Protocol for the diagnostic performance of C reactive protein, procalcitonin and interleukin-6 for serious bacterial infections among children ≤36 months old presenting with fever without source: a systematic review and meta-analysis.

INTRODUCTION: The management of fever without source in children ≤36 months old remains a diagnostic challenge as the underlying aetiologies can vary from self-limiting viral infections to serious bacterial infections (SBIs). Biomarkers such as C reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) have varying thresholds in the prediction of SBIs due to differences in SBI definitions, SBI prevalence, patient characteristics and timing of presentation. This protocol describes a systematic review and meta-analysis that aims to determine the thresholds at which CRP, PCT and IL-6 can perform optimally in distinguishing the presence of SBIs in children ≤36 months old, as well as to determine their performances in early detection of bacterial infections within 48 hours of fever onset. METHODS AND ANALYSIS: We will systematically search electronic databases including MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane CENTRAL, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Science Citation Index from 1 July 2023 to 31 July 2023. We will include studies that report the diagnostic accuracy of CRP, PCT and IL-6 in detecting SBIs in children aged ≤36 months presenting with fever without apparent source. Randomised controlled trials (RCTs) and non-randomised studies including non-RCTs and controlled before-and-after studies will be included. A meta-analysis will be performed and diagnostic performances of these biomarkers will be reported. ETHICS AND DISSEMINATION: The results of this study will provide guidance on clinical decision-making in young children presenting with fever without source. Ethics approval will not be required for this study. The authors aim to publish the findings in a peer-reviewed journal as well as present at international conferences. PROSPERO REGISTRATION NUMBER: CRD42023439093.

Cost-utility analysis of sacituzumab govitecan versus chemotherapy for the treatment of metastatic triple-negative breast cancer in Singapore.

OBJECTIVE: To assess the cost-effectiveness of sacituzumab govitecan for treating relapsed or refractory metastatic triple-negative breast cancer (TNBC) in Singapore. METHODS: A three-state partitioned survival model was developed to evaluate the cost-effectiveness of sacituzumab govitecan from a healthcare system perspective over 5 years. Clinical inputs were obtained from the ASCENT trial. Health state utilities were retrieved from the literature and direct costs were sourced from public healthcare institutions in Singapore. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. RESULTS: Compared with single-agent chemotherapy, sacituzumab govitecan was associated with a base-case incremental cost-effectiveness ratio (ICER) of S$328,000 (US$237,816) per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that the ICER was most sensitive to the cost of sacituzumab govitecan and progression-free utility values. Regardless of variation in these parameters, the ICER remained high, and a substantial price reduction was required to reduce the ICER. CONCLUSION: At its current price, sacituzumab govitecan does not represent a cost-effective treatment for relapsed or refractory metastatic TNBC in Singapore. Our findings will be useful to inform funding decisions alongside other factors including clinical effectiveness, safety, and budget impact considerations.

Pharmacogenomics Implementation Training Improves Self-Efficacy and Competency to Drive Adoption in Clinical Practice.

Background: Administration of pharmacogenomics (PGx) testing in clinical practice has been suboptimal, presumably due to lack of PGx education. Here, we aim to evaluate the standpoint of PGx testing among a diverse group of healthcare professionals (HCPs) through conducting surveys before and after training. Materials and Methods: Training modules were designed to cover three key learning objectives and deployed in five sections. A pre- and post-training survey questionnaire was used to evaluate participants' self-assessments on employing PGx in clinical practice. Results and Conclusion: Out of all enrollments, 102 survey responses were collected. Overall, respondents agree on the benefits of PGx testing, but have inadequate self-efficacy and competency in utilizing PGx data. Our results show that a 90 min long training significantly improves these, and could lead to greater anticipation of PGx adoption.

The Impact of Traumatic Brain Injury on Neurocognitive Outcomes in Children: a Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the burden of paediatric traumatic brain injury (TBI) on neurocognition via a systematic review and meta-analysis. METHODS: Studies that compared neurocognitive outcomes of paediatric patients with TBI and controls were searched using Medline, Embase, PsycINFO and Cochrane Central Register of Controlled Trials, between January 1988 and August 2019. We presented a random-effects model, stratified by TBI severity, time of assessment post injury and age. RESULTS: Of 5919 studies, 41 (patients=3717) and 33 (patients=3118) studies were included for the systematic review and meta-analysis, respectively. Studies mostly measured mild TBI (n=26, patients=2888) at 0-3 months postinjury (n=17, patients=2502). At 0-3 months postinjury, standardised mean differences between TBI and controls for executive function were -0.04 (95% CI -0.14 to 0.07; I2=0.00%), -0.18 (95% CI -0.29 to -0.06; I2=26.1%) and -0.95 (95% CI -1.12 to -0.77; I2=10.1%) for mild, moderate and severe TBI, respectively; a similar effect was demonstrated for learning and memory. Severe TBI had the worst outcomes across all domains and persisted >24 months postinjury. Commonly used domains differed largely from workgroup recommendations. Risk of bias was acceptable for all included studies. CONCLUSION: A dose-dependent relationship between TBI severity and neurocognitive outcomes was evident in executive function and in learning and memory. Cognitive deficits were present for TBIs of all severity but persisted among children with severe TBI. The heterogeneity of neurocognitive scales makes direct comparison between studies difficult. Future research into lesser explored domains and a more detailed assessment of neurocognitive deficits in young children are required to better understand the true burden of paediatric TBI.

A review of umbilical venous catheter-related complications at a tertiary neonatal unit in Singapore.

INTRODUCTION: Umbilical venous catheters (UVCs), commonly inserted in neonates for vascular access, are not without complications. METHODS: A single-centre retrospective cohort study that reviewed complications related to UVC insertion in neonates was conducted in a tertiary neonatal unit in Singapore from January 2016 to July 2017. Ideal UVC position was defined as catheter tip within 0.5 cm above or below the diaphragm. Catheter-related sepsis was defined as clinical or biochemical abnormalities suggesting any new-onset or worsening sepsis 72 hours before or after removal of UVCs, with or without positive culture. Catheter-associated bloodstream infection (CABSI) was defined as positive microbiological growth in one or more blood cultures obtained from a symptomatic infant up to two days after UVC placement or within 48 hours of catheter removal. RESULTS: 108 patients had UVC insertions. Mean gestational age and birth weight were 30.4 ± 4.0 weeks and 1,536.2 g ± 788.9 g, respectively. Mean UVC duration was 6.6 days. The UVC was in an ideal position in 27 (25.0%), deep in 13 (12.0%) and short in 35 (32.4%) neonates. One-third of the UVCs (n = 33) were malpositioned. Catheter-related sepsis was observed in 16 (14.8%) neonates, with 5 (4.6%) having CABSI. The most common organism was coagulase-negative Staphylococcus. Other complications include peritoneal extravasation in 3 (2.8%) patients, with two requiring surgical intervention. Venous thrombosis occurred in 2 (1.9%) neonates and was managed conservatively. CONCLUSION: Although complication rates were in line with international norms, UVCs were associated with serious complications and should be judiciously used.

Protocol for a systematic review and meta-analysis of long-term neurocognitive outcomes in paediatric traumatic brain injury.

INTRODUCTION: Children who suffer from traumatic brain injury (TBI) are at risk of permanent brain damage and developmental deficits. Reports on neurodevelopmental outcomes in paediatric TBI suffer from small sample size and varying outcome definitions in the neurocognitive domains tested. This protocol describes a systematic review and meta-analysis of paediatric TBI in the following key neurocognitive domains: executive function, perceptual-motor function, language, learning and memory, social cognition and complex attention. METHODS: A comprehensive search comprising studies from Medline, Cochrane, Embase and PsycINFO published from 1988 to 2019 will be conducted. We will include studies on children ≤18 years old who suffer from mild, moderate and severe TBI as determined by the Glasgow Coma Scale that report neurocognitive outcomes in domains predetermined by the Diagnostic and Statistical Manual of Mental Disorders fifth edition criteria. Systematic reviews, meta-analyses, randomised controlled trials, case-control, cohort and cross-sectional studies will be included. References from systematic reviews and meta-analyses will be hand-searched for relevant articles. A meta-analysis will be performed and effect sizes will be calculated to summarise the magnitude of change in each neurocognitive domain compared at different timepoints and stratified by severity of TBI. Included studies will be pooled using pooled standardised mean differences with a random effects model to determine an overall effect. In the scenario that we are unable to pool the studies, we will perform a narrative analysis. ETHICS AND DISSEMINATION: Ethics approval is not required for this study.The authors of this study will publish and present the findings in a peer-reviewed journal as well as national and international conferences. The results of this study will provide understanding into the association between different severities of paediatric TBI and long-term neurocognitive outcomes. PROSPERO REGISTRATION NUMBER: CRD42020152680.

Anhydrous polymer-based coating with sustainable controlled release functionality for facile, efficacious impregnation, and delivery of antimicrobial peptides.

Anhydrous polymers are actively explored as alternative materials to overcome limitations of conventional hydrogel-based antibacterial coating. However, the requirement for strong organic solvent in polymerization reactions often necessitates extra protection steps for encapsulation of target biomolecules, lowering encapsulation efficiency, and increasing process complexity. This study reports a novel coating strategy that allows direct solvation and encapsulation of antimicrobial peptides (HHC36) into anhydrous polycaprolactone (PCL) polymer-based dual layer coating. A thin 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) film is layered onto the peptide-impregnated PCL as a diffusion barrier, to modulate and enhance release kinetics. The impregnated peptides are eventually released in a controlled fashion. The use of 2,2,2-trifluoroethanol (TFE), as polymerization and solvation medium, induces the impregnated peptides to adopt highly stable turned conformation, conserving peptide integrity, and functionality during both encapsulation and subsequent release processes. The dual layer coating showed sustained antibacterial functionality, lasting for 14 days. In vivo assessment using an experimental mouse wounding model demonstrated good biocompatibility and significant antimicrobial efficacy of the coating under physiological conditions. The coating was translated onto silicone urinary catheters and showed promising antibacterial efficacy, even outperforming commercial silver-based Dover cather. This anhydrous polymer-based platform holds immense potential as an effective antibacterial coating to prevent clinical device-associated infections. The simplicity of the coating process enhances its industrial viability.

T helper cell-specific regulation of inducible costimulator expression via distinct mechanisms mediated by T-bet and GATA-3.

Inducible costimulator (ICOS) expression is critical for T cell-mediated immunity. We showed previously that T cell receptor and CD28 co-engagement up-regulate ICOS expression in activated T cells via the induction of NFATc2. Here, we examined the regulation of ICOS expression by Th-specific transcription factors T-bet and GATA-3. Overexpression of T-bet or GATA-3 alone could enhance, and NFATc2 could further synergize with either of them to increase, icos transcription. Although T-bet acted on the icos promoter, GATA-3 operated via an icos 3'-un-translated region element. Interestingly, NFATc2 was found to bind promiscuously the icos promoter in developing Th0, Th1, and Th2 cells but became selectively associated with T-bet at the promoter and with GATA-3 at the 3'-untranslated region in fully differentiated Th1 and Th2 cells, respectively. Collectively, our results reveal a temporally evolving circuit in which the non-selectively expressed NFATc2 cooperates with Th-restricted T-bet or GATA-3 to direct transcription of a costimulatory gene via distinct regulatory elements in different Th cells undergoing differentiation.