Non-pharmacological management of infant and young child procedural pain.

BACKGROUND: Infant acute pain and distress is commonplace. Infancy is a period of exponential development. Unrelieved pain and distress can have implications across the lifespan.  This is an update of a previously published review in the Cochrane Database of Systematic Reviews, Issue 10 2011 entitled 'Non-pharmacological management of infant and young child procedural pain'. OBJECTIVES: To assess the efficacy of non-pharmacological interventions for infant and child (up to three years) acute pain, excluding kangaroo care, and music. Analyses were run separately for infant age (preterm, neonate, older) and pain response (pain reactivity, immediate pain regulation).  SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2 of 12, 2015), MEDLINE-Ovid platform (March 2015), EMBASE-OVID platform (April 2011 to March 2015), PsycINFO-OVID platform (April 2011 to February 2015), and CINAHL-EBSCO platform (April 2011 to March 2015). We also searched reference lists and contacted researchers via electronic list-serves. New studies were incorporated into the review. We refined search strategies with a Cochrane-affiliated librarian. For this update, nine articles from the original 2011 review pertaining to Kangaroo Care were excluded, but 21 additional studies were added. SELECTION CRITERIA: Participants included infants from birth to three years. Only randomised controlled trials (RCTs) or RCT cross-overs that had a no-treatment control comparison were eligible for inclusion in the analyses. However, when the additive effects of a non-pharmacological intervention could be assessed, these studies were also included. We examined studies that met all inclusion criteria except for study design (e.g. had an active control) to qualitatively contextualize results. There were 63 included articles in the current update. DATA COLLECTION AND ANALYSIS: Study quality ratings and risk of bias were based on the Cochrane Risk of Bias Tool and GRADE approach. We analysed the standardized mean difference (SMD) using the generic inverse variance method. MAIN RESULTS: Sixty-three studies, with 4905 participants, were analysed. The most commonly studied acute procedures were heel-sticks (32 studies) and needles (17 studies). The largest SMD for treatment improvement over control conditions on pain reactivity were: non-nutritive sucking-related interventions (neonate: SMD -1.20, 95% CI -2.01 to -0.38) and swaddling/facilitated tucking (preterm: SMD -0.89; 95% CI -1.37 to -0.40). For immediate pain regulation, the largest SMDs were: non-nutritive sucking-related interventions (preterm: SMD -0.43; 95% CI -0.63 to -0.23; neonate: SMD -0.90; 95% CI -1.54 to -0.25; older infant: SMD -1.34; 95% CI -2.14 to -0.54), swaddling/facilitated tucking (preterm: SMD -0.71; 95% CI -1.00 to -0.43), and rocking/holding (neonate: SMD -0.75; 95% CI -1.20 to -0.30). Fifty two of our 63 trials did not report adverse events. The presence of significant heterogeneity limited our confidence in the findings for certain analyses, as did the preponderance of very low quality evidence. AUTHORS' CONCLUSIONS: There is evidence that different non-pharmacological interventions can be used with preterms, neonates, and older infants to significantly manage pain behaviors associated with acutely painful procedures. The most established evidence was for non-nutritive sucking, swaddling/facilitated tucking, and rocking/holding. All analyses reflected that more research is needed to bolster our confidence in the direction of the findings. There are significant gaps in the existing literature on non-pharmacological management of acute pain in infancy.

Distress regulation in infancy: attachment and temperament in the context of acute pain.

OBJECTIVE: The relationship between attachment, temperamental fear, and pain-related distress was examined in a sample of 130 caregiver-infant dyads to explore the differential susceptibility hypothesis. METHOD: Infant distress was measured during routine immunization at 12 months, and attachment and temperamental fear were measured at 12 to 18 months (meanage = 13.74, SD = 1.35) using the Strange Situation Procedure and parent-rated Infant Behavior Questionnaire-Revised, respectively. RESULTS: Immediately before immunization, avoidant infants exhibited significantly less distress than secure infants. Temperamental fear moderated the relationship between attachment and regulation; under conditions of high temperamental fear, avoidant infants regulated distress more slowly than secure infants, whereas under conditions of low temperamental fear, secure infants regulated distress more slowly than avoidant and disorganized infants. CONCLUSION: The findings suggest that attachment interacts with extremes in temperamental fear to produce differences in the regulation of distress. The results partially support the differential susceptibility hypothesis.

Burkholderia pseudomallei penetrates the brain via destruction of the olfactory and trigeminal nerves: implications for the pathogenesis of neurological melioidosis.

ABSTRACT Melioidosis is a potentially fatal disease that is endemic to tropical northern Australia and Southeast Asia, with a mortality rate of 14 to 50%. The bacterium Burkholderia pseudomallei is the causative agent which infects numerous parts of the human body, including the brain, which results in the neurological manifestation of melioidosis. The olfactory nerve constitutes a direct conduit from the nasal cavity into the brain, and we have previously reported that B. pseudomallei can colonize this nerve in mice. We have now investigated in detail the mechanism by which the bacteria penetrate the olfactory and trigeminal nerves within the nasal cavity and infect the brain. We found that the olfactory epithelium responded to intranasal B. pseudomallei infection by widespread crenellation followed by disintegration of the neuronal layer to expose the underlying basal layer, which the bacteria then colonized. With the loss of the neuronal cell bodies, olfactory axons also degenerated, and the bacteria then migrated through the now-open conduit of the olfactory nerves. Using immunohistochemistry, we demonstrated that B. pseudomallei migrated through the cribriform plate via the olfactory nerves to enter the outer layer of the olfactory bulb in the brain within 24 h. We also found that the bacteria colonized the thin respiratory epithelium in the nasal cavity and then rapidly migrated along the underlying trigeminal nerve to penetrate the cranial cavity. These results demonstrate that B. pseudomallei invasion of the nerves of the nasal cavity leads to direct infection of the brain and bypasses the blood-brain barrier. IMPORTANCE Melioidosis is a potentially fatal tropical disease that is endemic to northern Australia and Southeast Asia. It is caused by the bacterium Burkholderia pseudomallei, which can infect many organs of the body, including the brain, and results in neurological symptoms. The pathway by which the bacteria can penetrate the brain is unknown, and we have investigated the ability of the bacteria to migrate along nerves that innervate the nasal cavity and enter the frontal region of the brain by using a mouse model of infection. By generating a mutant strain of B. pseudomallei which is unable to survive in the blood, we show that the bacteria rapidly penetrate the cranial cavity using the olfactory (smell) nerve and the trigeminal (sensory) nerve that line the nasal cavity.

Antibodies and their receptors: different potential roles in mucosal defense.

Over recent years it has become increasingly apparent that mucosal antibodies are not only restricted to the IgM and IgA isotypes, but that also other isotypes and particularly IgG can be found in significant quantities at some mucosal surfaces, such as in the genital tract. Their role is more complex than traditionally believed with, among other things, the discovery of novel function of mucosal immunoglobulin receptors. A thorough knowledge in the source and function and mucosal immunoglobulins is particularly important in development of vaccines providing mucosal immunity, and also in the current climate of microbicide development, to combat major world health issues such as HIV. We present here a comprehensive review of human antibody mediated mucosal immunity.

Quorum sensing negatively regulates multinucleate cell formation during intracellular growth of Burkholderia pseudomallei in macrophage-like cells.

Burkholderia pseudomallei is a Gram-negative environmental bacterium and the causative agent of melioidosis, a potentially fatal, acute or chronic disease endemic in the tropics. Acyl homoserine lactone (AHL)-mediated quorum sensing and signalling have been associated with virulence and biofilm formation in numerous bacterial pathogens. In the canonical acyl-homoserine lactone signalling paradigm, AHLs are detected by a response regulator. B. pseudomallei encodes three AHL synthases, encoded by bpsI1, bpsI2 and bpsI3, and five regulator genes. In this study, we mutated the B. pseudomallei AHL synthases individually and in double and triple combination. Five AHLs were detected and quantified by tandem liquid chromatography-mass spectroscopy. The major AHLs produced were N-octanoylhomoserine lactone and N-(3-hydroxy-decanoyl)homoserine lactone, the expression of which depended on bpsI1 and bpsI2, respectively. B. pseudomallei infection of macrophage cells causes cell fusion, leading to multinucleated cells (3 or more nuclei per cell). A triple mutant defective in production of all three AHL synthases was associated with a striking phenotype of massively enhanced host cellular fusion in macrophages. However, neither abrogation of host cell fusion, achieved by mutation of bimA or hcp1, nor enhancement of fusion altered intracellular replication of B. pseudomallei. Furthermore, when tested in murine models of acute melioidosis the AHL synthase mutants were not attenuated for virulence. Collectively, this study identifies important new aspects of the genetic basis of AHL synthesis in B. pseudomallei and the roles of these AHLs in systemic infection and in cell fusion in macrophages for this important human pathogen.

Interaction of Burkholderia pseudomallei and Burkholderia thailandensis with human monocyte-derived dendritic cells.

Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic in areas of South-East Asia and northern Australia, and is classed as a category B select agent by the Centers for Disease Control and Prevention (CDC). Factors that determine whether host infection is achieved or if disease is chronic or acute are unknown but the type of host immune response that is mounted is important. B. pseudomallei can replicate within macrophages, causing them to multinucleate. In light of the common lineage of macrophages with dendritic cells (DCs), and the role played by DCs in orchestration of the immune response, we investigated the interactions of a variety of B. pseudomallei and B. thailandensis strains with DCs. This study demonstrates that, in the majority of cases, infection of human monocyte-derived dendritic cells is dramatically decreased or cleared by 12 h post-infection, showing a lack of ability to replicate and survive within DCs. Additionally we have shown that B. pseudomallei activates DCs, as measured by cytokine secretion, and live bacteria are not required for activation.

Non-pharmacological management of infant and young child procedural pain.

BACKGROUND: Infant acute pain and distress is commonplace. Infancy is a period of exponential development. Unrelieved pain and distress can have implications across the lifespan.  OBJECTIVES: To assess the efficacy of non-pharmacological interventions for infant and child (up to three years) acute pain, excluding breastmilk, sucrose, and music. Analyses accounted for infant age (preterm, neonate, older) and pain response (pain reactivity, pain-related regulation).  SEARCH STRATEGY: We searched CENTRAL in The Cochrane Library (2011, Issue 1), MEDLINE (1966 to April 2011), EMBASE (1980 to April 2011), PsycINFO (1967 to April 2011), Cumulative Index to Nursing and Allied Health Literature (1982 to 2011), Dissertation Abstracts International (1980 to 2011) and www.clinicaltrials.gov. We also searched reference lists and contacted researchers via electronic list-serves. SELECTION CRITERIA: Participants included infants from birth to three years. Only randomized controlled trials (RCTs) or RCT cross-overs that had a no-treatment control comparison were eligible for inclusion in the analyses. We examined studies that met all inclusion criteria except for study design (e.g. had an active control) to qualitatively contextualize results. DATA COLLECTION AND ANALYSIS: We refined search strategies with three Cochrane-affiliated librarians. At least two review authors extracted and rated 51 articles. Study quality ratings were based on a scale by Yates and colleagues. We analyzed the standardized mean difference (SMD) using the generic inverse variance method. We also provided qualitative descriptions of 20 relevant but excluded studies. MAIN RESULTS: Fifty-one studies, with 3396 participants, were analyzed. The most commonly studied acute procedures were heel-sticks (29 studies) and needles (n = 10 studies). The largest SMD for treatment improvement over control conditions on pain reactivity were: non-nutritive sucking-related interventions (preterm: SMD -0.42; 95% CI -0.68 to -0.15; neonate: SMD -1.45, 95% CI -2.34 to -0.57), kangaroo care (preterm: SMD -1.12, 95% CI -2.04 to -0.21), and swaddling/facilitated tucking (preterm: SMD -0.97; 95% CI -1.63 to -0.31). For immediate pain-related regulation, the largest SMDs were: non-nutritive sucking-related interventions (preterm: SMD -0.38; 95% CI -0.59 to -0.17; neonate: SMD -0.90, 95% CI -1.54 to -0.25), kangaroo care (SMD -0.77, 95% CI -1.50 to -0.03), swaddling/facilitated tucking (preterm: SMD -0.75; 95% CI -1.14 to -0.36), and rocking/holding (neonate: SMD -0.75; 95% CI -1.20 to -0.30). The presence of significant heterogeneity limited our confidence in the lack of findings for certain analyses. AUTHORS' CONCLUSIONS: There is evidence that different non-pharmacological interventions can be used with preterms, neonates, and older infants to significantly manage pain behaviors associated with acutely painful procedures.

Maternal relationship style, paediatric health care use and infant health.

OBJECTIVE: The aim of the current exploratory study was to examine the relationships between maternal relationship style, paediatric health care use and infant health variables in a sample of middle-class and ethnically diverse mother-infant dyads. METHODS: An initial cross-sectional cohort study obtained demographic and self-report data on mothers' relationship styles. As an extension of the original study, infants' patient files were reviewed for the year following initial recruitment to obtain data regarding the use of paediatric health care services and infant health. The final sample included 64 mothers and their infants. RESULTS: Correlational analyses revealed that mothers' higher endorsement of a dismissive relationship style were associated with fewer acute care visits and fewer reported infant illnesses. CONCLUSIONS: Compared with other relationship styles, mothers who highly endorsed a dismissive relationship style tended to use fewer acute paediatric health care services and reported fewer infant health problems. However, further longitudinal research is needed to clarify these relationships.

Mothers' facial expressions of pain and fear and infants' pain response during immunization.

The goal of the current study was to examine the relationship between mothers' spontaneous facial expressions of pain and fear immediately preceding their infants' immunizations and infants' facial expressions of pain immediately following immunizations. Infants' observations of mothers' faces prior to immunization also were examined to explore whether these observations moderated the effect of mothers' facial expressions on infant pain. The final sample included 58 mothers and their infants. Video data were used to code maternal facial expressions, infants' observations, and infants' expressions of pain. Infants who observed their mothers' faces had mothers who expressed significantly more fear pre-needle. Furthermore, mothers' facial expressions of mild fear pre-needle were associated with lower levels of infants' pain expression post-needle. A regression analysis confirmed maternal facial expressions of mild fear pre-needle as the strongest predictor of infant pain post-needle after controlling for infants' observations of mothers' faces. Mothers' subtle facial expressions of fear may indicate a relationship history of empathic caregiving that functions to support infants' abilities to regulate distress following painful procedures. Interventions aimed at improving caregiver sensitivity to infants' emotional cues may prove beneficial to infants in pain. Future directions in research are discussed.

A comparative analysis of gene expression patterns and cell phenotypes between cervical and peripheral blood mononuclear cells.

Studies of the immunological environment in the female genital tract (FGT) are critical for the development of vaccines or microbicides to halt the spread of sexually transmitted infections. Challenges arise due to the difficulties of sampling from this site, and the majority of studies have been conducted utilising peripheral blood mononuclear cells. Identifying functional differences between immune cells of the FGT and peripheral blood would aid in our understanding of mucosal immunology. We compared the gene expression profile of mononuclear cells at these two sites. Messenger RNA expression analysis was performed using gene expression arrays on matched cervical mononuclear cells and peripheral blood mononuclear cells. Further cellular phenotyping was done by 10 colour flow cytometry. Of the 22,185 genes expressed by these samples, 5345 genes were significantly differentially expressed between the cell populations. Most differences can be explained by significantly lower levels of T and B cells and higher levels of macrophages and dendritic cells in the FGT compared with peripheral blood. Several immunologically relevant pathways such as apoptosis and innate immune signalling, and a variety of cytokines and cytokine receptors were differentially expressed. This study highlights the importance of the unique immunological environment of the FGT and identifies important differences between systemic and mucosal immune compartments.

Cervical HIV-specific IgA in a population of commercial sex workers correlates with repeated exposure but not resistance to HIV.

We conducted a comprehensive cross-sectional analysis of total and HIV-specific cervical antibody levels in HIV-1-resistant, uninfected, and infected women in order to examine the role of HIV-specific antibody responses in the female genital tract and examine the effect on antibody levels of various epidemiologic factors in this population. Cervical lavages were collected from 272 subjects of the Pumwani commercial sex worker cohort. Total and HIV-specific genital tract IgA and IgG levels were measured using an ELISA and correlated with behavioral and demographic factors. No significant difference was seen between cervical HIV-specific IgA levels in infected, uninfected, and resistant individuals, nor were any correlations between cervical HIV-specific IgA and neutralization capacity or viral shedding seen. We did, however, note increased HIV-specific IgA in HIV-negative women with four or more clients per day, and decreased HIV-specific IgA in both long-term nonprogressors and long-term survivors. These results show that there is not a strong cohort-wide correlation between HIV-specific cervical IgA levels and resistance to infection by HIV-1 as previously believed, but there is a correlation between exposure to HIV and HIV-specific cervical IgA. Our findings do not preclude the possibility that functional differences in the cervical IgA of HEPS women may play a role in resistance, but argue that HIV-specific responses may not be a universal protective factor. They also indicate that resistance to HIV is a complex condition related to more factors than exposure. Further studies of correlates of immune protection in these individuals would be beneficial to the field.

Mucosal immunity in healthy adults after parenteral vaccination with outer-membrane vesicles from Neisseria meningitidis serogroup B.

BACKGROUND: Nasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cell memory. Whether parenteral Neisseria meningitidis serogroup B (MenB) vaccination influences natural mucosal immunity is unknown. OBJECTIVES: To determine whether parenteral MenB vaccination affects mucosal immunity in young adults and whether this immunity differs from that induced in the blood. METHODS: Otherwise healthy volunteers were immunized with MenB outer membrane vesicle vaccine before and after routine tonsillectomy. Mucosal and systemic immunity were assessed in 9 vaccinees and 12 unvaccinated control subjects by measuring mononuclear cell proliferation, cytokine production, Th1/Th2 surface marker expression, and antibody to MenB antigens. RESULTS: Parenteral vaccination induced a marked increase in systemic T cell immunity against MenB and a Th1 bias. In contrast, although mucosal T cell proliferation in response to MenB neither increased nor decreased following vaccination, mononuclear cell interferon gamma, interleukin (IL)-5, and IL-10 production increased, and the Th1/Th2 profile lost its Th1 bias. CONCLUSIONS: Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

Understanding caregiver judgments of infant pain: contrasts of parents, nurses and pediatricians.

BACKGROUND: Research suggests that caregivers' beliefs pertaining to infant pain and which infant pain cues are perceived to be important play an integral role in pediatric pain assessment and management. OBJECTIVES: Following a recent quasi-experimental study reporting on caregiver background and age differences in actual infant pain judgments, the present study clarified these findings by analyzing caregivers' pain beliefs and the cues they use to make pain assessments, and by examining how the wording of belief questions influenced caregivers' responses. METHODS: After making pain judgments based on video footage of infants between two and 18 months of age receiving immunizations, parents, nurses and pediatricians were required to respond to questionnaires regarding pain beliefs and importance of cues. RESULTS: Parents generally differed from pediatricians. Parents tended to have less optimal beliefs regarding medicating the youngest infants, were more influenced by question wording, and reported using many more cues when judging older infants than other caregiver groups. In terms of beliefs, influence of question wording and cue use, nurses tended to fall in between both groups; they displayed similarities to both parents and pediatricians. CONCLUSIONS: Paralleling the original findings on pain judgments, these findings suggest that parents differ from pediatricians in their pain beliefs and the cues they use to make pain judgments. Moreover, some similarities were found between parents and nurses, and between nurses and pediatricians. Finally, caution must be taken when interpreting research pertaining to beliefs about infant pain because question wording appears to influence interpretation.

Parenteral influenza vaccination influences mucosal and systemic T cell-mediated immunity in healthy adults.

We sought to determine whether palatine tonsils (PTs) harbor naturally acquired influenza-specific T cell immunity and whether routine parenteral immunization with influenza vaccine influences mucosal and systemic T cell reactivity. We demonstrate that tonsillar and peripheral blood mononuclear cells (PBMCs) proliferate strongly to influenza antigens, suggesting that naturally acquired immunity exists within both the mucosal and systemic compartments. Influenza vaccination induced significantly stronger T cell responses in both PTs and blood, in addition to increasing titers of anti-influenza antibodies in serum and saliva. More-rapid proliferative responses of PTs after vaccination were associated with a shift from a response involving both CD45RA+ and CD45RO+ T cells to an entirely CD45RO+-dependent response. Interestingly, the ratio of interferon- gamma to interleukin-5 was dramatically higher in cultures of PT T cells responding to influenza than in PBMCs. Our data indicate that parenteral influenza vaccination influences both mucosal and systemic naturally acquired T cell immunity.