32 wk of gestation) infants are at increased risk of eating difficulties compared with their term-born peers. Little is known about the impact of late and moderately preterm (LMPT; 32-36 wk of gestation) birth on eating difficulties in early childhood., Objectives: The aims were to assess the prevalence of eating difficulties in infants born LMPT at 2 y corrected age and to explore the impact of neonatal and neurodevelopmental factors., Design: A geographic population-based cohort of 1130 LMPT and 1255 term-born controls was recruited at birth. The parents of 651 (59%) LMPT and 771 (62%) term-born infants completed questionnaires at 2 y corrected age to assess neurodevelopmental outcomes. Parents also completed a validated questionnaire to assess eating behaviors in 4 domains: refusal/picky eating, oral motor problems, oral hypersensitivity, and eating behavior problems. Infants with scores >90th percentile were classified with eating difficulties in each domain. Neonatal data were collected at discharge, and sociodemographic information was collected via maternal interview. Poisson regression was used to assess between-group differences in eating difficulties and to explore associations with neonatal factors and neurodevelopmental outcomes at 2 y of age., Results: In unadjusted analyses, LMPT infants were at increased risk of refusal/picky eating (RR: 1.53; 95% CI: 1.03, 2.25) and oral motor problems (RR: 1.62; 95% CI: 1.06, 2.47). Prolonged nasogastric feeding >2 wk (RR: 1.87; 95% CI: 1.07, 3.25), behavior problems (RR: 2.95; 95% CI: 1.93, 4.52), and delayed social competence (RR: 2.28; 95% CI: 1.49, 3.48) were independently associated with eating difficulties in multivariable analyses. After adjustment for these factors, there was no excess of eating difficulties in LMPT infants., Conclusions: Infants born LMPT are at increased risk of oral motor and picky eating problems at 2 y corrected age. However, these are mediated by other neurobehavioral sequelae in this population. This trial was registered on the UK Clinical Research Network Portfolio at http://public.ukcrn.org.uk/search/ as UKCRN Study ID 7441., (© 2016 American Society for Nutrition.)

Objective: To describe neonatal outcomes and explore variation in delivery of care for infants born late (34-36  weeks) and moderately (32-33 weeks) preterm (LMPT)., Design/setting: Prospective population-based study comprising births in four major maternity centres, one midwifery-led unit and at home between September 2009 and December 2010. Data were obtained from maternal and neonatal records., Participants: All LMPT infants were eligible. A random sample of term-born infants (≥37 weeks) acted as controls., Outcome Measures: Neonatal unit (NNU) admission, respiratory and nutritional support, neonatal morbidities, investigations, length of stay and postnatal ward care were measured. Differences between centres were explored., Results: 1146 (83%) LMPT and 1258 (79% of eligible) term-born infants were recruited. LMPT infants were significantly more likely to receive resuscitation at birth (17.5% vs 7.4%), respiratory (11.8% vs 0.9%) and nutritional support (3.5% vs 0.3%) and were less likely to be fed breast milk (64.2% vs 72.2%) than term infants. For all interventions and morbidities, a gradient of increasing risk with decreasing gestation was evident. Although 60% of late preterm infants were never admitted to a NNU, 83% required medical input on postnatal wards. Clinical management differed significantly between services., Conclusions: LMPT infants place high demands on specialist neonatal services. A substantial amount of previously unreported specialist input is provided in postnatal wards, beyond normal newborn care. Appropriate expertise and planning of early care are essential if such infants are managed away from specialised neonatal settings. Further research is required to clarify optimal and cost-effective postnatal management for LMPT babies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To assess behavioral outcomes and social competence at 2 years of age in infants born late and moderately preterm (LMPT; 32-36 wk gestation)., Method: One thousand one hundred and thirty LMPT infants and 1255 term-born (≥37 wk) controls were recruited at birth to a prospective geographical population-based study. Parents completed the Brief Infant and Toddler Social Emotional Assessment (BITSEA) at 2 years corrected age to assess infants' behavior problems and social competence. Cognitive development was assessed using the Parent Report of Children's Abilities-Revised. Parent questionnaires at 2 years were completed for 638 (57%) LMPT and 765 (62%) term-born infants. Group differences in the prevalence of behavior problems and delayed social competence between LMPT infants and term-born controls were adjusted for age, sex, small-for-gestational-age, socioeconomic status and cognitive impairment., Results: Late and moderately preterm infants were at significantly increased risk of delayed social competence compared with term-born controls (26.4% vs. 18.4%; adjusted-relative risk [RR] 1.28; 95% CI, 1.03-1.58), but there was no significant group difference in the prevalence of behavior problems (21.0% vs. 17.6%; adjusted-RR 1.13, 0.89-1.42). Non-white ethnicity (RR 1.68, 1.26-2.24), medium (RR 1.60, 1.14-2.24) and high (RR 1.98, 1.41-2.75) socioeconomic risk and recreational drug use during pregnancy (RR 1.70, 1.03-2.82) were significant independent predictors of delayed social competence in LMPT infants., Conclusion: Birth at 32 to 36 weeks of gestation confers a specific risk for delayed social competence at 2 years of age. This may be indicative of an increased risk for psychiatric disorders later in childhood.

Objective: This study explores the associations between lifestyle factors and late and moderate preterm birth (LMPT: 32(+0)-36(+6) weeks' gestation), a relatively under-researched group., Study Design: A population-based case-cohort study was undertaken involving 922 LMPT and 965 term (37+ weeks' gestation) singleton live and stillbirths born between 1 September 2009 and 31 December 2010 to women residing in Leicestershire and Nottinghamshire, UK. Poisson multivariable regression models were fitted to estimate relative risks (RR) of LMPT birth associated with maternal smoking, alcohol and recreational drug use, and diet., Results: Women who smoked during pregnancy were at 38% increased risk of LMPT birth compared with non-smokers (RR 1.38, 95% CI (1.04 to 1.84)). Low consumption of fruit and vegetables was associated with a 31% increased risk compared with those who reported eating higher consumption levels (RR 1.31 (1.03 to 1.66)). Women who did not have any aspects of a Mediterranean diet were nearly twice as likely to deliver LMPT compared with those whose diet included more Mediterranean characteristics (RR 1.81 (1.04 to 3.14)). Women who smoked and consumed low levels of fruit and vegetables (5% of women) were at particularly high risk (RR=1.81 (1.29 to 2.55)). There was no significant effect of alcohol or recreational drug use on LMPT birth., Conclusions: Smoking and poor diet during pregnancy, factors that strongly impact on very preterm birth, are also important at later gestations and experienced together are associated with an elevated rate of risk. Our findings suggest early cessation of smoking during pregnancy may be an effective strategy to reduce LMPT births., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species-rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species-rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species-mediated mechanisms in ischemic myocardium., Methods and Results: Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5(-/-) mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5(-/-) platelets post-MI., Conclusions: ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment., (© 2015 American Heart Association, Inc.)

Objective: There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm (LMPT; 32(+0)-36(+6) weeks). This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth., Design: 1130 LMPT and 1255 term-born children were recruited at birth. At 2 years corrected age, parents completed a questionnaire to assess neurosensory (vision, hearing, motor) impairments and the Parent Report of Children's Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses., Results: Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls (RR 4.89, 95% CI 1.07 to 22.25). Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% (RR 2.09, 95% CI 1.19 to 3.64). LMPT infants were at twice the risk for neurodevelopmental disability (RR 2.19, 95% CI 1.27 to 3.75). Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge., Conclusions: Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To assess the prevalence of positive screens using the Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire and follow-up interview in late and moderately preterm (LMPT; 32-36 weeks) infants and term-born controls., Study Design: Population-based prospective cohort study of 1130 LMPT and 1255 term-born infants. Parents completed the M-CHAT questionnaire at 2-years corrected age. Parents of infants with positive questionnaire screens were followed up with a telephone interview to clarify failed items. The M-CHAT questionnaire was re-scored, and infants were classified as true or false positives. Neurosensory, cognitive, and behavioral outcomes were assessed using parent report., Results: Parents of 634 (57%) LMPT and 761 (62%) term-born infants completed the M-CHAT questionnaire. LMPT infants had significantly higher risk of a positive questionnaire screen compared with controls (14.5% vs 9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up, significantly more LMPT infants than controls had a true positive screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained significant after excluding infants with neurosensory impairments (2.0% vs 0.5%; RR 3.67; 1.19, 11.3)., Conclusions: LMPT infants are at significantly increased risk for positive autistic screen. An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations. Infants with false positive screens are at risk for cognitive and behavioral problems., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Edges in natural scenes can result from a number of different causes. In this study, we investigated the statistical differences between edges arising from occlusions and nonocclusions (reflectance differences, surface change, and cast shadows). In the first experiment, edges in natural scenes were identified using the Canny edge detection algorithm. Observers then classified these edges as either an occlusion edge (one region of an image occluding another) or a nonocclusion edge. The nonocclusion edges were further subclassified as due to a reflectance difference, a surface change, or a cast shadow. We found that edges were equally likely to be classified as occlusion or nonocclusion edges. Of the nonocclusion edges, approximately 33% were classified as reflectance changes, 9% as cast shadows, and 58% as surface changes. We also analyzed local statistical properties like contrast, average edge profile, and slope of the edges. We found significant differences between the contrast values for each category. Based on the local contrast statistics, we developed a maximum likelihood classifier to label occlusion and nonocclusion edges. An 80%-20% cross validation demonstrated that the human classification could be predicted with 83% accuracy. Overall, our results suggest that for many edges in natural scenes, there exists local statistical information regarding the cause of the edge. We believe that this information can potentially be used by the early visual system to begin the process of segregating objects from their backgrounds., (© 2014 ARVO.)

Studies of visual masking have provided a wide range of important insights into the processes involved in visual coding. However, very few of these studies have employed natural scenes as masks. Little is known on how the particular features found in natural scenes affect visual detection thresholds and how the results obtained using unnatural masks relate to the results obtained using natural masks. To address this issue, this paper describes a psychophysical study designed to obtain local contrast detection thresholds for a database of natural images. Via a three-alternative forced-choice experiment, we measured thresholds for detecting 3.7 cycles/° vertically oriented log-Gabor noise targets placed within an 85 × 85-pixels patch (1.9° patch) drawn from 30 natural images from the CSIQ image database (Larson & Chandler, Journal of Electronic Imaging, 2010). Thus, for each image, we obtained a masking map in which each entry in the map denotes the root mean squared contrast threshold for detecting the log-Gabor noise target at the corresponding spatial location in the image. From qualitative observations we found that detection thresholds were affected by several patch properties such as visual complexity, fineness of textures, sharpness, and overall luminance. Our quantitative analysis shows that except for the sharpness measure (correlation coefficient of 0.7), the other tested low-level mask features showed a weak correlation (correlation coefficients less than or equal to 0.52) with the detection thresholds. Furthermore, we evaluated the performance of a computational contrast gain control model that performed fairly well with an average correlation coefficient of 0.79 in predicting the local contrast detection thresholds. We also describe specific choices of parameters for the gain control model. The objective of this database is to provide researchers with a large ground-truth dataset in order to further investigate the properties of the human visual system using natural masks., (© 2014 ARVO.)

Objective: To investigate temporal trends in multiple birth rates and associated stillbirth and neonatal mortality by socioeconomic deprivation and maternal age in England., Design: Population cohort study., Setting: England., Participants: All live births and stillbirths (1 January 1997 to 31 December 2008)., Main Outcome Measures: Multiple maternity rate, stillbirth and neonatal death rate by year of birth, decile of socioeconomic deprivation and maternal age., Results: The overall rate of multiple maternities increased over time (+0.64% per annum 95% CI (0.47% to 0.81%)) with an increase in twin maternities (+0.85% per annum 95% CI (0.67% to 1.0%)) but a large decrease in triplet and higher order maternities (-8.32% per annum 95% CI (-9.39% to -7.25%)). Multiple maternities were significantly lower in the most deprived areas, and this was most evident in the older age groups. Women over 40 years of age from the most deprived areas had a 34% lower rate of multiple births compared with similar aged women from the most deprived areas (rate ratio (RR) 0.66 95% CI (0.61 to 0.73)). Multiple births remain at substantially higher risk of neonatal mortality (RR 6.30 95% CI (6.07 to 6.53)). However, for stillbirths, while twins remain at higher risk, this has decreased over time (1997-2000: RR 2.89 (2.69 to 3.10); 2005-2008: RR 2.22 95% CI (2.06 to 2.40)). Socioeconomic inequalities existed in mortality for singletons and multiple births., Conclusions: This period has seen increasing rates of twin pregnancies and decreasing rates of higher order births which have coincided with changes in recommendations regarding assisted reproductive techniques. Socioeconomic differences in multiple births may reflect differential access to these treatments. Improved monitoring of multiple pregnancies is likely to have led to the reductions in stillbirths over this time.

Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell-derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation.

Background: Understanding length of stay for babies in neonatal care is vital for planning services and for counselling parents. While previous work has focused on the length of stay of babies who survive to discharge, when investigating resource use within neonatal care, it is important to also incorporate information on those babies who die while in care. We present an analysis using competing risks methodology which allows the simultaneous modelling of babies who die in neonatal care and those who survive to discharge., Methods: Data were obtained on 2723 babies born at 24-28 weeks gestational age in 2006-10 and admitted to neonatal care. Death and discharge alive are two mutually exclusive events and can be treated as competing risks. A flexible parametric modelling approach was used to analyse these two competing events and obtain estimates of the absolute probabilities of death or discharge., Results: The absolute probabilities of death or discharge are presented in graphical form showing the cause-specific cumulative incidence over time by gender, gestational age and birthweight. The discharge of babies alive generally occurred over a longer time period for babies of lower gestational age and smaller birthweight than for bigger babies., Conclusion: This study has presented a useful statistical method for modelling the length of stay where there are significant rates of in-unit mortality. In health care systems that are increasingly focusing on costs and resource planning, it is essential to consider not only length of stay of survivors but also for those patients who die before discharge., (© 2013 John Wiley & Sons Ltd.)

Activated platelets release many inflammatory molecules with important roles in accelerating vascular inflammation. Much is known about platelet and platelet-derived mediator interactions with endothelial cells and leukocytes, but few studies have examined the effects of platelets on components of the vascular wall. Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to injury including the production of inflammatory molecules, cell proliferation, cell migration, and a decline in the expression of differentiation markers. In this study, we demonstrate that the platelet-derived chemokine platelet factor 4 (PF4/CXCL4) stimulates VSMC injury responses both in vitro and in vivo in a mouse carotid ligation model. PF4 drives a VSMC inflammatory phenotype including a decline in differentiation markers, increased cytokine production, and cell proliferation. We also demonstrate that PF4 effects are mediated, in part, through increased expression of the transcription factor Krüppel-like factor 4. Our data indicate an important mechanistic role for platelets and PF4 in VSMC injury responses both in vitro and in vivo.

Platelets are most recognized as the cellular mediator of thrombosis, but they are increasingly appreciated for their immunomodulatory roles, including responses to Plasmodium infection. Platelet interactions with endothelial cells and leukocytes contribute significantly to the pathogenesis of experimental cerebral malaria (ECM). Recently, it has been suggested that platelets not only have an adverse role in cerebral malaria, but platelets may also be protective in animal models of uncomplicated malaria. We now demonstrate that these diverse and seemingly contradictory roles for platelets extend to cerebral malaria models and are dependent on the timing of platelet activation during infection. Our data show that platelets are activated very early in ECM and have a central role in initiation of the acute-phase response to blood-stage infection. Unlike platelet depletion or inhibition postinfection, preinfection platelet depletion or treatment with a platelet inhibitor is not protective. Additionally, we show that platelet-driven acute-phase responses have a major role in protecting mice from ECM by limiting parasite growth. Our data now suggest that platelets have a complex role in ECM pathogenesis: platelets help limit parasite growth early postinfection, but with continued platelet activation as the disease progresses, platelets contribute to ECM-associated inflammation.

Aims: Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants., Methods: DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement., Results: Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹  kg⁻¹; V = 593 ml kg⁻¹; t(½) = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h⁻¹  kg⁻¹; V = 640-970 ml kg⁻¹; t(½) = 101-144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data., Conclusions: This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Background: Estimates of the probability of survival of very preterm infants admitted to NICU care are vital for counseling parents, informing care, and planning services. In 1999, easy-to-use charts of survival according to gestation, birth weight, and gender were published in the United Kingdom. These charts are widely used in clinical care and for benchmarking survival, and they form the core of the Clinical Risk Index for Babies II score. Since their publication, the survival of preterm infants has improved, and the charts therefore need updating., Methods: A logistic model was fitted with gestational age, birth weight, and gender. Nonlinear functions were estimated by using fractional polynomials. Bootstrap methods were used to assess the internal validity of the final model. The final model was assessed both overall and for subgroups of infants by using Farrington's statistic, the c-statistic, Cox regression coefficients, and the Brier score., Results: A total of 2995 white singleton infants born at 23(+0) to 32(+6) weeks' gestation in 2008 through 2010 were identified; 2751 (91.9%) infants survived to discharge. A prediction model was estimated and good model fit confirmed (area under receiver-operating characteristics curve = 0.86). Survival ranged from 27.7% (23 weeks) to 99.1% (32 weeks) for boys and from 34.5% (23 weeks) to 99.3% (32 weeks) for girls. Updated charts were produced showing estimated survival according to gestation, birth weight and gender, together with contour plots displaying points of equal survival., Conclusions: These survival charts have been updated and will be of use to clinicians, parents, and managers.

Objective: To assess the care given to the babies born at the threshold of viability over the last 20 years using regional and national data., Design: Population-based retrospective study., Setting: Former 'Trent' health region., Participants: Babies born between 1 January 1991 and 31 December 2010 at 22(+0) to 25(+6) weeks gestational age., Main Outcome Measure: Survival and use of respiratory support., Methods: Data of all babies born between 1 January 1991 and 31 December 2010 with a gestational age of 22(+0) to 25(+6) weeks and admitted to a neonatal unit were extracted from The Neonatal Survey. Use of respiratory support in terms of ventilation and continuous positive airway pressure (CPAP) for this group of babies was calculated as a proportion of the total used by the whole neonatal intensive care population within the defined study area., Results: The proportion of babies surviving to discharge increased significantly over time in those born at 24 and 25 weeks (p<0.01) but failed to achieve statistical significance for those at 23 weeks (p=0.08). No babies born at 22 weeks survived. The babies born at 22-25 weeks accounted for 26.3% of all ventilation and 21.5% of CPAP given., Conclusion: Our work concurs with the current UK guidelines. There could be advantages in focusing the care of babies born at 23 weeks to a small number of intensive care units to allow specialist expertise to develop in all aspects of the management of these babies. However, focusing care will not necessarily improve survival or reduce morbidity.

Platelets are most recognized for their vital role as the cellular mediator of thrombosis, but platelets also have important immune functions. Platelets initiate and sustain vascular inflammation in many disease conditions, including arthritis, atherosclerosis, transplant rejection, and severe malaria. We now demonstrate that platelets express T cell costimulatory molecules, process and present Ag in MHC class I, and directly activate naive T cells in a platelet MHC class I-dependent manner. Using an experimental cerebral malaria mouse model, we also demonstrate that platelets present pathogen-derived Ag to promote T cell responses in vivo, and that platelets can be used in a cell-based vaccine model to induce protective immune responses. Our study demonstrates a novel Ag presentation role for platelets.

Objective: To assess time trends in socioeconomic inequalities in overall and cause-specific stillbirth rates in England., Design: Population-based retrospective study., Setting: England., Participants: Stillbirths occurring among singleton infants born between 1 January 2000 and 31 December 2007., Main Outcome Measure: Cause-specific stillbirth rate per 10 000 births by deprivation tenth and year of birth. Deprivation measured using the UK index of multiple deprivation at Super Output Area level., Methods: Poisson regression models were used to estimate the relative deprivation gap (comparing the most and least deprived tenths) in rates of stillbirths (overall and cause-specific). Excess mortality was calculated by applying the rates seen in the least deprived tenth to the entire population at risk. Discussions with our local NHS multicentre ethics committee deemed that this analysis of national non-identifiable data did not require separate ethics approval., Results: There were 44 stillbirths per 10 000 births, with no evidence of a change in rates over time. Rates were twice as high in the most deprived tenth compared with the least (rate ratio (RR) 2.1, 95% CI 2.0 to 2.2) with no evidence of a change over time. There was a significant deprivation gap for all specific causes except mechanical events (RR 1.2, 95% CI 0.9 to 1.5). The widest gap was seen for stillbirths due to antepartum haemorrhages (RR 3.1, 95% CI 2.8 to 3.5). No evidence of a change in the rate of stillbirth or deprivation gap over time was seen for any specific cause., Conclusion: A wide deprivation gap exists in stillbirth rates for most causes and is not diminishing. Unexplained antepartum stillbirths accounted for 50% of the deprivation gap, and a better understanding of these stillbirths is necessary to reduce socioeconomic inequalities.

Objective: To investigate the burden of later disease associated with moderate/late preterm (32-36 weeks) and early term (37-38 weeks) birth., Design: Secondary analysis of data from the Millennium Cohort Study (MCS)., Setting: Longitudinal study of infants born in the United Kingdom between 2000 and 2002., Participants: 18,818 infants participated in the MCS. Effects of gestational age at birth on health outcomes at 3 (n = 14,273) and 5 years (n = 14,056) of age were analysed., Main Outcome Measures: Growth, hospital admissions, longstanding illness/disability, wheezing/asthma, use of prescribed drugs, and parental rating of their children's health., Results: Measures of general health, hospital admissions, and longstanding illness showed a gradient of increasing risk of poorer outcome with decreasing gestation, suggesting a "dose-response" effect of prematurity. The greatest contribution to disease burden at 3 and 5 years was in children born late/moderate preterm or early term. Population attributable fractions for having at least three hospital admissions between 9 months and 5 years were 5.7% (95% confidence interval 2.0% to 10.0%) for birth at 32-36 weeks and 7.2% (1.4% to 13.6%) for birth at 37-38 weeks, compared with 3.8% (1.3% to 6.5%) for children born very preterm (<32 weeks). Similarly, 2.7% (1.1% to 4.3%), 5.4% (2.4% to 8.6%), and 5.4% (0.7% to 10.5%) of limiting longstanding illness at 5 years were attributed to very preterm birth, moderate/late preterm birth, and early term birth., Conclusions: These results suggest that health outcomes of moderate/late preterm and early term babies are worse than those of full term babies. Additional research should quantify how much of the effect is due to maternal/fetal complications rather than prematurity itself. Irrespective of the reason for preterm birth, large numbers of these babies present a greater burden on public health services than very preterm babies.

A wide variety of recent studies have argued that the human visual system provides an efficient means of processing the information in the natural environment. However, the amount of information (entropy) in the signal can be estimated in a number of ways, and it is has been unclear how much of the information is carried by the different sources of redundancy. The primary difficulty is that there has been no rational way to estimate the entropy of such complex scenes. In this paper, we provide a technique that uses a recent approach to estimating the entropy and dimensionality of natural scenes [D. M. Chandler and D. J. Field, J. Opt. Soc. Am. A 24, 922-941 (2007)] to estimate the amount of information attributable to the power and phase spectra in natural-scene patches. By comparing the entropies of patches that have swapped phase spectra and fixed phase spectra, we demonstrate how to estimate both the amount of information in each type of spectrum and the amount of information that is shared by these spectra (mutual information). We applied this technique to small patches (4×4 and 8×8). From our estimates, we show that the power spectrum of 8×8 patches carries approximately 54% of the total information, the phase spectrum carries 56%, and 10% is mutual information (54%+56%-10%=100%). This technique is currently limited to relatively small image patches, due to the number of patches currently in our collection (on the order of 10⁶). However, the technique can, in theory, be extended to larger images. Even with these relatively small patches, we discuss how these results can provide important insights into both compression techniques and efficient coding techniques that work with relatively small image patches (e.g., JPEG, sparse coding, independent components analysis).

Objectives: To investigate socioeconomic inequalities in outcome of pregnancy and neonatal mortality associated with congenital anomalies., Design: Retrospective population based registry study., Setting: East Midlands and South Yorkshire regions of England (representing about 10% of births in England and Wales)., Participants: All registered cases of nine selected congenital anomalies with poor prognostic outcome audited as part of the United Kingdom's fetal anomaly screening programme with an end of pregnancy date between 1 January 1998 and 31 December 2007., Main Outcome Measures: Socioeconomic variation in the risk of selected congenital anomalies; outcome of pregnancy; incidence of live birth and neonatal mortality over time. Deprivation measured with the index of multiple deprivation 2004 at super output area level., Results: There were 1579 fetuses registered with one of the nine selected congenital anomalies. There was no evidence of variation in the overall risk of these anomalies with deprivation (rate ratio for the most deprived 10th with the least deprived 10th: 1.05, 95% confidence interval 0.89 to 1.23). The rate ratio varied with type of anomaly and maternal age (deprivation rate ratio adjusted for maternal age: 1.43 (1.17 to 1.74) for non-chromosomal anomalies; 0.85 (0.63 to 1.15) for chromosomal anomalies). Of the nine anomalies, 86% were detected in the antenatal period, and there was no evidence that this varied with deprivation (rate ratio 0.99, 0.84 to 1.17). The rate of termination after antenatal diagnosis of a congenital anomaly was lower in the most deprived areas compared with the least deprived areas (63% v 79%; rate ratio 0.80, 0.65 to 0.97). Consequently there were significant socioeconomic inequalities in the rate of live birth and neonatal mortality associated with the presence of any of these nine anomalies. Compared with the least deprived areas, the most deprived areas had a 61% higher rate of live births (1.61, 1.21 to 2.15) and a 98% higher neonatal mortality rate (1.98, 1.20 to 3.27) associated with a congenital anomaly., Conclusions: Antenatal screening for congenital anomalies has reduced neonatal mortality through termination of pregnancy. Socioeconomic variation in decisions regarding termination of pregnancy after antenatal detection, however, has resulted in wide socioeconomic inequalities in liveborn infants with a congenital anomaly and subsequent neonatal mortality.

The aim of this study was to report the birth prevalence and short-term outcome of congenital diaphragmatic hernia (CDH) in a large geographically defined population, and to assess the feasibility of performing a randomised control trial (RCT) in this population. Data were collected on all cases of CDH reported to the East Midlands and South Yorkshire Congenital Anomalies Register between 1997 and 2005. A total of 194 cases of CDH were identified from 547,025 births; a birth prevalence of 3.5/10,000. Overall 1-year survival was 42%. In total, 69% of cases resulted in a live birth, of these 61% survived to 1 year; 73% were diagnosed antenatally and 22% postnatally, with 1-year survivals 30% and 71%, respectively. A total of 54% were isolated cases and 46% associated with another anomaly, with more live births (80% vs. 56%) and better 1-year survival (62% vs. 19%) with isolated CDH. Overall, only 83 babies were born alive with an isolated CDH: the only group suitable for inclusion in a RCT. In conclusion, given the small numbers of live isolated CDH cases it is impossible that any network alone would be able to perform a valid RCT of treatments, highlighting the need for collaborative international trials to address this complex condition., (© 2010 Blackwell Publishing Ltd.)

Background: UK-born infants of South Asian ethnic origin are known to have lower birthweights than their White British counterparts. When plotted on currently used birthweight charts they can be misclassified as small for gestational age. Similarly, large for gestational age infants can be missed. This has important clinical implications in their management., Objective: To create birthweight centile charts for the UK-born South Asian infants to identify true small and large for gestational age infants., Methods: A retrospective cross-sectional analysis of infants born 1 January 2003 to 31 December 2006 was undertaken. The birthweights of the South Asian and White British infants were compared. The LMS method was used to construct centile charts for the South Asian infants., Results: 24,274 White British and 7,190 South Asian infants were included in the analysis. Overall, the South Asian males were 9-15% lighter than the White British males and the South Asian females were 9-13% lighter than the White British females. At term, the median birthweight for South Asian males was 329 g lower than that for White British males and for South Asian females 295 g less than the White British females., Conclusion: There are significant differences in the birthweights of White British and UK-born South Asian infants. Hence the standard birthweight centile charts which were designed using the birthweight data of White British infants appear to misclassify a proportion of South Asian infants. Use of ethnic specific birthweight charts would allow better detection of truly growth-restricted and macrosomic South Asian infants., (Copyright © 2011 S. Karger AG, Basel.)

Objective: To investigate time trends in socioeconomic inequalities in cause specific neonatal mortality in order to assess changing patterns in mortality due to different causes, particularly prematurity, and identify key areas of focus for future intervention strategies., Design: Retrospective cohort study., Setting: England., Participants: All neonatal deaths in singleton infants born between 1 January 1997 and 31 December 2007., Main Outcome Measure: Cause specific neonatal mortality per 10 000 births by deprivation tenth (deprivation measured with UK index of multiple deprivation 2004 at super output area level)., Results: 18 524 neonatal deaths occurred in singleton infants born in the 11 year study period. Neonatal mortality fell between 1997-9 and 2006-7 (from 31.4 to 25.1 per 10 000 live births). The relative deprivation gap (ratio of mortality in the most deprived tenth compared with the least deprived tenth) increased from 2.08 in 1997-9 to 2.68 in 2003-5, before a fall to 2.35 in 2006-7. The most common causes of death were immaturity and congenital anomalies. Mortality due to immaturity before 24 weeks' gestation did not decrease over time and showed the widest relative deprivation gap (2.98 in 1997-9; 4.14 in 2003-5; 3.16 in 2006-7). Mortality rates for all other causes fell over time. For congenital anomalies, immaturity, and accidents and other specific causes, the relative deprivation gap widened between 1997-9 and 2003-5, before a slight fall in 2006-7. For intrapartum events and sudden infant deaths (only 13.5% of deaths) the relative deprivation gap narrowed slightly., Conclusions: Almost 80% of the relative deprivation gap in all cause mortality was explained by premature birth and congenital anomalies. To reduce socioeconomic inequalities in mortality, a change in focus is needed to concentrate on these two influential causes of death. Understanding the link between deprivation and preterm birth should be a major research priority to identify interventions to reduce preterm birth.

Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Platelets have been long described as markers of transplant rejection, but the contribution of platelets to transplant rejection has not been critically examined. We demonstrate in this study that following T cell initiation of allograft rejection, platelets contribute to T cell recruitment and increased plasma inflammatory mediators and accelerate T cell-meditated skin graft rejection. Prior work from our laboratory has shown that platelets secrete glutamate when activated, which then induces platelet thromboxane production by signaling through platelet-expressed ionotropic glutamate receptors. Glutamate receptor antagonists therefore represent, to our knowledge, novel inhibitors of platelet-accelerated inflammation. We have found that plasma glutamate is increased in mice that receive skin grafts and that mice treated with glutamate receptor antagonists have improved graft survival and decreased plasma thromboxane, platelet factor 4 (CXCL4), and IFN-γ. Taken together, our work now demonstrates that subsequent to T cell initiation of skin graft rejection, platelets contribute to further T cell recruitment and that by blunting glutamate-mediated platelet activation, graft survival is improved.

Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4(-/-) mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4(-/-) mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM.

Background: Existing evidence indicates that once mature neonates with severe cardio-respiratory failure become eligible for Extra Corporeal Membrane Oxygenation (ECMO) their chances of intact survival are doubled if they actually receive ECMO. However, significant numbers survive with disability. NEST is a multi-centre randomised controlled trial designed to test whether, in neonates requiring ECMO, cooling to 34 degrees C for the first 48 to 72 hours of their ECMO course leads to improved later health status. Infants allocated to the control group will receive ECMO at 37 degrees C throughout their course, which is currently standard practice around the world. Health status of both groups will be assessed formally at 2 years corrected age., Methods/design: All infants recruited to the study will be cared for in one of the four United Kingdom (UK) ECMO centres. Babies who are thought to be eligible will be assessed by the treating clinician who will confirm eligibility, ensure that consent has been obtained and then randomise the baby using a web based system, based at the National Perinatal Epidemiology Unit (NPEU) Clinical Trials Unit. Trial registration.Babies allocated ECMO without cooling will receive ECMO at 37 degrees C +/- 0.2 degrees C. Babies allocated ECMO with cooling will be managed at 34 degrees C +/- 0.2 degrees C for up to 72 hours from the start of their ECMO run. The minimum duration of cooling will be 48 hours. Rewarming (to 37 degrees C) will occur at a rate of no more than 0.5 degrees C per hour. All other aspects of ECMO management will be identical., Primary Outcome: Cognitive score from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) at age of 2 years (24 - 27 months)., Discussion: For the primary analysis, children will be analysed in the groups to which they are assigned, comparing the outcome of all babies allocated to "ECMO with cooling" with all those allocated to "ECMO" alone, regardless of deviation from the protocol or treatment received. For the primary outcome the analysis will compare the mean scores for each group of surviving babies. The rationale for this choice of primary analysis is to give a fair representation of the average ability of assessable children, accepting the limitation that excluding deaths might impose.The consistency of the effect of cooling on the group of babies recruited to the trial will be explored to see whether cooling is of particular help, or not, to specific subgroups of infants, using the statistical test of interaction. Therefore pre-specified subgroup analyses include: (i) whether the ECMO is veno-arterial or veno-venous; (ii) whether the child's oxygenation index at the time of recruitment is <60 or > or = 60; (iii) initial aEEG pattern shown on the cerebral function monitor, and (iv) primary diagnostic group., Trial Registration: Current Controlled Trials ISRCTN72635512.

Objective: To see whether there was any difference in the effect of antenatal corticosteroids on neonatal outcomes according to different gestational ages at birth., Methods: This was a prospective cohort study in a geographically defined population (Trent region, UK). All infants admitted for neonatal care, of 23-32 weeks' gestation, born to Trent resident mothers over the 15-year period between 1993 and 2007 were included. Antenatal corticosteroid treatment was given to pregnant women at risk of preterm birth. The primary outcome was survival until discharge from neonatal unit. Secondary outcomes included length of stay on the neonatal unit, duration of artificial respiratory support (mechanical ventilation and continuous positive airway pressure (CPAP)) and chronic lung disease (CLD)., Results: The overall mortality among babies born between 24 and 29 weeks with maternal steroids was lower (n=850 out of 4370; 19.4%) as compared to their counterparts whose mothers did not receive steroids (n=323 out of 920; 35.1%) The gestation-specific mortality figures (%) in the steroid treated group between 24 and 29 weeks' gestation were 61.5, 36.9, 28.5, 17.5, 10.2 and 5.1, respectively, and this was significantly lower than the group without steroid treatment. There was a 9.9% reduction in mortality among babies born at 23 weeks' gestation in the steroid treated group (n=81 out of 102; 79.4%) compared to the non-steroid group (n=75 out of 84; 89.3%), but this did not reach statistical significance (p=0.068). There was no significant effect of antenatal steroid treatment on length of stay, duration of respiratory support and CLD among infants who survived until discharge. There was no trend in survival in the two groups over the 15-year study period., Conclusions: Antenatal corticosteroid treatment is associated with improved survival in babies born between 24 and 29 weeks' gestation. This, however, does not lead to any significant improvements in length of stay, duration of respiratory support and CLD among survivors.

Objectives: To assess socioeconomic inequalities in survival and provision of neonatal care among very preterm infants., Design: Prospective cohort study in a geographically defined population., Setting: Former Trent health region of the United Kingdom (covering about a twelfth of UK births)., Participants: All infants born between 22+0 and 32+6 weeks' gestation from 1 January 1998 to 31 December 2007 who were alive at the onset of labour and followed until discharge from neonatal care., Main Outcome Measures: Survival to discharge from neonatal care per 1000 total births and per 1000 very preterm births. Neonatal care provision for very preterm infants surviving to discharge measured with length of stay, provision of ventilation, and respiratory support. Deprivation measured with the UK index of multiple deprivation 2004 score at super output area level., Results: 7449 very preterm singleton infants were born in the 10 year period. The incidence of very preterm birth was nearly twice as high in the most deprived areas compared with the least deprived areas. Consequently rates of mortality due to very preterm birth per 1000 total births were almost twice as high in the most deprived areas compared with the least deprived (incidence rate ratio 1.94, 95% confidence interval 1.62 to 2.32). Mortality rates per 1000 very preterm births, however, showed little variation across all deprivation fifths (incidence rate ratio for most deprived fifth versus least deprived 1.02, 0.86 to 1.20). For infants surviving to discharge from neonatal care, measures of length of stay and provision of ventilation and respiratory support were similar across all deprivation fifths., Conclusions: The burden of mortality and morbidity is greater among babies born to women from deprived areas because of increased rates of very preterm birth. After very preterm birth, however, survival rates and neonatal care provision is similar for infants from all areas.

Patterns of spontaneous activity in the developing retina, LGN, and cortex are necessary for the proper development of visual cortex. With these patterns intact, the primary visual cortices of many newborn animals develop properties similar to those of the adult cortex but without the training benefit of visual experience. Previous models have demonstrated how V1 responses can be initialized through mechanisms specific to development and prior to visual experience, such as using axonal guidance cues or relying on simple, pairwise correlations on spontaneous activity with additional developmental constraints. We argue that these spontaneous patterns may be better understood as part of an "innate learning" strategy, which learns similarly on activity both before and during visual experience. With an abstraction of spontaneous activity models, we show how the visual system may be able to bootstrap an efficient code for its natural environment prior to external visual experience, and we continue the same refinement strategy upon natural experience. The patterns are generated through simple, local interactions and contain the same relevant statistical properties of retinal waves and hypothesized waves in the LGN and V1. An efficient encoding of these patterns resembles a sparse coding of natural images by producing neurons with localized, oriented, bandpass structure-the same code found in early visual cortical cells. We address the relevance of higher-order statistical properties of spontaneous activity, how this relates to a system that may adapt similarly on activity prior to and during natural experience, and how these concepts ultimately relate to an efficient coding of our natural world.

Objective: To assess changes in survival for infants born before 26 completed weeks of gestation., Design: Prospective cohort study in a geographically defined population., Setting: Former Trent health region of the United Kingdom., Subjects: All infants born at 22+0 to 25+6 weeks' gestation to mothers living in the region. Terminations were excluded but all other births of babies alive at the onset of labour or the delivery process were included., Main Outcome Measures: Outcome for all infants was categorised as stillbirth, death without admission to neonatal intensive care, death before discharge from neonatal intensive care, and survival to discharge home in two time periods: 1994-9 and 2000-5 inclusive., Results: The proportion of infants dying in delivery rooms was similar in the two periods, but a significant improvement was seen in the number of infants surviving to discharge (P<0.001). Of 497 infants admitted to neonatal intensive care in 2000-5, 236 (47%) survived to discharge compared with 174/490 (36%) in 1994. These changes were attributable to substantial improvements in the survival of infants born at 24 and 25 weeks. During the 12 years of the study none of the 150 infants born at 22 weeks' gestation survived. Of the infants born at 23 weeks who were admitted to intensive care, there was no significant improvement in survival to discharge in 2000-5 (12/65 (18%) in 2000-5 v 15/81 (19%) in 1994-9)., Conclusions: Survival of infants born at 24 and 25 weeks of gestation has significantly increased. Although over half the cohort of infants born at 23 weeks was admitted to neonatal intensive care, there was no improvement in survival at this gestation. Care for infants born at 22 weeks remained unsuccessful.

The authors tested the hypothesis that the birth prevalence of gastroschisis is positively associated with use of recreational drugs in early pregnancy. A matched case-control study was carried out in three regions of the United Kingdom over the period January 2001 through August 2003. For each case, three liveborn controls were matched by initial intended place of delivery, region, and maternal age. Maternal hair analysis provided independent verification of recreational drug use. Conditional logistic regression was used to estimate mutually adjusted odds ratios. Estimates were revised using data from hair analysis. Statistically significant adjusted odds ratios for gastroschisis were associated with first-trimester use of 1) any recreational drug (odds ratio (OR) = 2.2, 95% confidence interval (CI): 1.2, 4.3) and 2) vasoconstrictive recreational drugs (defined as cocaine, amphetamines, and ecstasy) (OR = 3.3, 95% CI: 1.0, 10.5). Other significant exposures included aspirin use (OR = 20.4, 95% CI: 2.2, 191.5), cigarette smoking (OR = 1.7, 95% CI: 1.1, 2.6), and prior history of gynecologic infection/disease (OR = 2.6, 95% CI: 1.2, 5.6). Recreational drug use is a significant risk factor for gastroschisis and is one of a constellation of potentially preventable exposures which include cigarette smoking, aspirin use, and history of gynecologic infection/disease. Maternal hair analysis proved an acceptable and valuable method of independently verifying recreational drug use.

Two recent studies suggest that natural scenes and paintings show similar statistical properties. But does the content or region of origin of an artwork affect its statistical properties? We addressed this question by having judges place paintings from a large, diverse collection of paintings into one of three subject-matter categories using a forced-choice paradigm. Basic statistics for images whose caterogization was agreed by all judges showed no significant differences between those judged to be 'landscape' and 'portrait/still-life', but these two classes differed from paintings judged to be 'abstract'. All categories showed basic spatial statistical regularities similar to those typical of natural scenes. A test of the full painting collection (140 images) with respect to the works' place of origin (provenance) showed significant differences between Eastern works and Western ones, differences which we find are likely related to the materials and the choice of background color. Although artists deviate slightly from reproducing natural statistics in abstract art (compared to representational art), the great majority of human art likely shares basic statistical limitations. We argue that statistical regularities in art are rooted in the need to make art visible to the eye, not in the inherent aesthetic value of natural-scene statistics, and we suggest that variability in spatial statistics may be generally imposed by manufacture.