Children’s Health Research Institute

Routine practice fails to incorporate research evidence in a timely and reliable fashion. Many quality improvement (QI) efforts aim to close these gaps between clinical research and practice. However, in sharp contrast to the paradigm of evidence-based medicine, these efforts often proceed on the basis of intuition and anecdotal accounts of successful strategies for changing provider behavior or achieving organizational change. We review problems with current approaches to QI research and outline the steps required to make QI efforts based as much on evidence as the practices they seek to implement.

The objective is to provide guidance for pregnant women and obstetric care and exercise professionals on prenatal physical activity. The outcomes evaluated were maternal, fetal or neonatal morbidity, or fetal mortality during and following pregnancy. Literature was retrieved through searches of MEDLINE, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science Core Collection, CINAHL Plus with Full Text, Child Development & Adolescent Studies, Education Resources Information Center, SPORTDiscus, ClinicalTrials.gov and the Trip Database from inception up to 6 January 2017. Primary studies of any design were eligible, except case studies. Results were limited to English-language, Spanish-language or French-language materials. Articles related to maternal physical activity during pregnancy reporting on maternal, fetal or neonatal morbidity, or fetal mortality were eligible for inclusion. The quality of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation methodology. The Guidelines Consensus Panel solicited feedback from end users (obstetric care providers, exercise professionals, researchers, policy organisations, and pregnant and postpartum women). The development of these guidelines followed the Appraisal of Guidelines for Research and Evaluation II instrument. The benefits of prenatal physical activity are moderate and no harms were identified; therefore, the difference between desirable and undesirable consequences (net benefit) is expected to be moderate. The majority of stakeholders and end users indicated that following these recommendations would be feasible, acceptable and equitable. Following these recommendations is likely to require minimal resources from both individual and health systems perspectives.

OBJECTIVE: Gestational diabetes mellitus (GDM), gestational hypertension (GH) and pre-eclampsia (PE) are associated with short and long-term health issues for mother and child; prevention of these complications is critically important. This study aimed to perform a systematic review and meta-analysis of the relationships between prenatal exercise and GDM, GH and PE. DESIGN: Systematic review with random effects meta-analysis and meta-regression. DATA SOURCES: Online databases were searched up to 6 January 2017. STUDY ELIGIBILITY CRITERIA: Studies of all designs were included (except case studies) if published in English, Spanish or French, and contained information on the Population (pregnant women without contraindication to exercise), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone ["exercise-only"] or in combination with other intervention components [e.g., dietary; "exercise + co-intervention"]), Comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and Outcomes (GDM, GH, PE). RESULTS: A total of 106 studies (n=273 182) were included. 'Moderate' to 'high'-quality evidence from randomised controlled trials revealed that exercise-only interventions, but not exercise+cointerventions, reduced odds of GDM (n=6934; OR 0.62, 95% CI 0.52 to 0.75), GH (n=5316; OR 0.61, 95% CI 0.43 to 0.85) and PE (n=3322; OR 0.59, 95% CI 0.37 to 0.9) compared with no exercise. To achieve at least a 25% reduction in the odds of developing GDM, PE and GH, pregnant women need to accumulate at least 600 MET-min/week of moderate-intensity exercise (eg, 140 min of brisk walking, water aerobics, stationary cycling or resistance training). SUMMARY/CONCLUSIONS: In conclusion, exercise-only interventions were effective at lowering the odds of developing GDM, GH and PE.

Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Research has shown that epigenetic mechanisms provide an "extra" layer of transcriptional control that regulates how genes are expressed. These mechanisms are critical components in the normal development and growth of cells. Epigenetic abnormalities have been found to be causative factors in cancer, genetic disorders and pediatric syndromes as well as contributing factors in autoimmune diseases and aging. In this review, we examine the basic principles of epigenetic mechanisms and their contribution to human health as well as the clinical consequences of epigenetic errors. In addition, we address the use of epigenetic pathways in new approaches to diagnosis and targeted treatments across the clinical spectrum.

BACKGROUND: It is commonly believed that nature has positive impacts on children's health, including physical, mental and social dimensions. This review focuses on how accessibility to, exposure to and engagement with nature affects the mental health of children and teenagers. METHODS: Ten academic databases were used to systematically search and identify primary research papers in English or French from 1990 to 1 March 2017. Papers were included for review based on their incorporation of nature, children and teenagers (0-18 years), quantitative results and focus on mental health. RESULTS: Of the 35 papers included in the review, the majority focused on emotional well-being and attention deficit disorder/hyperactivity disorder. Other outcome measures included overall mental health, self-esteem, stress, resilience, depression and health-related quality of life. About half of all reported findings revealed statistically significant positive relationships between nature and mental health outcomes and almost half reported no statistical significance. CONCLUSIONS: Findings support the contention that nature positively influences mental health; however, in most cases, additional research with more rigorous study designs and objective measures of both nature and mental health outcomes are needed to confirm statistically significant relationships. Existing evidence is limited by the cross-sectional nature of most papers.

Abstract We assessed differences in parental reports of parenting stress, child behavior problems, and dysphoria in 150 families who had children with autism (n = 30), behavior disorders (n = 30), Down syndrome (n = 30), or normal development (n = 60). We measured stress with the Parenting Stress Index, child behavior problems with the Eyberg Child Behavior Inventory, and dysphoria with the Beck Depression Inventory. We controlled data for sociodemographic differences across groups, and results indicated the following: (1) Parents of children with autism and behavior disorders experienced statistically and clinically higher levels of parenting stress than parents in the other two groups. (2) Parents of children with behavior disorders reported that their children presented behavioral difficulties that were statistically and clinically more intense and numerous than those of all other children. (3) Mothers of children with autism and behavior disorders experienced statistically and clinically higher levels of dysphoria than mothers in the other two groups, which appeared to be specifically related to the stresses of parenting exceptional children rather than to personal dysfunction. In contrast, mothers of children with Down syndrome did not differ from mothers of nondisabled children on any of the measures. Finally, no major effect of the children's age or gender was found across the four groups, except for the fact that mothers of younger (less than 7 yrs, 5 mos.) autistic children reported greater dysphoria than mothers in the other three groups.

Superovulation or ovarian stimulation is currently an indispensable assisted reproductive technology (ART) for human subfertility/infertility treatment. Recently, increased frequencies of imprinting disorders have been correlated with ARTs. Significantly, for Angelman and Beckwith-Wiedemann Syndromes, patients have been identified where ovarian stimulation was the only procedure used by the couple undergoing ART. In many cases, increased risk of genomic imprinting disorders has been attributed to superovulation in combination with inherent subfertility. To distinguish between these contributing factors, carefully controlled experiments are required on spontaneously ovulated, in vivo-fertilized oocytes and their induced-ovulated counterparts, thereby minimizing effects of in vitro manipulations. To this end, effects of superovulation on genomic imprinting were evaluated in a mouse model, where subfertility is not a confounding issue. This work represents the first comprehensive examination of the overall effects of superovulation on imprinted DNA methylation for four imprinted genes in individual blastocyst stage embryos. We demonstrate that superovulation perturbed genomic imprinting of both maternally and paternally expressed genes; loss of Snrpn, Peg3 and Kcnq1ot1 and gain of H19 imprinted methylation were observed. This perturbation was dose-dependent, with aberrant imprinted methylation more frequent at the high hormone dosage. Superovulation is thought to primarily affect oocyte development; thus, effects were expected to be limited to maternal alleles. Our study revealed that maternal as well as paternal H19 methylation was perturbed by superovulation. We postulate that superovulation has dual effects during oogenesis, disrupting acquisition of imprints in growing oocytes, as well as maternal-effect gene products subsequently required for imprint maintenance during pre-implantation development.

Epidemiologic and clinical research has provided a large body of evidence supporting the developmental origins of health and disease (DOHaD), but there has been a relative dearth of mechanistic studies in humans due to the complexity of working with large, longitudinal cohorts. Nonetheless, animal models of undernutrition have provided substantial evidence for the potential epigenetic, metabolic, and endocrine mechanisms behind DOHaD. Furthermore, recent research has explored the interaction between the environment and the gastrointestinal system by investigating how the gut microbial ecology may impact the capacity for nutrient processing and absorption in a manner that may limit growth. This review presents a summary of current research that supports the concept of DOHaD, as well as potential mechanisms and interactions that explain how nutrition in utero and during early childhood influences lifelong health.

BACKGROUND: The objectives of this study were to compare educational and social outcomes for young survivors of childhood cancer with a population control group of individuals who were never diagnosed with cancer and to identify risk and protective factors for these outcomes. METHODS: In this multicenter, Canadian, retrospective cohort study, 800 survivors age 17 years or younger were matched by age and gender with a group of 923 control participants. Using a mailed survey that was completed by parents, educational outcomes were assessed with questions about the child's enrollment in disability or special-education programs, repeating a grade, and academic or other school problems. Using friendships was the measure of social outcomes. RESULTS: Based on parental reports, significantly more survivors than controls repeated a grade (21% vs. 9%), attended learning-disability (19% vs. 7%) or special-education programs (20% vs. 8%), had educational or other school problems (46% vs. 23%), had no close friends (19% vs. 8%), and were less likely to use friends as confidants (58% vs. 67%). Survivors of central nervous system (CNS) tumors reportedly were more likely than controls to have educational problems and no close friends, followed by survivors of leukemia, and survivors of neuroblastoma. Among survivors, cranial radiation increased the likelihood of having educational difficulties and having no close friends compared with survivors who did not receive cranial radiation. Survivors who reportedly had high self-esteem and whose parents had postsecondary education had fewer educational and social problems. CONCLUSIONS: Children and adolescents who survived cancer, particularly those who had CNS tumors, leukemia, and neuroblastoma, required close monitoring for early educational and social difficulties, and such children should be offered educational rehabilitation and social skills training to maximize their academic and social success.

Hair analyses for exogenous compounds, specifically drugs of abuse, have been a useful tool in detecting long-term drug exposure. More recently, studies have delved into the exposure of endogenous compounds in hair. Cortisol is synthesized in the adrenal cortex in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. While catecholamines generally indicate acute stress, cortisol can be used as an indicator for sub-acute and chronic stress. Studies on the effects of chronic stress are most often subjective in nature, relying on questionnaires asking the participant to recall on past stressors. This can lead to the issue of recall and reporting bias. A new objective measure of chronic stress is needed for a more accurate understanding of the effects of chronic stress on the body. This review uses emerging evidence to describe the usefulness of hair analysis for cortisol and discusses the current methods used.

BACKGROUND: Vaccine injections are the most common painful needle procedure experienced throughout the lifespan. Many strategies are available to mitigate this pain; however, they are uncommonly utilized, leading to unnecessary pain and suffering. Some individuals develop a high level of fear and subsequent needle procedures are associated with significant distress. OBJECTIVE: The present work is part of an update and expansion of a 2009 knowledge synthesis to include the management of vaccine-related pain across the lifespan and the treatment of individuals with high levels of needle fear. This article will provide a conceptual foundation for understanding: (a) painful procedures and their role in the development and maintenance of high levels of fear; (b) treatment strategies for preventing or reducing the experience of pain and the development of fear; and (c) interventions for mitigating high levels of fear once they are established. RESULTS: First, the general definitions, lifespan development and functionality, needle procedure-related considerations, and assessment of the following constructs are provided: pain, fear, anxiety, phobia, distress, and vasovagal syncope. Second, the importance of unmitigated pain from needle procedures is highlighted from a developmental perspective. Third, the prevalence, course, etiology, and consequences of high levels of needle fear are described. Finally, the management of needle-related pain and fear are outlined to provide an introduction to the series of systematic reviews in this issue. DISCUSSION: Through the body of work in this supplement, the authors aim to provide guidance in how to treat vaccination-related pain and its sequelae, including high levels of needle fear.

OBJECTIVES: To present the 6-month prevalence and sociodemographic correlates of mental disorders and mental health-related service contacts in a sample of children (4 to 11 years) and youth (12 to 17 years) in Ontario. METHODS: The 2014 Ontario Child Health Study is a provincially representative survey of 6537 families with children aged 4 to 17 years in Ontario. DSM-IV-TR mental disorders were assessed using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) and included mood (major depressive episode), anxiety (generalized anxiety, separation anxiety, social phobia, specific phobia), and behaviour disorders (attention-deficit/hyperactivity disorder, oppositional-defiant disorder, conduct disorder).The MINI-KID was administered independently to the primary caregiver and youth aged 12 to 17 years in the family's home. RESULTS: Past 6-month prevalence of any mental disorder ranged from 18.2% to 21.8% depending on age and informant. Behaviour disorders were the most common among children, and anxiety disorders were the most common among youth. Among children and youth with a parent-identified mental disorder, 25.6% of children and 33.7% of youth had contact with a mental health provider. However, 60% had contact with one or more of the providers or service settings assessed, most often through schools. CONCLUSIONS: Between 18% and 22% of children and youth in Ontario met criteria for a mental disorder but less than one-third had contact with a mental health provider. These findings provide support for strengthening prevention and early intervention efforts and enhancing service capacity to meet the mental health needs of children and youth in Ontario.

Female fertility is determined to a large extent by the quality (developmental competence) of the oocyte as reflected in its ability to undergo meiosis, be fertilized, and give rise to a healthy embryo. Growth of the mammalian oocyte is coordinated with that of the follicle that encloses it by the actions of signals that pass in both directions between the germline and somatic components. This review summarizes what is known about the roles played by 2 different modes of intrafollicular signalling in oogenesis: paracrine factors activating receptors on the opposite cell type, and direct sharing of small molecules throughout the follicle via gap junction channels. Recent evidence indicates that these 2 modes of signalling interact to regulate oocyte growth and granulosa cell proliferation and that defects in either can contribute to female infertility.

OBJECTIVE: To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects. METHODS: Between January 31, 1981, and February 9, 1986, 250 infants of < or =800 g were admitted for intensive care in British Columbia, 98 (39%) of whom survived to late adolescence. Teens with major sensorimotor handicaps and/or IQ <70 were excluded (n = 19). Of the 79 eligible ELBW teens, 53 (67%) were assessed at 17.3 (16.3-19.7) years (birth weight: 720 [520-800 g]; gestation: 26 [23-29] weeks). The test battery screened the following areas: cognitive (Wechsler Intelligence Scale for Adults Third Edition, 3 subtests), academic (Wide Range Achievement Test-3), attention (Connors' Continuous Performance Task), self-report (Harter Self-Perception Profile for Adolescents; Job Search Attitude Inventory), and parent report (Child Behavior Check List). A comparison group of term born control subjects (n = 31) were also assessed (birth weight: 3506 [3068-4196] g; gestation: 40 [39-42] weeks) at age 17.8 (16.5-19.0) years. Multivariate analysis of variance (group x gender) was conducted for each domain (cognitive, academic, self-report, and parent report). RESULTS: The ELBW group showed lower cognitive scores (vocabulary, block design, and digit symbol) and academic skills (reading and arithmetic) compared with control subjects, with no gender differences. There were no differences in attention between the 2 groups using a repetitive computer task. ELBW teens reported lower scholastic, athletic, job competence, and romantic confidence and viewed themselves as more likely to need help from others in finding a job. In the behavioral domain, parents reported their ELBW teens to display more internalizing, more externalizing, and more total problems than the control teens, with ELBW boys showing more problems. ELBW teens showed a higher percentage of clinically significant behavior problems than control subjects. CONCLUSIONS: In a provincial cohort of unimpaired survivors of birth weight < or =800 g, psychosocial and educational vulnerabilities persist into late adolescence and may complicate the transition to adult life compared with their peers.

The retinoblastoma (RB) family of proteins are found in organisms as distantly related as humans, plants, and insects. These proteins play a key role in regulating advancement of the cell division cycle from the G1 to S-phases. This is achieved through negative regulation of two important positive regulators of cell cycle entry, E2F transcription factors and cyclin dependent kinases. In growth arrested cells transcriptional activity by E2Fs is repressed by RB proteins. Stimulation of cell cycle entry by growth factor signaling leads to activation of cyclin dependent kinases. They in turn phosphorylate and inactivate the RB family proteins, leading to E2F activation and additional cyclin dependent kinase activity. This propels the cell cycle irreversibly forward leading to DNA synthesis. This review will focus on the basic biochemistry and cell biology governing the regulation and activity of mammalian RB family proteins in cell cycle control.

OBJECTIVE: We aimed to identify the relationship between maternal prenatal exercise and birth complications, and neonatal and childhood morphometric, metabolic and developmental outcomes. DESIGN: Systematic review with random-effects meta-analysis and meta-regression. DATA SOURCES: Online databases were searched up to 6 January 2017. STUDY ELIGIBILITY CRITERIA: Studies of all designs were eligible (except case studies and reviews) if published in English, Spanish or French, and contained information on the relevant population (pregnant women without contraindication to exercise), intervention (subjective/objective measures of frequency, intensity, duration, volume or type of exercise, alone ('exercise-only') or in combination with other intervention components (eg, dietary; 'exercise+cointervention')), comparator (no exercise or different frequency, intensity, duration, volume, type or trimester of exercise) and outcomes (preterm birth, gestational age at delivery, birth weight, low birth weight (<2500 g), high birth weight (>4000 g), small for gestational age, large for gestational age, intrauterine growth restriction, neonatal hypoglycaemia, metabolic acidosis (cord blood pH, base excess), hyperbilirubinaemia, Apgar scores, neonatal intensive care unit admittance, shoulder dystocia, brachial plexus injury, neonatal body composition (per cent body fat, body weight, body mass index (BMI), ponderal index), childhood obesity (per cent body fat, body weight, BMI) and developmental milestones (including cognitive, psychosocial, motor skills)). RESULTS: A total of 135 studies (n=166 094) were included. There was 'high' quality evidence from exercise-only randomised controlled trials (RCTs) showing a 39% reduction in the odds of having a baby >4000 g (macrosomia: 15 RCTs, n=3670; OR 0.61, 95% CI 0.41 to 0.92) in women who exercised compared with women who did not exercise, without affecting the odds of growth-restricted, preterm or low birth weight babies. Prenatal exercise was not associated with the other neonatal or infant outcomes that were examined. CONCLUSIONS: Prenatal exercise is safe and beneficial for the fetus. Maternal exercise was associated with reduced odds of macrosomia (abnormally large babies) and was not associated with neonatal complications or adverse childhood outcomes.

The origin and regulation of stem cells sustaining trophoblast renewal in the human placenta remain unclear. Decorin, a leucine-rich proteoglycan restrains trophoblast proliferation, migration/invasiveness and endovascular differentiation, and local decorin overproduction is associated with preeclampsia (PE). Here, we tested the role of decorin in human trophoblast stem cell self-renewal and differentiation, using two models: an immortalized first trimester trophoblast cell line HTR-8/SVneo (HTR) and freshly isolated primary trophoblast (p-trophoblast) from early first trimester (6-9 weeks) placentas. Self-renewal capacity was measured by spheroid forming ability of single cells on ultra-low attachment plates for multiple generations. Markers of embryonic stem (ES) cells, trophoblast stem (TS) cells and trophoblast were used to identify stem cell hierarchy. Differentiation markers for syncytial and extravillous (EVT) pathways were employed to identify differentiated cells. Bewo cells were additionally used to explore DCN effects on syncytialization. Results reveal that the incidence of spheroid forming stem-like cells was 13-15% in HTR and 0.1-0.4%, in early first trimester p-trophoblast, including a stem cell hierarchy of two populations of ES and TS-like cells. DCN restrained ES cell self-renewal, promoted ES to TS transition and maintenance of TS cell stem-ness, but inhibited TS cell differentiation into both syncytial and EVT pathways.

OBJECTIVES: Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; < or =28 weeks), very low gestational age (VLGA; 29-32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit. METHODS: Seventy-six infants, 54 preterm (< or =32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2). RESULTS: Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants. CONCLUSIONS: ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to "resetting" basal arousal systems in preterm infants.

Objective To examine the influence of prenatal exercise on depression and anxiety during pregnancy and the postpartum period. Design Systematic review with random effects meta-analysis and meta-regression. Data sources Online databases were searched up to 6 January 2017. Study eligibility criteria Studies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the Population (pregnant women without contraindication to exercise), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise), Comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and Outcome (prenatal or postnatal depression or anxiety). Results A total of 52 studies (n=131 406) were included. ‘Moderate’ quality evidence from randomised controlled trials (RCTs) revealed that exercise-only interventions, but not exercise+cointerventions, reduced the severity of prenatal depressive symptoms (13 RCTs, n=1076; standardised mean difference: −0.38, 95% CI −0.51 to –0.25, I 2 =10%) and the odds of prenatal depression by 67% (5 RCTs, n=683; OR: 0.33, 95% CI 0.21 to 0.53, I 2 =0%) compared with no exercise. Prenatal exercise did not alter the odds of postpartum depression or the severity of depressive symptoms, nor anxiety or anxiety symptoms during or following pregnancy. To achieve at least a moderate effect size in the reduction of the severity of prenatal depressive symptoms, pregnant women needed to accumulate at least 644 MET-min/week of exercise (eg, 150 min of moderate intensity exercise, such as brisk walking, water aerobics, stationary cycling, resistance training). Summary/Conclusions Prenatal exercise reduced the odds and severity of prenatal depression.

LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.