Appraisal of Australian and New Zealand paediatric sepsis guidelines.

OBJECTIVE: Clinical practice guidelines (CPGs) are an important tool for the management of children with sepsis. The quality, consistency and concordance of Australian and New Zealand (ANZ) childhood sepsis CPGs with the Australian Commission on Safety and Quality in Healthcare (ACSQHC) sepsis clinical care standards and international sepsis guidelines is unclear. METHODS: We accessed childhood sepsis CPGs for all ANZ states and territories through Paediatric Research in Emergency Departments International Collaborative members. The guidelines were assessed for quality using the AGREE-II instrument. Consistency between CPG treatment recommendations was assessed, as was concordance with the ACSQHC sepsis clinical care standards and international sepsis guidelines. RESULTS: Overall, eight CPGs were identified and assessed. CPGs used a narrative and pathway format, with those using both having the highest quality overall. CPG quality was highest for description of scope and clarity of presentation, and lowest for editorial independence. Consistency between guidelines for initial treatment recommendations was poor, with substantial variation in the choice and urgency of empiric antimicrobial administration; the choice, volume and urgency of fluid resuscitation; and the choice of first-line vasoactive agent. Most CPGs were concordant with time-critical components of the ACSQHC sepsis clinical care standard, although few addressed post-acute care. Concordance with international sepsis guidelines was poor. CONCLUSION: Childhood sepsis CPGs in current use in ANZ are of variable quality and lack consistency with key treatment recommendations. CPGs are concordant with the ACSQHC care standard, but not with international sepsis guidelines. A bi-national sepsis CPG may reduce unnecessary variation in care.

Sepsis epidemiology in Australian and New Zealand children (SENTINEL): protocol for a multicountry prospective observational study.

INTRODUCTION: Sepsis affects 25.2 million children per year globally and causes 3.4 million deaths, with an annual cost of hospitalisation in the USA of US$7.3 billion. Despite being common, severe and expensive, therapies and outcomes from sepsis have not substantially changed in decades. Variable case definitions, lack of a reference standard for diagnosis and broad spectrum of disease hamper efforts to evaluate therapies that may improve sepsis outcomes. This landscape analysis of community-acquired childhood sepsis in Australia and New Zealand will characterise the burden of disease, including incidence, severity, outcomes and cost. Sepsis diagnostic criteria and risk stratification tools will be prospectively evaluated. Sepsis therapies, quality of care, parental awareness and understanding of sepsis and parent-reported outcome measures will be described. Understanding these aspects of sepsis care is fundamental for the design and conduct of interventional trials to improve childhood sepsis outcomes. METHODS AND ANALYSIS: This prospective observational study will include children up to 18 years of age presenting to 12 emergency departments with suspected sepsis within the Paediatric Research in Emergency Departments International Collaborative network in Australia and New Zealand. Presenting characteristics, management and outcomes will be collected. These will include vital signs, serum biomarkers, clinician assessment of severity of disease, intravenous fluid administration for the first 24 hours of hospitalisation, organ support therapies delivered, antimicrobial use, microbiological diagnoses, hospital and intensive care unit length-of-stay, mortality censored at hospital discharge or 30 days from enrolment (whichever comes first) and parent-reported outcomes 90 days from enrolment. We will use these data to determine sepsis epidemiology based on existing and novel diagnostic criteria. We will also validate existing and novel sepsis risk stratification criteria, characterise antimicrobial stewardship, guideline adherence, cost and report parental awareness and understanding of sepsis and parent-reported outcome measures. ETHICS AND DISSEMINATION: Ethics approval was received from the Royal Children's Hospital of Melbourne, Australia Human Research Ethics Committee (HREC/69948/RCHM-2021). This included incorporated informed consent for follow-up. The findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: ACTRN12621000920897; Pre-results.

The characteristics of SARS-CoV-2-positive children in Australian hospitals: a PREDICT network study.

OBJECTIVES: To examine the clinical characteristics and short term outcomes for children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who presented to Australian hospitals during 2020 and 2021. DESIGN, SETTING: Retrospective case review study in nineteen hospitals of the Paediatric Research in Emergency Departments International Collaborative (PREDICT) network from all Australian states and territories, including seven major paediatric tertiary centres and eight Victorian hospitals. PARTICIPANTS: SARS-CoV-2-positive people under 18 years of age who attended emergency departments or were admitted to hospital during 1 February 2020 - 31 December 2021. MAIN OUTCOME MEASURES: Epidemiological and clinical characteristics, by hospital care type (emergency department [ED] or inpatient care). RESULTS: A total of 1193 SARS-CoV-2-positive children and adolescents (527 girls, 44%) attended the participating hospitals (107 in 2020, 1086 in 2021). Their median age was 3.8 years (interquartile range [IQR], 0.8-11.4 years); 63 were Aboriginal or Torres Strait Islander people (5%). Other medical conditions were recorded for 293 children (25%), including asthma (86, 7%) and premature birth (68, 6%). Medical interventions were not required during 795 of 1181 ED presentations (67%); children were discharged directly home in 764 cases (65%) and admitted to hospital in 282 (24%; sixteen to intensive care units). The 384 admissions to hospital (including 102 direct admissions) of 341 children (25 infants under one month of age) included 23 to intensive care (6%); the median length of stay was three days (IQR, 1-9 days). Medical interventions were not required during 261 admissions (68%); 44 children received respiratory support (11%) and 21 COVID-19-specific treatments, including antiviral and biologic agents (5%). Being under three months of age (v one year to less than six years: odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.0) and pre-existing medical conditions (OR, 2.5; 95% CI, 1.9-3.2) were the major predictors of hospital admission. Two children died, including one without a known pre-existing medical condition. CONCLUSION: During 2020 and 2021, most SARS-CoV-2-positive children and adolescents who presented to participating hospitals could be managed as outpatients. Outcomes were generally good, including for those admitted to hospital.

Sustainability of evidence-based practices in the management of infants with bronchiolitis in hospital settings - a PREDICT study protocol.

BACKGROUND: Understanding how and why de-implementation of low-value practices is sustained remains unclear. The Paediatric Research in Emergency Departments International CollaboraTive (PREDICT) Bronchiolitis Knowledge Translation (KT) Study was a cluster randomised controlled trial conducted in 26 Australian and New Zealand hospitals (May-November 2017). Results showed targeted, theory-informed interventions (clinical leads, stakeholder meetings, train-the-trainer workshop, targeted educational package, audit/feedback) were effective at reducing use of five low-value practices for bronchiolitis (salbutamol, glucocorticoids, antibiotics, adrenaline and chest x-ray) by 14.1% in acute care settings. The primary aim of this study is to determine the sustainability (continued receipt of benefits) of these outcomes at intervention hospitals two-years after the removal of study supports. Secondary aims are to determine sustainability at one-year after removal of study support at intervention hospitals; improvements one-and-two years at control hospitals; and explore factors that influence sustainability at intervention hospitals and contribute to improvements at control hospitals. METHODS: A mixed-methods study design. The quantitative component is a retrospective medical record audit of bronchiolitis management within 24 hours of emergency department (ED) presentations at 26 Australian (n = 20) and New Zealand (n = 6) hospitals, which participated in the PREDICT Bronchiolitis KT Study. Data for a total of 1800 infants from intervention and control sites (up to 150 per site) will be collected to determine if improvements (i.e., no use of all five low-value practices) were sustained two- years (2019) post-trial (primary outcome; composite score); and a further 1800 infants from intervention and control sites will be collected to determine sustained improvements one- year (2018) post-trial (secondary outcome). An a priori definition of sustainability will be used. The qualitative component will consist of semi-structured interviews with three to five key emergency department and paediatric inpatient medical and nursing staff per site (total n = 78-130). Factors that may have contributed to sustaining outcomes and/or interventions will be explored and mapped to an established sustainability framework. DISCUSSION: This study will improve our understanding of the sustainability of evidence-based bronchiolitis management in infants. Results will also advance implementation science research by informing future de-implementation strategies to reduce low-value practices and sustain practice change in paediatric acute care. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry No: ACTRN12621001287820.

Treatment patterns and frequency of key outcomes in acute severe asthma in children: a Paediatric Research in Emergency Departments International Collaborative (PREDICT) multicentre cohort study.

RATIONALE: Severe acute paediatric asthma may require treatment escalation beyond systemic corticosteroids, inhaled bronchodilators and low-flow oxygen. Current large asthma datasets report parenteral therapy only. OBJECTIVES: To identify the use and type of escalation of treatment in children presenting to hospital with acute severe asthma. METHODS: Retrospective cohort study of children with an emergency department diagnosis of asthma or wheeze at 18 Australian and New Zealand hospitals. The main outcomes were use and type of escalation treatment (defined as any of intensive care unit admission, nebulised magnesium, respiratory support or parenteral bronchodilator treatment) and hospital length of stay (LOS). MEASUREMENTS AND MAIN RESULTS: Of 14 029 children (median age 3 (IQR 1-3) years; 62.9% male), 1020 (7.3%, 95% CI 6.9% to 7.7%) had treatment escalation. Children with treatment escalation had a longer LOS (44.2 hours, IQR 27.3-63.2 hours) than children without escalation 6.7 hours, IQR 3.5-16.3 hours; p<0.001). The most common treatment escalations were respiratory support alone (400; 2.9%, 95% CI 2.6% to 3.1%), parenteral bronchodilator treatment alone (380; 2.7%, 95% CI 2.5% to 3.0%) and both respiratory support and parenteral bronchodilator treatment (209; 1.5%, 95% CI 1.3% to 1.7%). Respiratory support was predominantly nasal high-flow therapy (99.0%). The most common intravenous medication regimens were: magnesium alone (50.4%), magnesium and aminophylline (24.6%) and magnesium and salbutamol (10.0%). CONCLUSIONS: Overall, 7.3% children with acute severe asthma received some form of escalated treatment, with 4.2% receiving parenteral bronchodilators and 4.3% respiratory support. There is wide variation treatment escalation.

Australian and New Zealand Guideline for Mild to Moderate Head Injuries in Children.

OBJECTIVE: Children frequently present with head injuries to acute care settings. Although international paediatric clinical practice guidelines for head injuries exist, they do not address all considerations related to triage, imaging, observation versus admission, transfer, discharge and follow-up of mild to moderate head injuries relevant to the Australian and New Zealand context. The Paediatric Research in Emergency Departments International Collaborative (PREDICT) set out to develop an evidence-based, locally applicable, practical clinical guideline for the care of children with mild to moderate head injuries presenting to acute care settings. METHODS: A multidisciplinary Guideline Working Group (GWG) developed 33 questions in three key areas - triage, imaging and discharge of children with mild to moderate head injuries presenting to acute care settings. We identified existing high-quality guidelines and from these guidelines recommendations were mapped to clinical questions. Updated literature searches were undertaken, and key new evidence identified. Recommendations were created through either adoption, adaptation or development of de novo recommendations. The guideline was revised after a period of public consultation. RESULTS: The GWG developed 71 recommendations (evidence-informed = 35, consensus-based = 17, practice points = 19), relevant to the Australian and New Zealand setting. The guideline is presented as three documents: (i) a detailed Full Guideline summarising the evidence underlying each recommendation; (ii) a Guideline Summary; and (iii) a clinical Algorithm: Imaging and Observation Decision-making for Children with Head Injuries. CONCLUSIONS: The PREDICT Australian and New Zealand Guideline for Mild to Moderate Head Injuries in Children provides high-level evidence and practical guidance for front line clinicians.

Highly Enantioselective Extraction of Phenylglycine by a Chiral Macrocyclic Receptor Based on Supramolecular Interactions.

Using supramolecular interactions, a novel macrocyclic receptor is able to selectively extract zwitterionic phenylglycine from neutral aqueous solutions into chloroform with up to 91.8% ee. Modeling studies, nuclear magnetic resonance experiments, and X-ray diffraction analysis were carried out to explain the high enantioselectivity observed.

Investigating spillover of multidrug-resistant tuberculosis from a prison: a spatial and molecular epidemiological analysis.

BACKGROUND: Congregate settings may serve as institutional amplifiers of tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB). We analyze spatial, epidemiological, and pathogen genetic data prospectively collected from neighborhoods surrounding a prison in Lima, Peru, where inmates experience a high risk of MDR-TB, to investigate the risk of spillover into the surrounding community. METHODS: Using hierarchical Bayesian statistical modeling, we address three questions regarding the MDR-TB risk: (i) Does the excess risk observed among prisoners also extend outside the prison? (ii) If so, what is the magnitude, shape, and spatial range of this spillover effect? (iii) Is there evidence of additional transmission across the region? RESULTS: The region of spillover risk extends for 5.47 km outside of the prison (95% credible interval: 1.38, 9.63 km). Within this spillover region, we find that nine of the 467 non-inmate patients (35 with MDR-TB) have MDR-TB strains that are genetic matches to strains collected from current inmates with MDR-TB, compared to seven out of 1080 patients (89 with MDR-TB) outside the spillover region (p values: 0.022 and 0.008). We also identify eight spatially aggregated genetic clusters of MDR-TB, four within the spillover region, consistent with local transmission among individuals living close to the prison. CONCLUSIONS: We demonstrate a clear prison spillover effect in this population, which suggests that interventions in the prison may have benefits that extend to the surrounding community.

Patterns of paediatric emergency presentations to a tertiary referral centre in the Northern Territory.

OBJECTIVE: To describe epidemiological data concerning paediatric attendances at the ED of Royal Darwin Hospital (RDH). METHODS: We conducted a retrospective cohort study of paediatric emergency presentations to the RDH ED during 2004 and 2013. Epidemiological data, including demographics, admission rates and diagnostic grouping, were analysed using descriptive and comparative statistical methods. We compared data with findings from a baseline epidemiological study by the Paediatric Research in Emergency Departments International Collaborative (PREDICT) conducted in 2004. RESULTS: A total of 12 745 and 15 378 paediatric presentations (age 0-18 years) to the RDH ED were analysed for the years 2004 and 2013 respectively. In 2004, the mean age of children presenting to RDH was 7.1 years, and 56.0% were female. Indigenous patients accounted for 31.2% of presentations at RDH and were significantly more likely to be admitted than non-Indigenous patients (31.6% vs 12.8%, OR 3.24, 95% CI 2.95-3.55). Children <5 years old accounted for the highest number of presentations (45.2%) and admissions (51.2%), and there was a high proportion of adolescent presentations (18.0%). Similar to the PREDICT study, viral infectious conditions (bronchiolitis, gastroenteritis, upper respiratory tract infections) were the most common cause for presentations. Key differences included a higher proportion of patients presenting with cellulitis and head injury at RDH and an increasing proportion of adolescent psychiatric presentations at RDH from 2004 to 2013. CONCLUSION: This study provides important information regarding paediatric presentations to a major referral hospital in the Northern Territory. Overall, there was a disproportionate rate of presentation and admission among Indigenous children. Other key findings were higher proportions of cellulitis, head injury and adolescent presentations. These findings can assist in service planning and in directing future research specific to children in the Northern Territory.

The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru.

BACKGROUND: The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis. METHODS: To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census. RESULTS: The Latin American Mediterranean (LAM) clade (OR 2.4, p<0.001) was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively). CONCLUSIONS: Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs.

Synthesis and bioactivity of Luffarin I.

The first synthesis of Luffarin I, sesterterpenolide isolated from sponge Luffariella geometrica, has been accomplished from commercially available sclareol. The key strategy involved in this synthesis is the diastereoselective reduction of an intermediate ketone. Luffarin I against human solid tumor cell lines showed antiproliferative activities (GI50) in the range 12-17 µM.

Severe group A streptococcal infections in a paediatric intensive care unit.

AIM: To describe the clinical presentation, management and outcomes for children with invasive group A streptococcal (GAS) infection in a paediatric intensive care unit (PICU). METHODS: We reviewed the clinical and laboratory records of patients admitted to a PICU in Melbourne with invasive GAS infection from April 2010 to April 2013. Outcomes recorded included survival, organ failure, need for extracorporeal support, renal replacement therapy and prolonged neuromuscular weakness. RESULTS: Twelve cases of invasive GAS infection were identified. The most common clinical presentations were pneumonia (n=5), bacteraemia with no septic focus (n=4) and septic arthritis (n=3). Necrotising fasciitis occurred in one patient and another patient presented with ischaemic lower limbs requiring amputation. Of the eight isolates with available emm typing results, the most common emm type was emm1 (n=4) followed by emm4, 12 and 22. Nine patients had multi-organ failure. Ten patients required mechanical ventilation for a median duration of 8 days. Nine patients required inotropic and/or vasopressor support and four patients extracorporeal membrane oxygenation support. Eleven patients survived. A prolonged period of neuromuscular weakness following the initial severe illness was common (n=5), but most children returned to normal or near normal neurological function. CONCLUSIONS: Invasive GAS disease in children may cause severe multi-organ failure with resultant prolonged intensive care stay and significant morbidity. However, a high rate of survival and return to normal functioning may be achieved with multi-system intensive care support and multi-disciplinary rehabilitation.

Outbreak of nosocomial sepsis in the Special Care Nursery at Port Moresby General Hospital due to multiresistant Klebsiella pneumoniae: high impact on mortality.

We report an outbreak of nosocomial infection caused by Klebsiella pneumoniae in the Special Care Nursery of Port Moresby General Hospital. In the 13 months between October 2007 and October 2008, this organism was cultured from the blood of 57 neonates, of whom 23 died. 16 of the 20 organisms cultured in the first 3 months were cephalosporin sensitive, but during the next 10 months the proportion of sensitive organisms dropped dramatically to 10 of 37. Of the 31 multidrug-resistant organisms 6 were resistant to all the routinely available drugs. Response to the outbreak is discussed. The report highlights the urgent need for the implementation of improved infection control practices and the promotion of rational antibiotic policies.