BackgroundDespite improvements in child survival in the past four decades, an estimated 6.3 million children under the age of five die each year, and more than 40% of these deaths occur in the neonatal period. Interventions to reduce neonatal mortality are needed. Kangaroo mother care (KMC) is one such life-saving intervention; however it has not yet been fully integrated into health systems around the world. Utilizing a conceptual framework for integration of targeted health interventions into health systems, we hypothesize that caregivers play a critical role in the adoption, diffusion, and assimilation of KMC. The objective of this research was to identify barriers and enablers of implementation and scale up of KMC from caregivers’ perspective.MethodsWe searched Pubmed, Embase, Web of Science, Scopus, and WHO regional databases using search terms ‘kangaroo mother care’ or ‘kangaroo care’ or ‘skin to skin care’. Studies published between January 1, 1960 and August 19, 2015 were included. To be eligible, published work had to be based on primary data collection regarding barriers or enablers of KMC implementation from the family perspective. Abstracted data were linked to the conceptual framework using a deductive approach, and themes were identified within each of the five framework areas using Nvivo software.ResultsWe identified a total of 2875 abstracts. After removing duplicates and ineligible studies, 98 were included in the analysis. The majority of publications were published within the past 5 years, had a sample size less than 50, and recruited participants from health facilities. Approximately one-third of the studies were conducted in the Americas, and 26.5% were conducted in Africa.We identified four themes surrounding the interaction between families and the KMC intervention: buy in and bonding (i.e. benefits of KMC to mothers and infants and perceptions of bonding between mother and infant), social support (i.e. assistance from other people to perform KMC), sufficient time to perform KMC, and medical concerns about mother or newborn health. Furthermore, we identified barriers and enablers of KMC adoption by caregivers within the context of the health system regarding financing and service delivery. Embedded within the broad social context, barriers to KMC adoption by caregivers included adherence to traditional newborn practices, stigma surrounding having a preterm infant, and gender roles regarding childcare.ConclusionEfforts to scale up and integrate KMC into health systems must reduce barriers in order to promote the uptake of the intervention by caregivers.

BackgroundNewborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization.ObjectiveSmall-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs.MethodsChemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist–encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow–derived DCs enabled benchmarking of the TLR8 agonist–encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25–loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice.ResultsAlthough alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited TH-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist–adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4+ T-cell numbers.ConclusionTLR8 agonist–encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines.

Kangaroo Mother Care (KMC) is an evidence-based intervention that reduces neonatal morbidity and mortality. However, adoption among health systems has varied. Understanding the interaction between health system functions—leadership, financing, healthcare workers (HCWs), technologies, information and research, and service delivery—and KMC is essential to understanding KMC adoption. We present a systematic review of the barriers and enablers of KMC implementation from the perspective of health systems, with a focus on HCWs and health facilities. Using the search terms ‘kangaroo mother care’, ‘skin to skin (STS) care’ and ‘kangaroo care’, we searched Embase, Scopus, Web of Science, Pubmed, and World Health Organization Regional Databases. Reports and hand searched references from publications were also included. Screening and data abstraction were conducted by two independent reviewers using standardized forms. A conceptual model to assess KMC adoption themes was developed using NVivo software. Our search strategy yielded 2875 studies. We included 86 studies with qualitative data on KMC implementation from the perspective of HCWs and/or facilities. Six themes emerged on barriers and enablers to KMC adoption: buy-in and bonding; social support; time; medical concerns; training; and cultural norms. Analysis of interactions between HCWs and facilities yielded further barriers and enablers in the areas of training, communication, and support. HCWs and health facilities serve as two important adopters of Kangaroo Mother Care within a health system. The complex components of KMC lead to multifaceted barriers and enablers to integration, which inform facility, regional, and country-level recommendations for increasing adoption. Further research of methods to promote context-specific adoption of KMC at the health systems level is needed.

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Background: Newborns have elevated plasma adenosine levels, which may influence their immunological function.Results: Compared with adults, newborns have elevated plasma 5′-NT and alkaline phosphatase activities and lower adenosine deaminase activity.Conclusion: Soluble enzymes significantly influence extracellular purine metabolism in blood, and the levels of these enzymes in newborns promote elevated adenosine.Significance: Higher adenosine generation in newborn blood may promote an anti-inflammatory immunological status.

Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

BackgroundNewborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).MethodsTLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.ResultsHybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.ConclusionsHybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.

Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6 months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1β, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines.