Sepsis-Induced Immunosuppression in Neonates

Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortality in the early acute phase of sepsis with an overwhelming hyper-inflammatory immune response. Emerging evidence from adults suggests that hypo- and hyper-inflammation can occur during any phase of sepsis and that sepsis-immunosuppression is associated with increased mortality, morbidity, and risk to subsequent infection. In adults, sepsis-induced immunosuppression (SII) is characterised by alterations of innate and adaptive immune responses, including, but not limited to, a prominent bias toward anti-inflammatory cytokine secretion, diminished antigen presentation to T cells, and reduced activation and proliferation of T cells. It is unclear if sepsis-immunosuppression also plays a role in the adverse outcomes associated with neonatal sepsis. This review will focus on exploring if key characteristics associated with SII in adults are observed in neonates with sepsis

Gene filtering strategies for machine learning guided biomarker discovery using neonatal sepsis RNA-seq data

Machine learning (ML) algorithms are powerful tools that are increasingly being used for sepsis biomarker discovery in RNA-Seq data. RNA-Seq datasets contain multiple sources and types of noise (operator, technical and non-systematic) that may bias ML classification. Normalisation and independent gene filtering approaches described in RNA-Seq workflows account for some of this variability and are typically only targeted at differential expression analysis rather than ML applications. Pre-processing normalisation steps significantly reduce the number of variables in the data and thereby increase the power of statistical testing, but can potentially discard valuable and insightful classification features. A systematic assessment of applying transcript level filtering on the robustness and stability of ML based RNA-seq classification remains to be fully explored. In this report we examine the impact of filtering out low count transcripts and those with influential outliers read counts on downstream ML analysis for sepsis biomarker discovery using elastic net regularised logistic regression, L1-reguarlised support vector machines and random forests. We demonstrate that applying a systematic objective strategy for removal of uninformative and potentially biasing biomarkers representing up to 60% of transcripts in different sample size datasets, including two illustrative neonatal sepsis cohorts, leads to substantial improvements in classification performance, higher stability of the resulting gene signatures, and better agreement with previously reported sepsis biomarkers. We also demonstrate that the performance uplift from gene filtering depends on the ML classifier chosen, with L1-regularlised support vector machines showing the greatest performance improvements with our experimental data

Identifying safe care processes when GPs work in or alongside emergency departments: realist evaluation

Background: Increasing pressure on emergency services has led to the development of different models of care delivery including GPs working in or alongside emergency departments (EDs), but with a lack of evidence for patient safety outcomes. Aim: We aimed to explore how care processes work and how patient safety incidents associated with GPs working in ED settings may be mitigated. Design and Setting: We used realist methodology with a purposive sample of 13 EDs with different GP service models. We sought to understand the relationship between contexts, mechanisms and outcomes to develop theories about how and why patient safety incidents may occur, and how safe care was perceived to be delivered. Method: We collected qualitative data (observations, semi-structured audio-recorded staff interviews and local patient safety incident reports). We coded data using ‘if, then, because’ statements to refine initial theories developed from an earlier rapid realist literature review and analysis of a sample of national patient safety incident reports. Results: We developed a programme theory to describe how safe patient care was perceived to be delivered in these service models including: an experienced streaming nurse using local guidance and early warning scores; support for GPs’ clinical decision-making with clear governance processes relevant to the intended role (traditional GP approach or emergency medicine approach); and strong clinical leadership to promote teamwork and improve communication between services. Conclusion: Our findings can be used as a focus for more in-depth human factors investigations to optimise work conditions in this complex care delivery settin

The impact of cytokine levels in young South African children with and without HIV-associated acute lower respiratory infections

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.The Alan King Westcare Project grant by the Lung Institute of Western Australia, a National Health and Medical Research Council (NHMRC) project grant and the National Research Foundation South Africa.http://wileyonlinelibrary.com/journal/jmv2021-12-14hj2021Paediatrics and Child Healt

Programme theories to describe how different general practitioner service models work in different contexts in or alongside emergency departments (GP-ED): realist evaluation

Background: Addressing increasing patient demand and improving emergency department (ED) patient flow is a key ambition for NHS England. Delivering general practitioner (GP) services in or alongside EDs (GP-ED) was advocated in 2017 for this reason, supported by £100million (US$130million) of capital funding. Current evidence shows no overall improvement in addressing demand and reducing waiting times, but considerable variation in how different service models operate, subject to local context. Methods: We conducted mixed-methods analysis using inductive and deductive approaches for qualitative (observations, interviews) and quantitative data (time series analyses of attendances, re-attendances, hospital admissions, length of stay) based on previous research using a purposive sample of 13 GP-ED service models (3 inside-integrated; 4 inside-parallel service; 3 outside-onsite; and 3 with no GPs) in England and Wales. We used realist methodology to understand the relationship between contexts, mechanisms and outcomes to develop programme theories about how and why different GP-ED service models work. Results: GP-ED service models are complex, with variation in scope and scale of the service, influenced by individual, departmental and external factors. Quantitative data were of variable quality: overall no reduction in attendances and waiting times, a mixed picture for hospital admissions and length of hospital stay. Our programme theories describe how the GP-ED service models operate: inside the ED, integrated with patient flow and general ED demand, with a wider GP role than usual primary care; outside the ED, addressing primary care demand with an experienced streaming nurse facilitating the ‘right patients’ are streamed to the GP; or within the ED as a parallel service with most variability in the level of integration and GP role. Conclusion: Our programme theories inform recommendations on how services could be modified in particular contexts to address local demand, or whether alternative healthcare services should be considered

Antimicrobial protein and Peptide concentrations and activity in human breast milk consumed by preterm infants at risk of late-onset neonatal sepsis

Objective: We investigated the levels and antimicrobial activity of antimicrobial proteins and peptides (AMPs) in breast milk consumed by preterm infants, and whether deficiencies of these factors were associated with late-onset neonatal sepsis (LOS), a bacterial infection that frequently occurs in preterm infants in the neonatal period. Study design: Breast milk from mothers of preterm infants (≤32 weeks gestation) was collected on days 7 (n = 88) and 21 (n = 77) postpartum. Concentrations of lactoferrin, LL-37, beta-defensins 1 and 2, and alpha-defensin 5 were measured by enzyme-linked immunosorbent assay. The antimicrobial activity of breast milk samples against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, and Streptococcus agalactiae was compared to the activity of infant formula, alone or supplemented with physiological levels of AMPs. Samples of breast milk fed to infants with and without subsequent LOS were compared for levels of AMPs and inhibition of bacterial growth. Results: Levels of most AMPs and antibacterial activity in preterm breast milk were higher at day 7 than at day 21. Lactoferrin was the only AMP that limited pathogen growth >50% when added to formula at a concentration equivalent to that present in breast milk. Levels of AMPs were similar in the breast milk fed to infants with and without LOS, however, infants who developed LOS consumed significantly less breast milk and lower doses of milk AMPs than those who were free from LOS. Conclusions: The concentrations of lactoferrin and defensins in preterm breast milk have antimicrobial activity against common neonatal pathogens

Testing models of regulated membrane fusion

Bibliography: p. 110-12