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Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)‐infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non‐ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor‐basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30‐Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G‐CSF, interferon (IFN)‐γ, interleukin (IL)‐5, and MCP‐1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN‐α, IFN‐γ, IL‐4, IL‐5, IL‐13, tumour necrosis factor‐α, and MIP‐1α were significantly lower in HIV‐infected cases than in HIV‐uninfected cases, while IP‐10 and monokine induced by interferon‐γ were significantly higher in HIV‐infected cases than in HIV‐uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV‐infected children have impaired inflammatory responses to respiratory infections compared with HIV‐uninfected children. [ABSTRACT FROM AUTHOR]

Background Late-onset sepsis (LOS) with Staphylococcus epidermidis is common in preterm infants, but the immunological mechanisms underlying heightened susceptibility are poorly understood. Our aim is to characterize the ontogeny of cytokine responses to live S. epidermidis in preterm infants with and without subsequent Gram-positive LOS. Methods We conducted a prospective, observational cohort study of preterm infants (<30 weeks gestational age [GA]) with blood sampling on Days 1, 7, 14, 21, and 28 of life. Cytokine responses in peripheral whole blood stimulated with live S. epidermidis were analyzed by 11-plex immunoassay. Results Of 129 infants (mean GA, 26.2 weeks; mean birth weight, 887g), 23 (17.8%) had confirmed LOS with Gram-positive organisms and 15 (11.6%) had clinical sepsis, with median onsets at 13 and 15 days, respectively. Blood cytokine responses to an in vitro S. epidermidis challenge were similar between infected and uninfected infants on Day 1, but diverged thereafter. Infants with subsequent LOS displayed broadly reduced S. epidermidis– induced responses from Day 7 onwards, compared to those who did not develop LOS. This pattern was observed with chemokines (interleukin [IL]-8, monocyte chemotactic protein–1, and macrophage inflammatory protein–1α), pro-inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor–α) and the regulatory cytokine IL-10. Conclusions Cytokine responses to a live S. epidermidis challenge are impaired in infants with LOS and precede the onset of clinical illness. Quantifying pathogen-specific cytokine responses at Day 7 may identify those high-risk preterm infants at the greatest risk of LOS, and prospective replication is warranted. [ABSTRACT FROM AUTHOR]

Aims: Infection‐induced inflammation is associated with adverse long‐term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late‐onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. Method: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg−1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg−1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. Results: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3–30.4) and birthweight of 689 g (370–1285). PTX was well tolerated and without treatment‐limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six‐fold difference in exposure between 24 and 35 weeks postmenstrual age. Conclusions: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants. A population pharmacokinetic model was developed to characterize the six‐fold range in exposure in the studied infants despite using a weight‐based dosing regimen for these critically ill preterm infants. [ABSTRACT FROM AUTHOR]

Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to 'immature' innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37-40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-κB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. Key messages: [ABSTRACT FROM AUTHOR]

Background: The immature fragile skin of preterm infants represents an inadequate protective barrier. The emollient and anti-infective properties of coconut oil make it a potentially beneficial topical agent for this population. Objectives: Our aim was to evaluate feasibility, safety, and the effects of topical coconut oil on skin condition in very preterm infants. Methods: An open-label randomised controlled trial in preterm infants <30 weeks' gestation was conducted. Enrolled infants were randomised to receive either routine care or topical coconut oil (5 mL/kg) twice daily for 21 days, starting within 24 h of birth. The neonatal skin condition was the primary outcome, and was assessed using the Neonatal Skin Condition Score (NSCS) on days 1, 7, 14, and 21. The number of coconut oil applications was recorded to assess clinical feasibility and all enrolled infants were monitored for adverse effects of topical coconut application, such as skin irritation. Results: A total of 72 infants born <30 weeks' gestation were enrolled (36 infants per arm), with comparable demographic characteristics. Topical application of coconut oil was feasible and without adverse effects. The NSCS was maintained in the coconut oil group throughout the intervention period, but deteriorated from a median (IQR) of 3 (3-4) on day 1 to 4 (4-4) on day 21 in the control group (p = 0.01). There were no differences in common neonatal outcomes, including sepsis, necrotising enterocolitis, retinopathy of prematurity, chronic lung disease, and mortality. Conclusions: Topical coconut oil maintained a better skin condition in very preterm infants without adverse effects. This simple, safe, and affordable intervention warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: A host defense function for Alkaline phosphatases (ALPs) is suggested by the contribution of intestinal ALP to detoxifying bacterial lipopolysaccharide (endotoxin) in animal models in vivo and the elevation of ALP activity following treatment of human cells with inflammatory stimuli in vitro. However the activity of ALP in human plasma (primarily tissue-nonspecific ALP; TNAP) on lipopolysaccharide and other microbial products has not been assessed, nor has its expression been studied in preterm newborns, a vulnerable population at high risk of sepsis. In this context, the aim of our study was to characterize the activity of TNAP on Toll-like receptor (TLR) agonists and assess the concentrations of plasma ALP during late-onset sepsis in preterm newborns. Methods: Recombinant human TNAP was incubated with microbial products and phosphate release was measured by malachite green assay. Plasma ALP activity was measured serially in a cohort of preterm (N = 129) infants at high risk of late-onset sepsis (LOS). Results: TNAP dephosphorylates poly-inosine:cytosine (Toll-like receptor (TLR) 3 agonist) and LPS from Klebsiella pneumoniae and Salmonella minnesota (TLR4 agonists). Plasma ALP significantly increased postnatally over the first 4 weeks of life in preterm and term newborns. Bacteremic LOS in preterm infants (gestational age ≤ 30 weeks) was associated with significantly elevated plasma ALP at 4 weeks postnatal age. Conclusions: TNAP, the main circulating isozyme of ALP, de-phosphorylates TLR agonists, demonstrates a post-natal age dependent increase in preterm and term plasma across the first 4 weeks of life, and is elevated in association with preterm LOS.

Background: The Alberta Hip and Knee Replacement Project developed a new evidence-based clinical pathway (NCP) for total hip (THR) and knee (TKR) replacement. The aim was to facilitate the delivery of services in a timely and cost-effective manner while achieving the highest quality of care for the patient across the full continuum of care from patient referral to an orthopedic surgeon through surgery, recovery, and rehabilitation. The purpose of this article is to provide an overview of the study design, rationale, and execution of this project as a model for health technology assessment based on comparative effectiveness of alternative clinical pathways. Methods: A pragmatic randomized controlled trial study design was used to evaluate the NCP compared with the standard of care (SOC) for these procedures. The pragmatic study design was selected as a rigorous approach to produce high quality evidence suitable for informing decisions between relevant interventions in real clinical practice. The NCP was evaluated in three of the nine regional health authorities (RHAs) in Alberta with dedicated central intake clinics offering multidisciplinary care teams, constituting 80 percent of THR and TKR surgeries performed annually in Alberta. Patients were identified in the offices of twenty orthopedic surgeons who routinely performed THR or TKR surgeries. Evaluation outcome measures were based on the six dimensions of the Alberta Quality Matrix for Health (AQMH): acceptability, accessibility, appropriateness, effectiveness, efficiency and safety. Data were collected prospectively through patient self-completed questionnaires at baseline and 3 and 12 months after surgery, ambulatory and inpatient chart reviews, and electronic administrative data. Results: The trial design was successful in establishing similar groups for rigorous evaluation. Of the 4,985 patients invited to participate, 69 percent of patients consented. A total of 3,434 patients were randomized: 1,712 to SOC and 1,722 to the NCP. The baseline characteristics of patients in the two study arms, including demographics, comorbidity as measured by CDS and exposure to pain medications, and health-related quality of life, as measured by Western Ontario and McMaster Universities Osteoarthritis Index and Short Form-36, were similar. Conclusions: The Alberta Hip and Knee Replacement Project demonstrates the feasibility and advantages of applying a pragmatic randomized controlled trial to ascertain comparative effectiveness. This is a model for health technology assessment that incorporates how clinical pathways can be effectively evaluated. [ABSTRACT FROM AUTHOR]