Oxygen Delivery and Oxygen Consumption in Pediatric Fluid Refractory Septic Shock During the First 42 h of Therapy and Their Relationship to 28-Day Outcome

Background: In septic shock, both oxygen delivery (DO2) and oxygen consumption (VO2) are dysfunctional. The current therapeutic regimens are geared to normalize global oxygen delivery (DO2) to tissues via goal directed therapies but mortality remains high at 10–20%.Methods: We studied cardiac index (CI), systemic vascular resistance index (SVRI), central venous oxygen saturation (ScvO2), central venous pressure (CVP), peripheral oxygen saturation (SpO2), mean blood pressure (MBP), body temperature, blood lactate, base excess and hemoglobin concentration (Hb) in a cohort of children admitted in “fluid-refractory” severe septic shock to pediatric intensive care, over 4.5-years. We calculated their 6 h global oxygen delivery (DO2) and global oxygen consumption (VO2) over the first 42 h and looked at factors associated with VO2/DO2 ratio (i.e., global oxygen extraction, gO2ER) and 28-day mortality.Results: Sixty-two children mean age (SD) 7.19 (5.44) years were studied. Fifty-seven (93%) children were sedated and mechanically ventilated and all received adrenaline or noradrenaline or both and added milrinone in 6 (9.6%). At 28 days, 9 (14.5%) were dead. The global oxygen extraction ratio (gO2ER) was consistently lower amongst the survivors and independently predicted mortality (ROC AUC = 0.75). A lactate level of 4 mmol/l or above, when associated with a concurrent metabolic acidosis predicted mortality with a sensitivity of 100% (95% CI 90.5–100) and a specificity of 67.7% (95% CI 62.2–72.9). A gO2ER of 0.48 or above on admission to the PICU was associated with death with a 66.7% sensitivity (95%CI 29.9–92.5) and 90.5% specificity (95%CI 79.3–96.8). A global O2ER of >0.48 combined with a concurrent blood lactate >4.0 mmol/l at any time within the first 42 h of therapy predicted death with a sensitivity of 63.9% (95% CI, 46.2–79.1) and specificity of 97.8% (95% CI, 95.7–99.0). A radar plot identified MBP-CVP difference, and CI as additional goals of therapy that may offer a survival benefit.Conclusions: Global O2ER of >0.48 with a concurrent blood lactate >4.0 mmol/l in children with metabolic acidosis was an independent factor associated with death in fluid resistant septic shock. Trends of gO2ER seem useful to recognize survivors and non-survivors early in the illness

Advancing sepsis clinical research: harnessing transcriptomics for an omics-based strategy - a comprehensive scoping review

Sepsis continues to be recognized as a significant global health challenge across all ages and is characterized by a complex pathophysiology. In this scoping review, PRISMA-ScR guidelines were adhered to, and a transcriptomic methodology was adopted, with the protocol registered on the Open Science Framework. We hypothesized that gene expression analysis could provide a foundation for establishing a clinical research framework for sepsis. A comprehensive search of the PubMed database was conducted with a particular focus on original research and systematic reviews of transcriptomic sepsis studies published between 2012 and 2022. Both coding and non-coding gene expression studies have been included in this review. An effort was made to enhance the understanding of sepsis at the mRNA gene expression level by applying a systems biology approach through transcriptomic analysis. Seven crucial components related to sepsis research were addressed in this study: endotyping (n = 64), biomarker (n = 409), definition (n = 0), diagnosis (n = 1098), progression (n = 124), severity (n = 451), and benchmark (n = 62). These components were classified into two groups, with one focusing on Biomarkers and Endotypes and the other oriented towards clinical aspects. Our review of the selected studies revealed a compelling association between gene transcripts and clinical sepsis, reinforcing the proposed research framework. Nevertheless, challenges have arisen from the lack of consensus in the sepsis terminology employed in research studies and the absence of a comprehensive definition of sepsis. There is a gap in the alignment between the notion of sepsis as a clinical phenomenon and that of laboratory indicators. It is potentially responsible for the variable number of patients within each category. Ideally, future studies should incorporate a transcriptomic perspective. The integration of transcriptomic data with clinical endpoints holds significant potential for advancing sepsis research, facilitating a consensus-driven approach, and enabling the precision management of sepsis

Too Hot to Handle: A Survey of Attitudes towards Fever of 462 Pediatric Intensive Care Unit staff

The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 °C (IQR 38–38.5 °C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 °C acceptable without treatment. Conclusions: Staff on paediatric intensive care units in the United Kingdom and Ireland tends to treat temperatures within the febrile range. There was a willingness to conduct a randomized controlled trial of treatment of fever

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Recent advances in the photovoltaic applications of coordination polymers and metal organic frameworks

Coordination polymers and metal organic frameworks (CPs/MOFs) have attracted a great deal of attention in a variety of scientific fields due to their unique and intriguing structural properties. Photovoltaic applications of these porous polymers belong to a relatively new area of research. The current status of research on this subject amply highlights the usefulness of CPs/MOFs in improving the properties of next-generation photovoltaic devices (e.g., dye-sensitized solar cells). This review article was written to cover the recent advancements that have been achieved in this rapidly expanding area of research. It also compares and contrasts the energy conversion efficiencies in photovoltaic applications using different MOFs and other systems

Self healing biologically inspired Nanoreinforced polymer composite For improved fatigue tolerance And reliability of bioimplants

In this study, a self-healing, multi walled carbon nanotubes (MWNT) nanoreinforced polymer composite is formed which may be used as biomaterial to manufacture bioimplants like artificial blood vessels; or as coating material for metallic implants like pacemakers, artificial hip and knee to avoid corrosion and increase the life of the implant. The self-healing approach employs a releasable healing agent incorporated in a hollow fiber embedded in an epoxy resin system. The generation and filling of the crack is a simultaneous process. The crack propagates through the polymer composite and breaks the hollow fiber which results in the leaking of the liquid healing agent, which fills the crack. The catalyst is pre-coated on the outer surface of the fiber to facilitate the polymerization of the monomer healing agent. Virgin, damaged and healed samples of the nanoreinforced polymer composite are tested proving that the addition of functionalized carbon nanotubes in the healing agent leads to better fracture toughness and tensile strength recovery