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.

Early metabolic derangements and unfavorable outcomes in pediatric traumatic brain injury: a retrospective multi-center cohort study.

Background: To study the association in moderate and severe pediatric traumatic brain injury (TBI) between hyperglycemia, hyperlactatemia, acidosis and unfavorable outcome, as assessed by Pediatric Cerebral Performance Category (PCPC) on discharge from the pediatric intensive care unit (PICU). Methods: Children <16 years old with TBI and Glasgow Coma Scale (GCS) ≤13 in an Asian multi-center PICU TBI cohort from January 2014 to October 2017 were included in this study. We defined unfavorable outcome as PCPC ≥3-moderate disability, severe disability, vegetative state, and death. We performed logistic regression to investigate the association between metabolic changes with unfavorable outcome. We divided hyperglycemia (glucose >11.1 mmol/L) during PICU admission into early-onset (within 24 h), late-onset (beyond 48 h) and persistent (throughout first 72 h). Results: Among the 305 children analyzed, 136 (44.6%) had unfavorable outcome. Children with unfavorable outcome were more likely to have early hyperglycemia (75/136, 55.1% vs. 33/169, 19.5%; P<0.001), high lactate levels >2.0 mmol/L (74/136, 54.4% vs. 56/169, 32.5%; P<0.001) and initial acidosis (85/136, 62.5% vs. 78/169, 56.1%; P=0.003) compared to those with favorable outcome. After adjusting for gender, GCS ≤8 and presence of polytrauma, early hyperglycemia [adjusted odds ratio (aOR) =3.68, 95% CI: 2.12-6.39, P<0.001] and late hyperglycemia (aOR =13.30, 95% CI: 1.64-107.8, P=0.015] were independently associated with unfavorable outcome. All children with persistent hyperglycemia died. Conclusions: We described unfavorable outcome in pediatric TBI especially with persistent hyperglycemia. Future trials should investigate the causal relationship between glycemic trends, early intervention and outcome in this cohort.

Do paediatric early warning systems reduce mortality and critical deterioration events among children? A systematic review and meta-analysis.

Aim: We conducted a systematic review and meta-analysis to answer the question: Does the implementation of Paediatric Early Warning Systems (PEWS) in the hospital setting reduce mortality, cardiopulmonary arrests, unplanned codes and critical deterioration events among children, as compared to usual care without PEWS? Methods: We conducted a comprehensive search using Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature and Web of Science. We included studies published between January 2006 and April 2022 on children <18 years old performed in inpatient units and emergency departments, and compared patient populations with PEWS to those without PEWS. We excluded studies without a comparator, case control studies, systematic reviews, and studies published in non-English languages. We employed a random effects meta-analysis and synthesised the risk and rate ratios from individual studies. We used the Scottish Intercollegiate Guidelines Network (SIGN) to appraise the risk of bias. Results: Among 911 articles screened, 15 were included for descriptive analysis. Fourteen of the 15 studies were pre- versus post-implementation studies and one was a multi-centre cluster randomised controlled trial (RCT). Among 10 studies (580,604 hospital admissions) analysed for mortality, we found an increased risk (pooled RR 1.18, 95% CI 1.01-1.38, p = 0.036) in the group without PEWS compared to the group with PEWS. The sensitivity analysis performed without the RCT (436,065 hospital admissions) showed a non-significant relationship (pooled RR 1.17, 95% CI 0.98-1.40, p = 0.087). Among four studies (168,544 hospital admissions) analysed for unplanned code events, there was an increased risk in the group without PEWS (pooled RR 1.73, 95%CI 1.01-2.96, p = 0.046) There were no differences in the rate of cardiopulmonary arrests or critical deterioration events between groups. Our findings were limited by potential confounders and imprecision among included studies. Conclusions: Healthcare systems that implemented PEWS were associated with reduced mortality and code rates. We recognise that these gains vary depending on resource availability and efferent response systems.PROSPERO registration: CRD42021269579.

Redesigning therapies for pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an incurable rare genetic disorder of children and young adults caused by mutations in the PANK2 gene, which encodes an enzyme critical for the biosynthesis of coenzyme A. Although PKAN affects only a small number of patients, it shares several hallmarks of more common neurodegenerative diseases of older adults such as Alzheimer's disease and Parkinson's disease. Advances in etiological understanding and treatment of PKAN could therefore have implications for our understanding of more common diseases and may shed new lights on the physiological importance of coenzyme A, a cofactor critical for the operation of various cellular metabolic processes. The large body of knowledge that accumulated over the years around PKAN pathology, including but not limited to studies of various PKAN models and therapies, has contributed not only to progress in our understanding of the disease but also, importantly, to the crystallization of key questions that guide future investigations of the disease. In this review, we will summarize this knowledge and demonstrate how it forms the backdrop to new avenues of research.

Associations of initial haemodynamic profiles and neurological outcomes in children with traumatic brain injury: a secondary analysis.

INTRODUCTION: Initial low systolic blood pressure (SBP) in paediatric traumatic brain injury (TBI) is associated with mortality. There is limited literature on how other haemodynamic parameters including heart rate (HR); diastolic blood pressure (DBP); mean arterial pressure (MAP); and shock index, paediatric age-adjusted (SIPA) affect not only mortality but also long-term neurological outcomes in paediatric TBI. We aimed to analyse the associations of these haemodynamic variables (HR, SBP, MAP, DBP and SIPA) with mortality and long-term neurological outcomes in isolated moderate-to-severe paediatric TBI. METHODS: This was a secondary analysis of our primary study that analysed the association of TBI-associated coagulopathy with mortality and neurological outcome in isolated, moderate-to-severe paediatric head injury. A trauma registry-based, retrospective study of children <18 years old who presented to the emergency department with isolated, moderate-to-severe TBI from January 2010 to December 2016 was conducted. The association between initial haemodynamic variables and less favourable outcomes using Glasgow Outcome Scale-Extended Paediatric) at 6 months post injury was analysed using logistic regression. RESULTS: Among 152 children analysed, initial systolic and diastolic hypotension (<5th percentile) (OR) for SBP 11.40, 95% CI 3.60 to 36.05, p<0.001; OR for DBP 15.75, 95% CI 3.09 to 80.21, p<0.001) and Glasgow Coma Scale scores <8 (OR 14.50, 95% CI 3.65 to 57.55, p<0.001) were associated with 'moderate-to-severe neurological disabilities', 'vegetative state' and 'death'. After adjusting for confounders, only SBP was significant (adjusted OR 5.68, 95% CI 1.40 to 23.08, p=0.015). CONCLUSIONS: Initial systolic hypotension was independently associated with mortality and moderate-to-severe neurological deficits at 6 months post injury. Further work is required to understand if early correction of hypotension will improve long-term outcomes.

Early posttraumatic seizures in pediatric traumatic brain injury: a multicenter analysis.

OBJECTIVE: Early posttraumatic seizures (EPTSs) in children after traumatic brain injury (TBI) increase metabolic stress on the injured brain. The authors sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes among children with moderate to severe TBI in Asia. METHODS: A secondary analysis of a retrospective TBI cohort among participating centers of the Pediatric Acute & Critical Care Medicine Asian Network was performed. Children < 16 years of age with a Glasgow Coma Scale (GCS) score ≤ 13 who were admitted to pediatric intensive care units between January 2014 and October 2017 were included. Logistic regression analysis was performed to study risk factors for EPTS and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes. Poor functional outcomes were defined as moderate disability, severe disability, and coma as defined by the Pediatric Cerebral Performance Category scale. RESULTS: Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8-8.9 years); 162 children (51.8%) had severe TBI (GCS score < 8), and 76 children (24.3%) had EPTS. After adjusting for age, sex, and the presence of nonaccidental trauma (NAT), only younger age was significantly associated with EPTS (adjusted odds ratio [aOR] 0.85, 95% CI 0.78-0.92; p < 0.001). Forty-nine children (15.6%) in the cohort died, and 87 (32.9%) of the 264 surviving patients had poor functional outcomes. EPTS did not increase the risk of death. After adjusting for age, sex, TBI due to NAT, multiple traumas, and a GCS score < 8, the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05-4.10; p = 0.036). CONCLUSIONS: EPTSs were common among children with moderate to severe TBI in Asia and were associated with poor functional outcomes among children who survived TBI.

White matter extension of the Melbourne Children's Regional Infant Brain atlas: M-CRIB-WM.

Brain atlases providing standardised identification of neonatal brain regions are key in investigating neurological disorders of early childhood. Our previously developed Melbourne Children's Regional Infant Brain (M-CRIB) and M-CRIB 2.0 neonatal brain atlases provide standardised parcellation of 100 brain regions including cortical, subcortical, and cerebellar regions. The aim of this study was to extend M-CRIB atlas coverage to include 54 white matter (WM) regions. Participants were 10 healthy term-born neonates that were used to create the initial M-CRIB atlas. WM regions were manually segmented based on T2 images and co-registered diffusion tensor imaging-based, direction-encoded colour maps. Our labelled regions imitate the Johns Hopkins University neonatal atlas, with minor anatomical modifications. All segmentations were reviewed and approved by a paediatric radiologist and a neurosurgery research fellow for anatomical accuracy. The resulting neonatal WM atlas comprises 54 WM regions: 24 paired regions, and six unpaired regions comprising five corpus callosum subdivisions, and one pontine crossing tract. Detailed protocols for manual WM parcellations are provided, and the M-CRIB-WM atlas is presented together with the existing M-CRIB cortical, subcortical, and cerebellar parcellations in 10 individual neonatal MRI data sets. The novel M-CRIB-WM atlas, along with the M-CRIB cortical and subcortical atlases, provide neonatal whole brain MRI coverage in the first multi-subject manually parcellated neonatal atlas compatible with atlases commonly used at older time points. The M-CRIB-WM atlas is publicly available, providing a valuable tool that will help facilitate neuroimaging research into neonatal brain development in both healthy and diseased states.

Analysis of emergency department prediction tools in evaluating febrile young infants at risk for serious infections.

OBJECTIVE: Febrile infants≤3 months old constitute a vulnerable group at risk of serious infections (SI). We aimed to (1) study the test performance of two clinical assessment tools-the National Institute for Health and Care Excellence (NICE) Traffic Light System and Severity Index Score (SIS) in predicting SI among all febrile young infants and (2) evaluate the performance of three low-risk criteria-the Rochester Criteria (RC), Philadelphia Criteria (PC) and Boston Criteria (BC) among well-looking febrile infants. METHODS: A retrospective validation study was conducted. Serious illness included both bacterial and serious viral illness such as meningitis and encephalitis. We included febrile infants≤3 months old presenting to a paediatric emergency department in Singapore between March 2015 and February 2016. Infants were assigned to high-risk and low-risk groups for SI according to each of the five tools. We compared the performance of the NICE guideline and SIS at initial clinical assessment for all infants and the low-risk criteria-RC, PC and BC-among well-looking infants. We presented their performance using sensitivity, specificity, positive, negative predictive values and likelihood ratios. RESULTS: Of 1057 infants analysed, 326 (30.8%) were diagnosed with SI. The NICE guideline had an overall sensitivity of 93.3% (95% CI 90.0 to 95.7), while the SIS had a sensitivity of 79.1% (95% CI 74.3 to 83.4). The incidence of SI was similar among infants who were well-looking and those who were not. Among the low-risk criteria, the RC performed with the highest sensitivity in infants aged 0-28 days (98.2%, 95% CI 90.3% to 100.0%) and 29-60 days (92.4%, 95% CI 86.0% to 96.5%), while the PC performed best in infants aged 61-90 days (100.0%, 95% CI 95.4% to 100.0%). CONCLUSIONS: The NICE guideline achieved high sensitivity in our study population, and the RC had the highest sensitivity in predicting for SI among well-appearing febrile infants. Prospective validation is required.

Hip fractures in young adults: a retrospective cross-sectional study of characteristics, injury mechanism, risk factors, complications and follow-up.

This study characterises risk factors, complications and follow-up of minimal trauma hip fractures in young adults, adding to limited information examining the management framework. This group have severe systemic disease and significant risk of post-operative complications and subsequent fractures. Improved medical referral pathways enable management of osteoporosis and comorbid diseases. AIMS: There is a paucity of literature examining minimal trauma hip fractures in young adults, despite extensive management guidelines for older patients. This study aims to characterise risk factors, complications and follow-up of hip fractures to guide management pathways. METHODS: This is a retrospective study of patients presenting with hip fracture to a single institution from 2009 to 2015. Hip fractures were identified using ICD-10 codes and clinical information documented from medical records. Patients were categorised into minimal trauma (MTF) and high-energy fracture (HEF) groups based on mechanism of injury. RESULTS: Of 2512 patients admitted with hip fracture, 2.5% (n = 62) were aged 15-49 years. Two patients were excluded with pathological fractures, and seven were excluded with no recorded mechanism of injury. MTF occurred in 43 patients and 10 sustained HEF. These groups had similar demographics, fracture locations and treatments. The MTF group had higher American Society of Anaesthesiologists scores (MTF 2.44 ± 0.9; HEF 1.43 ± 0.5; p = 0.025) and higher rates of chronic endocrine disease (MTF 34.9%; HEF 0%; p = 0.046). Rates of post-operative surgical (MTF 24.0%; HEF 12.5%) and medical complications (MTF 27.8%; HEF 12.5%) were high in MTF patients. Subsequent fractures occurred in five (13.9%) MTF patients during the study period compared with none in the HEF group. Only 16 (44.4%) of the MTF patients were referred to endocrine care. CONCLUSION: Young adults with MTF of the hip have more severe systemic disease and are at risk of post-operative complications and subsequent fractures. Referral of patients to endocrine care is recommended to manage osteoporosis and comorbid diseases.