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Current diagnostics do not permit reliable differentiation of bacterial from viral causes of lower respiratory tract infection (LRTI), which may lead to over-treatment with antibiotics for possible bacterial community-acquired pneumonia (CAP).We sought to describe variation in the diagnosis and treatment of bacterial CAP among children hospitalized with LRTIs and determine the association between CAP diagnosis and outcomes.This multicenter cross-sectional study included children hospitalized between 2017 and 2019 with LRTIs at 42 children's hospitals.We calculated the proportion of children with LRTIs who were diagnosed with and treated for bacterial CAP. After adjusting for confounders, hospitals were grouped into high, moderate, and low CAP diagnosis groups. Multivariable regression was used to examine the association between high and low CAP diagnosis groups and outcomes.We identified 66,581 patients hospitalized with LRTIs and observed substantial variation across hospitals in the proportion diagnosed with and treated for bacterial CAP (median 27%, range 12%-42%). Compared with low CAP diagnosing hospitals, high diagnosing hospitals had higher rates of CAP-related revisits (0.6% [95% confidence interval: 0.5, 0.7] vs. 0.4% [0.4, 0.5], p = .04), chest radiographs (58% [53, 62] vs. 46% [41, 51], p = .02), and blood tests (43% [33, 53] vs. 26% [19, 35], p = .046). There were no significant differences in length of stay, all-cause revisits or readmissions, CAP-related readmissions, or costs.There was wide variation across hospitals in the proportion of children with LRTIs who were treated for bacterial CAP. The lack of meaningful differences in clinical outcomes among hospitals suggests that some institutions may over-diagnose and overtreat bacterial CAP.

Background Paediatric traumatic brain injury (TBI) is recognised to have significant longer-term neurocognitive effects. Childhood is a time of high risk for head injury. Functional recovery is variable with a combination of any or all of physical, cognitive and emotional impairment. Immune activation and alteration in cytokine levels are present following TBI which may differ from adults. Methods Pro- and anti-inflammatory cytokines including Interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-17A, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were examined at baseline and following in vitro treatment with endotoxin of whole blood, in the following children: severe TBI (sTBI: initial Glasgow coma scale(GCS) ≤ 8), mild TBI (mTBI; GCS 14/15) at 0-4d and at 10-14d post-TBI and compared to healthy age-matched controls. Results The study enrolled 208 children, including 110 with TBI cohort (n = 104 mild; 6 severe) and controls (n = 98). At baseline all children with TBI had increased IL-6. The mTBI group had significantly increased IFN-γ versus controls. In sTBI at baseline, IFN-γ was decreased compared to controls. At baseline IL-8, IL-10, IL-17A, and TNF-α were decreased in mTBI compared to controls. This persisted at 2 week post-mTBI. The AUC for detecting mTBI was 0.801 CI (0.73–086) using IL6/IL10 ratio. mTBI showed a greater fold change in IL-8 and TNF-α in response to endotoxin stimulation, a response that persisted at 2 weeks. Children with sTBI did not have a significant IL-6 response to endotoxin, but did show an increase in IL-17A. Conclusion Children with all TBI including mTBI show altered cytokine profiles and altered endotoxin responses. Although cytokines increased in sTBI especially in response to endotoxin, suppressed responses were found in mTBI coupled with persistent immune dysfunction post-injury.

Magnetic resonance imaging (MRI) scoring systems are used in the neonatal period to predict outcome in infants with neonatal encephalopathy. Our aim was to assess the relationship between three MRI scores and neurodevelopmental outcome assessed using Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), at two years in infants with neonatal encephalopathy.Term-born neonates with evidence of perinatal asphyxia born between 2011 and 2015 were retrospectively reviewed. MRI scanning was performed within the first two weeks of life and scored using Barkovich, National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and Weeke systems by a single assessor blinded to the infants clinical course. Neurodevelopmental outcome was assessed using composite scores on the Bayley-III at two years. Multiple linear regression analyses were used to assess the association between MRI scores and Bayley-III composite scores, with postmenstrual age at scan and sex included as covariates.Of the 135 recruited infants, 90 infants underwent MRI, and of these, 66 returned for follow-up. MRI abnormalities were detected with the highest frequency using the Weeke score (Barkovich 40%, NICHD NRN 50%, Weeke 77%). The inter-rater agreement was good for the Barkovich score and excellent for NICHD NRN and Weeke scores. There was a significant association between Barkovich, NICHD NRN, and Weeke scores and Bayley-III cognitive and motor scores. Only the Weeke score was associated with Bayley-III language scores.Our findings confirm the predictive value of existing MRI scoring systems for cognitive and motor outcome and suggest that more detailed scoring systems have predictive value for language outcome.

Background To investigate mechanisms of injury and recovery in neonatal encephalopathy (NE), we performed targeted metabolomic analysis of plasma using liquid chromatography with tandem mass spectrometry (LC/MS/MS) from healthy term neonates or neonates with NE. Methods Plasma samples from the NE (n = 45, day of life 0-1) or healthy neonatal (n = 30, ≥36 weeks gestation) cohorts had LC/MS/MS metabolomic profiling with a 193-plex targeted metabolite assay covering >366 metabolic pathways. Metabolite levels were compared to 2-year neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development III (Bayley-III). Results Out of 193 metabolites, 57 met the pre-defined quality control criteria for analysis. Significant (after false discovery rate correction) KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways included aminoacyl-tRNA biosynthesis, arginine biosynthesis, and metabolism of multiple amino acids. Significant disease pathways included seizures. In regression models, histidine and C6 sugar amine were significantly associated with cognitive, motor, and language and betaine with cognitive and motor Bayley-III composite scores. The addition of histidine, C6 sugar amine, and betaine to a Sarnat score-based clinical regression model significantly improved model performance (Akaike information criterion and adjusted r2) for Bayley-III cognitive, motor, and language scores. Conclusions Plasma metabolites may help to predict neurological outcomes in neonatal brain injury and enhance current clinical predictors. Impact Plasma metabolites may help to predict neurological outcomes in NE and supplement current clinical predictors. Current metabolomics research is limited in terms of clinical application and association with long-term outcomes. Our study presents novel associations of plasma metabolites from the first 24 h of life and 2-year neurodevelopmental outcomes for infants with NE. Our metabolomics discovery provides insight into possible disease mechanisms and methods to rescue and/or supplement metabolic pathways involved in NE. Our metabolomics discovery of metabolic pathway supplementations and/or rescue mechanisms may serve as adjunctive therapies for NE.

Background Cardiotocography (CTG) is a screening test used to detect fetal hypoxia in labour. It has a high false positive rate resulting in many potentially unnecessary caesarean sections. Fetal blood sampling (FBS) is a second-line test of the acid-base status of the fetus. It is used to provide either reassurance that it is safe for labour to continue or objective evidence of compromise so that delivery can be expedited. Digital fetal scalp stimulation (dFSS) to elicit a fetal heart rate acceleration is an alternative less invasive second-line test of fetal wellbeing. This study aims to provide robust evidence on the role of these two second-line tests in assessing fetal wellbeing and potentially preventing operative delivery. Methods A multi-centre parallel group randomised controlled trial (RCT) is planned in four maternity centres in Ireland. The study aims to recruit 2500 nulliparous women with a term (≥37+0 weeks) singleton pregnancy who require a second-line test of fetal wellbeing in labour due to an abnormal CTG. Women will be allocated randomly to dFSS or FBS on a 1:1 ratio. The primary outcome is caesarean section. With 1250 women in each arm, the study will have 90% power to detect a difference of 5–6%, at a two-sided alpha significance level of 5%, assuming a caesarean section rate of at least 20% in the dFSS group. Discussion If the proposed study shows evidence that dFSS is a safe, reliable and effective alternative to FBS, this would have ground-breaking implications for labour management worldwide. It could potentially lead to a reduction in invasive procedures and emergency caesarean sections. Trial registration ClinicalTrials.gov NCT05306756. Registered on 31 March 2022. The trial commenced enrolment on 10 May 2022. Ethical committee approval has been granted by the Research Ethics Committee (REC) of each hospital: Dublin/CWIUH REC: 12.06.2019; Cork/UCC REC: 29.11.2019; Galway/NUIG REC: 06.09.2019; Limerick/UL REC: 30.09.2019.

AIM Neonatal encephalopathy (NE) is associated with an increased risk of multi-organ injury. The lack of standardised definitions for multi-organ dysfunction in NE hinders accurate quantification of these complications. METHODS A simple multi-organ dysfunction in neonatal encephalopathy scoring (MODE) system was created to include the cardiovascular, respiratory, gastrointestinal, haematological and neurological systems with a maximum score of 15. The MODE score was then compared with the grade of NE, Bayley Scales of Infant Development (Bayley-III) at 2 years of age and mortality. The Bayley score was used as it gave an objective score making it easier to compare the MODE score. Bayley score of

BACKGROUND Nurses are often the first responders to resuscitations. Understanding their experiences of resuscitation will highlight the resuscitative context nurses work within and identify the conditions that support or hamper their delivery of safe and effective resuscitative care. AIM The aim of this integrative review is to develop an understanding of nurses' experience of resuscitation, to gain knowledge of their challenges and identify gaps in evidence. DESIGN Integrative review. METHODS The electronic databases CINAHL, MEDLINE, Scopus and Web of Science were systematically searched from 2000-2021. Methodological quality of the papers was evaluated using the Mixed Methods Appraisal Tool (MMAT). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist was used to guide and report the integrative review. RESULTS Eleven articles met criteria for review. Four themes arose from the literature that addressed nurses experiences of resuscitation: Chaos (external/internal), ethical dilemmas, clinical confidence and need for support. CONCLUSION Nurses' experiences of resuscitation are multifaceted. Addressing the challenges that nurses experience during resuscitation will help ensure that nurses' are supported in their professional growth and personal well-being. Relevance to clinical practice and research: Building nursing leadership capacity within resuscitations is an area of clinical practice/research that is gaining traction as a valid solution to address the challenges nurses experience during resuscitations. Whilst the barriers to debriefing requires a greater level of consideration within the workplace.

Background:We aimed to characterise the impact of Down syndrome on myocardial performance and loading conditions in infants with Down syndrome and CHD over the peri-operative period by comparing them with infants matched for cardiac lesion with a normal microarray.Methods:Left ventricular global longitudinal strain, right ventricular free wall longitudinal strain, left ventricular end-systolic wall stress, and right ventricular systolic pressure were measured in the two groups over the peri-operative period.Results:Fifty-five infants had a diagnosis of Down syndrome and these were compared with 29 control infants. Left ventricular global longitudinal strain decreased in both groups post-operatively with the Down syndrome group demonstrating some recovery pre-discharge (18 ± 3 versus 16 ± 3 %, p = 0.01). Right ventricular longitudinal strain significantly decreased in both groups post-operatively with the control group demonstrating better recovery by hospital discharge (14 ± 4 versus 18 ± 6 %, p < 0.01). End-systolic wall stress was lower and right ventricular systolic pressure was higher in the Down syndrome group throughout the study period (all p < 0.05). Down syndrome was an independent predictor of the duration of ventilation, post-operative use of inotropes, and intensive care stay. Right ventricular longitudinal strain was an independent predictor of duration of intensive care stay.Conclusion:This study demonstrates the difference between the two groups in relation to left and right ventricular function, particularly prior to discharge, and outlines the additional impact a diagnosis of Down syndrome has on myocardial performance during the peri-operative period.

BackgroundDown syndrome (DS) is a disorder characterised by marked immune dysfunction, increased mortality from sepsis, chronic inflammation, increased oxidative stress, sleep disturbance and possibly abnormal endogenous melatonin levels. Melatonin has a myriad of immune functions, and we hypothesised that this therapeutic agent could modulate the innate immune system in this cohort.MethodsWe investigated neutrophil and monocyte function (CD11b, TLR4 expression by flow cytometry), genes involved in TLR signalling (MyD88, IRAK4, TRIF), the inflammasome (NLRP3, IL-1β), and circadian rhythm (BMAL, CLOCK, CRY) by qPCR, and inflammatory cytokines (IL-2, IL-6, IL-8, IL-18, IL-1β, TNF-α, IFN-γ, IL-10, IL-1ra, VEGF, Epo, GM-CSF) by enzyme-linked immunosorbent assay (ELISA) following immunomodulation with LPS endotoxin and melatonin. 47 children with DS and 23 age- and sex-matched controls were recruited.ResultsWe demonstrated that melatonin has several significant effects by reducing CD11b and TLR4 expression, attenuating TLR signalling, genes involved in the inflammasome and has the potential to reduce LPS-induced inflammatory responses.ConclusionsImmunomodulatory effects of melatonin were found in both paediatric cohorts with more marked effects in the children with DS. Melatonin mediates immune response through a wide array of mechanisms and this immunomodulator may buffer the inflammatory response by regulating pro and anti-inflammatory signalling.ImpactWe highlight that melatonin mediates its immune response through a wide array of mechanisms, its effects appear to be dose dependant and children with Down syndrome may be more receptive to treatment with it.Immunomodulatory effects of melatonin were demonstrated with marked effects in the children with Down syndrome with a reduction of MyD88, IL-1ß and NLRP3 expression in whole-blood samples.Melatonin is a proposed anti-inflammatory agent with a well-established safety profile, that has the potential for mitigation of pro- and anti-inflammatory cytokines in paediatric Down syndrome cohorts, though further clinical trials are warranted.

The management of sagittal craniosynostosis has evolved over the decades as teams seek to refine their surgical approaches to idealize head shape with the least possible morbidity. Here, the authors identify the incidence of raised intracranial pressure (ICP) and its risk factors, requiring secondary surgical intervention after cranial vault remodeling (CVR) procedure at a single tertiary referral craniofacial unit. A retrospective case-control study was performed on the patients with isolated non-syndromic sagittal craniosynostosis. All patients who underwent CVR in our unit and had a minimum of 1.5 years follow-up were included. One hundred and eighty-four patients (134 male and 50 female) who underwent primary CVR surgery for isolated sagittal craniosynostosis were included. Thirteen patients (7.07%) had clinical evidence of late raised ICP resulting in repeat CVR procedures. Higher incidence of raised ICP in patients who had primary surgery before 6 months than after or at 6 months of age (P = 0.001). There were 23.5%, 5.6%, 3.2%, and 1.9% of secondary raised ICP patients who underwent the primary surgery between 1999-2004, 2005-2010, 2011-2015 and 2016-2018, respectively (P = 0.024). The risk of secondary raised ICP was higher in patients with isolated sagittal craniosynostosis whose primary surgery occurred before the age of 6 months (two times more likely). More extensive CVR can be performed safely in sagittal synostosis with promising outcomes. The late presentation with raised ICP reinforces the importance of long-term multidisciplinary protocol-based follow-up.

Abstract There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5–64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0–7.3 kPa: 45.0–54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. Impact There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5–7 kPa was inferred following systematic review.

AIM Neonatal encephalopathy (NE) is associated with altered cognitive, motor, sensory abilities and behavioural outcomes. This case-control study aimed to assess whether Quality of Life (QoL) and sleep disorders are affected in older children following NE compared to age-matched controls. METHODS Children at school-age post-NE were recruited and compared to age-matched controls. Sleep and QoL were assessed with the Pediatric Quality of Life Inventory and the Child Sleep Habit Questionnaire. RESULTS One hundred children were recruited with an age range of 4-6 years, including children post-NE (n=45) and age-matched controls (n = 55). Significantly higher pathological sleep scores were evident in 58% of children post-NE compared to controls (43.8 vs 40.2; p = 0.001). Children post-NE had increased bedtime resistance (p = 0.028) and sleep anxiety (p = 0.01) compared to controls. Children in the post-NE group had lower total QoL scores versus controls (mean score 82.5 vs 95.8; p

Summary Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)‐1β, IL‐1ra and IL‐18 are activated by the nucleotide‐binding and oligomerization domain (NOD)‐, leucine‐rich repeat domain (LRR)‐ and NOD‐like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme‐linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL‐1β and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4–7 years were analysed. An increase in serum IL‐1ra and IL‐18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL‐1ra in NE was decreased to normal levels at school age, whereas serum IL‐18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school‐age NE. NLRP3 and IL‐1β gene expression were up‐regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up‐regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention., Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Cytokine concentrations were measured by multiplex ELISA in neonates and children with NE in the absence or presence of LPS endotoxin. Increased inflammasome activation in the first day of life in NE persists in childhood

Objective To evaluate COVID-19 pandemic preparedness, available resources, and guidelines for neonatal care delivery among neonatal health care providers in low- and middle-income countries (LMICs) across all continents. Study design Cross-sectional, web-based survey administered between May and June, 2020. Results Of 189 invited participants in 69 LMICs, we received 145 (77%) responses from 58 (84%) countries. The pandemic provides significant challenges to neonatal care, particularly in low-income countries. Respondents noted exacerbations of preexisting shortages in staffing, equipment, and isolation capabilities. In Sub-Saharan Africa, 9/35 (26%) respondents noted increased mortality in non-COVID-19-infected infants. Clinical practices on cord clamping, isolation, and breastfeeding varied widely, often not in line with World Health Organization guidelines. Most respondents noted family access restrictions, and limited shared decision-making. Conclusions Many LMICs face an exacerbation of preexisting resource challenges for neonatal care during the pandemic. Variable approaches to care delivery and deviations from guidelines provide opportunities for international collaborative improvement.

In the USA, an interchangeability designation provides biosimilar sponsors with a pathway for achieving what is standard for small-molecule generics: pharmacy-level auto-substitution for an innovator. No other major health authority links interchangeability to automatic substitution, as all require the involvement of the prescriber or patient in a medication change. This editorial considers the clinical impact and practicality of auto-substitution. First, interchangeability is linked to non-medical switching (NMS), the practice of switching treatment in patients with stable disease for non-clinical reasons. NMS may generate negative sentiment in those unwilling or reluctant to switch, which can adversely impact treatment outcomes (i.e., nocebo effect). Indeed, in real-world studies of tumor necrosis factor inhibitors, discontinuation rates have been shown to be higher in patients switched to biosimilars for non-medical reasons than in historical cohorts maintained on innovators. Second, interchangeability may impede pharmacovigilance and traceability, as not all jurisdictions require innovators and biosimilars to have distinct biologic names. Third, an interchangeability designation from the US Food and Drug Administration only permits a biosimilar to be automatically substituted for its innovator, not other biosimilars (if available). Pharmacist education would be needed to avoid off-label, automatic substitution among biosimilars of a single innovator. Last, once granted, an interchangeability designation exists in perpetuity under current US federal law. However, the supply chains of innovators and biosimilars are maintained independently, with no requirement for reconfirmation of biosimilarity or interchangeability. We feel that additional guidance is needed for the auto-substitution of biosimilars and innovators to become a reality.

Background: For nearly thirty years, significant concerns have been raised about the public-provided mental health services for Aboriginal and Torres Strait Islander peoples. Staff have been identified as having little understanding of Indigenous culture, and this had resulted in inappropriate treatment. In attempting to understand what specialist knowledge exists to guide mental health nursing practice with Aboriginal and Torres Strait Islander peoples, the authors have turned to published peer-reviewed literature.Methods: The approach chosen to explore this area was an integrative review. This provided a method to identify, analyse, and synthesise a wide range of literature.Results: The available evidence points to the need that treatment planning must be focused on the promotion of social and emotional wellbeing and not simply the treatment of symptoms. It also emphasises the importance of cultural safety informed by awareness and understanding of social, cultural and historical factors that can impact the health and treatment of Aboriginal and Torres Strait Islander peoples. Within the literature, staff reported difficulty in understanding how knowledge about social and emotional wellbeing could translate into practice. Nurses working in mental health contexts reported not feeling adequately prepared for, or confident in this area of practice.Conclusions: There is a paucity of current literature on mental health nursing practice for Aboriginal and Torres Strait Islander peoples, with the literature available not providing clear guidance for effective and meaningful practice.

Objective Inappropriate use of antibiotics has been acknowledged as a significant contributor to the proliferation of antimicrobial resistance worldwide. Physician prescribing of antibiotics has been identified as a factor in the inappropriate use of antibiotics. One methodology that is used in an attempt to alter physician prescribing behaviours is audit and feedback. This study aimed to explore the perceptions of Irish General Practitioners (GPs) towards the national introduction of postal feedback on their antibiotic prescribing behaviours beginning in 2019. Design A qualitative descriptive methodology was used. Semi–structured interviews were conducted with GPs in receipt of postal audit and feedback. Method GPs working in Ireland and in receipt of postal audit and feedback on their antibiotic prescribing behaviours participated in phone-based interviews. The interviews were recorded and transcribed verbatim. The collected data was then analysed using an inductive thematic analysis. Results Twelve GPs participated in the study (female = 5). Three themes were identified from the analysis. The themes identified were the reliability and validity of the feedback received, feedback on antibiotic prescribing is useful but limited and feedback needs to be easily digestible. Conclusion While the postal audit and feedback were broadly welcomed by the participants, the themes identified a perceived limitation in the quality of the feedback data, the perception of a likely low public health impact of the feedback and difficulties with efficiently processing the audit and feedback information. These findings can help refine future audit and feedback interventions on antibiotic prescribing.

Pharmacological inhibition of MDM2/4, which activates the critical tumor suppressor p53, has been gaining increasing interest as a strategy for the treatment of acute myeloid leukemia (AML). While clinical trials of MDM2 inhibitors have shown promise, responses have been confined to largely molecularly undefined patients, indicating that new biomarkers and optimized treatment strategies are needed. We previously reported that the microRNA miR-10a is strongly overexpressed in some AML, and demonstrate here that it modulates several key members of the p53/Rb network, including p53 regulator MDM4, Rb regulator RB1CC1, p21 regulator TFAP2C, and p53 itself. The expression of both miR-10a and its downstream targets were strongly predictive of MDM2 inhibitor sensitivity in cell lines, primary AML specimens, and correlated to response in patients treated with both MDM2 inhibitors and cytarabine. Furthermore, miR-10a inhibition induced synergy between MDM2 inhibitor Nutlin-3a and cytarabine in both in vitro and in vivo AML models. Mechanistically this synergism primarily occurs via the p53-mediated activation of cytotoxic apoptosis at the expense of cytoprotective autophagy. Together these findings demonstrate that miR-10a may be useful as both a biomarker to identify patients most likely to respond to cytarabine+MDM2 inhibition and also a druggable target to increase their efficacy.

To assess the association between placental morphology and neonatal and infant anthropometry, including analysis by sex.Data from the ROLO Kids [Randomized COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analyzed including placental weight and morphology. Placental, anthropometric and skinfold measurements were recorded as markers of adiposity in 196 neonates and 215 infants at 6 months of age. Ratios including subscapular-to-triceps skinfold ratio and waist-to-height ratio were used as markers of central adiposity, while the sum of all skinfolds and subscapular plus triceps skinfolds were used as markers of general adiposity. Analysis was performed for total groups and by sex.On simple linear regression placental weight was associated with neonatal and infant anthropometric measurements. On multiple regression, the placental weight was associated with birth weight. In the neonatal period placental weight was associated with general adiposity in males only (sum of skinfolds (The placental phenotype is associated with anthropometry at birth and this association persists to early infancy with a stronger relationship noted in this cohort amongst males. This suggests sexual dimorphism may play a role in the impact of the placenta on infant anthropometry.

Culture is a crucial factor in understanding variations in stigma experiences among young people (age ≤25 years). Cultural beliefs influence the range of social responses that mental health issues elicit, including forms of treatment and role expectations of carers. The current article explores the influence that stigma and culture can have on young people with mental illness. It highlights that it is impossible for nurses to be cognizant of all belief systems related to mental illness. Hence, cultural safety is an approach that can facilitate engagement with the nuances of a young person's culture and provide the foundations of appropriate care. [ Journal of Psychosocial Nursing and Mental Health Services, 58 (11), 15–18.]

Cloverleaf skull deformity (CSD), or Kleeblattschadel, is a condition with severe and unpatterned multisuture craniosynostosis, resulting in a trilobar-shaped skull. This deformity mainly comprises a cranio-orbito-facial malformation that leads to a spectrum of multidisciplinary issues. Several syndromes are associated with CSD, such as Crouzon syndrome (CS). Here, we report the case of an infant with CS and the pathogenic c.1061C>G (p.Ser354Cys) variant of the fibroblast growth factor receptor 2 (FGFR2) gene. The child presented with the severe form of CSD despite having a normal, mid-trimester, sonographic scan.

Summary Induced pluripotent stem cells (iPSCs) are an invaluable resource for the study of human disease. However, there are no standardized methods for differentiation into hematopoietic cells, and there is a lack of robust, direct comparisons of different methodologies. In the current study we improved a feeder-free, serum-free method for generation of hematopoietic cells from iPSCs, and directly compared this with three other commonly used strategies with respect to efficiency, repeatability, hands-on time, and cost. We also investigated their capability and sensitivity to model genetic hematopoietic disorders in cells derived from Down syndrome and β-thalassemia patients. Of these methods, a multistep monolayer-based method incorporating aryl hydrocarbon receptor hyperactivation (“2D-multistep”) was the most efficient, generating significantly higher numbers of CD34+ progenitor cells and functional hematopoietic progenitors, while being the most time- and cost-effective and most accurately recapitulating phenotypes of Down syndrome and β-thalassemia., Graphical Abstract, Highlights • Direct comparison of 4 serum & feeder-free iPSC hematopoietic differentiation methods • Comparison: cost-benefit efficiency, sensitivity to model genetic blood diseases • Presents an improved iPSC hematopoietic differentiation: 7× efficiency at 50% cost • Improved method = most live cells, CD34+, CFU; lowest cost; greatest sensitivity, Tursky and colleagues addressed a vital, unmet need to aid method selection for iPSC hematopoietic differentiation for research and potentially clinical use, comparing four representative serum- and feeder-layer-free methods. Assessments include production efficiency of CD34+ and functional hematopoietic progenitor cells, cost-benefit analysis, and ability to recapitulate aberrant hematopoiesis. An optimized method proved the most efficient, cost-effective, and sensitive.

Down Syndrome (DS) is the most common chromosomal abnormality of live born babies. Individuals with DS are at increased risk of cardiopulmonary morbidities in the early neonatal period, infancy and childhood that manifest with elevated pulmonary arterial pressures and altered myocardial performance. Pulmonary hypertension (PH) during the early neonatal period remains under-recognised in this population. PH may occur with or without a congenital heart defect in children with DS and is more common than in the general population. Early detection and continued screening of PH throughout infancy and childhood for these at-risk children is crucial for prompt intervention and potential prevention of long-term sequelae on cardiac function. This review summarises the main physiological concepts behind the mechanisms of PH in children with DS and provides a summary of the current available literature on PH and its impact on myocardial performance.

Cone‐beam CT‐guided single dose of lung stereotactic body radiotherapy (SBRT) treatment with a flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a safe and highly effective treatment modality for selective small lung lesions. Four‐dimensional (4D) CT‐based treatment plans were generated using advanced AcurosXB algorithm for heterogeneity corrections. 6X‐FFF beam produced highly conformal radiosurgical dose distribution to the target and reduced lung SBRT fraction duration to less than 10 min for a single dose of 30 Gy, significantly improving patient comfort and clinic workflow. Early follow‐up CT imaging results (mean, 8 months) show high local control rates (100%) with no acute lung or rib toxicity. Longer clinical follow‐up in a larger patient cohort managed in this fashion is underway to further validate this treatment approach.

Aim To review multiorgan involvement and management in children with Down syndrome (DS). Methods A literature review of articles from 1980 to 2019 using the MEDLINE interface of PubMed was performed using the following search terms- [Down syndrome] or [Trisomy 21] AND [Cardiology] or [Respiratory] or [neurodevelopment] or [epilepsy] or [musculoskeletal] or [immune system] or [haematological] or [endocrine] or [gastrointestinal] or [ophthalmological] or [Ear Nose Throat] or [dermatology] or [renal]. Results Congenital heart disease particularly septal defects occur in over 60% of infants with DS and 5%-34% of infants develop persistent pulmonary hypertension of the newborn irrespective of a diagnosis of congenital heart disease. Early recognition and management of aspiration, obstructive sleep apnoea and recurrent lower respiratory tract infections (LRTI) could reduce risk of developing pulmonary hypertension in later childhood. Children with DS have an increased risk of autistic spectrum disorder, attention deficit disorder and epilepsy particularly infantile spasms, which are associated with poor neurodevelopmental outcomes. Congenital anomalies of the gastrointestinal and renal system as well as autoimmune diseases, coeliac disease, arthropathy, thyroid dysfunction fold diabetes mellitus and dermatological conditions are more common. Hearing and visual anomalies are also well recognised association with DS (Table 1). Conclusion Children with DS are at an increased risk of multiorgan comorbidities. Organ-specific health surveillance may provide holistic care for the children and families with DS throughout childhood.

Current guidelines recommend against neurodiagnostic testing for the evaluation of simple febrile seizures.(1) Assess overall and institutional rates of neurodiagnostic testing and (2) establish achievable benchmarks of care (ABCs) for children evaluated for simple febrile seizures at children's hospitals.Cross-sectional study of children 6 months to 5 years evaluated in the emergency department (ED) 2016-2019 with simple febrile seizures at 38 children's hospitals in Pediatric Health Information System database. We excluded children with epilepsy, complex febrile seizures, complex chronic conditions, and intensive care.Proportions of children who received neuroimaging, electroencephalogram (EEG), or lumbar puncture (LP) and rates of hospitalization for study cohort and individual hospitals. Hospital-specific outcomes were adjusted for patient demographics and severity of illness. We utilized hospital-specific values for each measure to calculate ABCs.We identified 51,015 encounters. Among the study cohort 821 (1.6%) children had neuroimaging, 554 (1.1%) EEG, 314 (0.6%) LP, and 2023 (4.0%) were hospitalized. Neurodiagnostic testing rates varied across hospitals: neuroimaging 0.4%-6.7%, EEG 0%-8.2%, LP 0%-12.7% in patients1-year old and 0%-3.1% in patients ≥1 year. Hospitalization rate ranged from 0%-14.5%. Measured outcomes were higher among hospitalized versus ED-only patients: neuroimaging 15.3% versus 1.0%, EEG% 24.7 versus 0.1% (p .001). Calculated ABCs were 0.6% for neuroimaging, 0.1% EEG, 0% LP, and 1.0% hospitalization.Rates of neurodiagnostic testing and hospitalization for simple febrile seizures were low but varied across hospitals. Calculated ABCs were 0%-1% for all measures, demonstrating that adherence to current guidelines is attainable.

Unusually for a viral infection, the immunological phenotype of severe COVID-19 is characterised by a depleted lymphocyte and elevated neutrophil count, with the neutrophil-to-lymphocyte ratio correlating with disease severity. Neutrophils are the most abundant immune cell in the bloodstream and comprise different subpopulations with pleiotropic actions that are vital for host immunity. Unique neutrophil subpopulations vary in their capacity to mount antimicrobial responses, including NETosis (the generation of neutrophil extracellular traps), degranulation and de novo production of cytokines and chemokines. These processes play a role in antiviral immunity, but may also contribute to the local and systemic tissue damage seen in acute SARS-CoV-2 infection. Neutrophils also contribute to complications of COVID-19 such as thrombosis, acute respiratory distress syndrome and multisystem inflammatory disease in children. In this Progress review, we discuss the anti-viral and pathological roles of neutrophils in SARS-CoV-2 infection, and potential therapeutic strategies for COVID-19 that target neutrophil-mediated inflammatory responses.

Background People who live in aged care homes have high rates of illness and frailty. Providing evidence-based care to this population is vital to ensure the highest possible quality of life. Objective In this study (CareTrack Aged, CT Aged), we aimed to develop a comprehensive set of clinical indicators for guideline-adherent, appropriate care of commonly managed conditions and processes in aged care. Methods Indicators were formulated from recommendations found through systematic searches of Australian and international clinical practice guidelines (CPGs). Experts reviewed the indicators using a multiround modified Delphi process to develop a consensus on what constitutes appropriate care. Results From 139 CPGs, 5609 recommendations were used to draft 630 indicators. Clinical experts (n = 41) reviewed the indicators over two rounds. A final set of 236 indicators resulted, mapped to 16 conditions and processes of care. The conditions and processes were admission assessment; bladder and bowel problems; cognitive impairment; depression; dysphagia and aspiration; end of life/palliative care; hearing and vision; infection; medication; mobility and falls; nutrition and hydration; oral and dental care; pain; restraint use; skin integrity and sleep. Conclusions The suite of CT Aged clinical indicators can be used for research and assessment of the quality of care in individual facilities and across organizations to guide improvement and to supplement regulation or accreditation of the aged care sector. They are a step forward for Australian and international aged care sectors, helping to improve transparency so that the level of care delivered to aged care consumers can be rigorously monitored and continuously improved.

Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

The search for biomarkers for autism spectrum disorder (henceforth autism) has received a lot of attention due to their potential clinical relevance. The clinical and aetiological heterogeneity of autism suggests the presence of subgroups. The lack of identification of a valid diagnostic biomarker for autism, and the inconsistencies seen in studies assessing differences between autism and typically developing control groups, may be partially explained by the vast heterogeneity observed in autism. The focus now is to better understand the clinical and biological heterogeneity and identify stratification biomarkers, which are measures that describe subgroups of individuals with shared biology. Using stratification approaches to assess treatment within pre-defined subgroups could clarify who may benefit from different treatments and therapies, and ultimately lead to more effective individualised treatment plans.

Study design Multiround wiki-based Delphi expert panel survey. Objective To provide proof of concept for an alternative method for creating sets of nationally-agreed point-of-care clinical indicators, and obtain consensus among end-user groups on "appropriate care" for the assessment, diagnosis, acute, and ongoing care of people with low back pain (LBP). Summary of background data The provision of inappropriate and low value care for LBP is a significant healthcare and societal burden. Vague clinical practice guideline (CPG) recommendations can be difficult to apply and measure in real world clinical practice, and a likely barrier to "appropriate care." Methods Draft "appropriate care" clinical indicators for LBP were derived from CPG recommendations published between 2011 and 2017. Included CPGs were independently appraised by two reviewers using the Appraisal of Guidelines for Research and Evaluation instrument. Headed by a Clinical Champion, a 20-member Expert Panel reviewed and commented on the draft indicators over a three-round modified e-Delphi process using a collaborative online wiki. At the conclusion of each review round, the research team and the Clinical Champion synthesized and responded to experts' comments and incorporated feedback into the next iteration of the draft indicators. Results From seven CPGs and six qualitative meta-syntheses, 299 recommendations and themes were used to draft 42 "appropriateness" indicators. In total, 17 experts reviewed these indicators over 18 months. A final set of 27 indicators comprising screening and diagnostic processes (n = 8), assessment (n = 3), acute (n = 5), and ongoing care (n = 9), and two which crossed the acute-ongoing care continuum. Most indicators were geared toward recommended care (n = 21, 78%), with the remainder focused on care to be avoided. Conclusion These 27 LBP clinical indicators can be used by healthcare consumers, clinicians, researchers, policy makers/funders, and insurers to guide and monitor the provision of "appropriate care" for LBP.Level of Evidence: 4.

Pattern recognition receptors (PRRs) of the innate immune system represent the critical front-line defense against pathogens, and new vaccine formulations target these PRR pathways to boost vaccine responses, through activation of cellular/Th1 immunity. The majority of pediatric vaccines contain aluminum (ALUM) or monophosphoryl lipid A (MPLA) as adjuvants to encourage immune activation. Evidence suggests that elements of the innate immune system, currently being targeted for vaccine adjuvanticity do not fully develop until puberty and it is likely that effective adjuvants for the neonatal and pediatric populations are being overlooked due to modeling of responses in adult systems. We recently reported that the activity of the cytosolic nucleic acid (CNA) sensing family of PRRs is strong in cord blood and peripheral blood of young children. This study investigates the function of CNA sensors in subsets of neonatal innate immune cells and shows that myeloid cells from cord blood can be activated to express T cell costimulatory markers, and also to produce Th1 promoting cytokines. CD80 and CD86 were consistently up-regulated in response to cytosolic Poly(I:C) stimulation in all cell types examined and CNA activation also induced robust Type I IFN and low levels of TNFα in monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells. We have compared CNA activation to adjuvants currently in use (MPLA or ALUM), either alone or in combination and found that cytosolic Poly(I:C) in combination with MPLA or ALUM can improve expression of activation marker levels above those observed with either adjuvant alone. This may prove particularly promising in the context of improving the efficacy of existing ALUM- or MPLA-containing vaccines, through activation of T cell-mediated immunity.

AIM Pulmonary haemorrhage (PH) is an acute catastrophic event with low incidence yet high mortality among neonates. We aimed to systematically review the management of PH. METHODS A search was carried out of the PubMed, EMBASE and Cochrane databases according to the PRISMA guidelines. Data were extracted on study design and size, patient demographics, primary and adjunctive treatment methods, and treatment outcomes. RESULTS Sixteen studies with 385 newborn infants were included and were significantly heterogeneous regarding treatment methods. Primary treatments included surfactant, high-frequency oscillatory ventilation (HFOV), epinephrine, coagulopathy management, intermittent positive pressure ventilation, cocaine and tolazoline. Adjunctive treatment methods included blood products, HFOV, increased positive end-expiratory pressure, vitamin K, surfactant, adrenaline, vasopressors and inotropes. All five studies using surfactant as primary treatment were effective in improving oxygenation index measures and preventing recurrence of PH, and three studies found no association between surfactant and death or long-term disability. Ventilatory support, epinephrine, management of coagulopathy and tolazoline were all found to be effective primary treatments for PH. CONCLUSION There are several effective methods of managing PH in neonates. Further understanding of the aetiology of PH and ongoing research will allow future prevention and improvements in management of PH.

Glial fibrillary acidic protein (GFAP) is a neuronal protein released after traumatic brain injury (TBI) and detectable in serum samples. GFAP correlates with symptom severity in adults and may be a marker of brain injury in children with milder symptoms or preverbal children.GFAP was examined in children with severe TBI (initial Glasgow Coma Scale score8), with mild TBI (Glasgow Coma Scale score 14/15), and at 0 to 4 and at 10 to 14 days after TBI and was compared with healthy age-matched controls. Mechanism, time points from injury, and symptoms were recorded.The study enrolled 208 children including 110 with TBI (n = 104 mild, 6 severe) and controls (n = 98). GFAP was higher in mild TBI than in controls and highest in the severe TBI cohort, with a maximum value at 6 hours from injury. Vomiting was significantly associated with higher GFAP levels, but no association was found with amnesia, loss of consciousness, and the Sports Concussion Assessment Tool. Children reporting1-point changes from their preinjury functioning on the Post-Concussive Symptom Inventory had higher initial GFAP but not total Post-Concussive Symptom Inventory score changes.GFAP identifies children with TBI, even at the milder end of the spectrum, and is strongly associated with postinjury vomiting. It may be a useful marker of pediatric TBI; however, sampling is time critical.

ObjectivesThis systematic review aimed to describe medication non-adherence among people living with multimorbidity according to the current literature, and synthesise predictors of non-adherence in this population.MethodsA systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. PubMed, EMBASE, CINAHL and PsycINFO were searched for relevant articles published in English language between January 2009 and April 2019. Quantitative studies reporting medication non-adherence and/or predictors of non-adherence among people with two or more chronic conditions were included in the review. A meta-analysis was conducted with a subgroup of studies that used an inclusive definition of multimorbidity to recruit participants, rather than seeking people with specific conditions. Remaining studies reporting prevalence and predictors of non-adherence were narratively synthesised.ResultsThe database search produced 10 998 records and a further 75 were identified through other sources. Following full-text screening, 178 studies were included in the review. The range of reported non-adherence differed by measurement method, at 76.5% for self-report, 69.4% for pharmacy data, and 44.1% for electronic monitoring. A meta-analysis was conducted with eight studies (n=8949) that used an inclusive definition of multimorbidity to recruit participants. The pooled prevalence of non-adherence was 42.6% (95% CI: 34.0 - 51.3%, k=8, I2=97%, pConclusionsThe review identified a heterogeneous literature in terms of conditions studied, and definitions and measures of non-adherence used. Results suggest that future attempts to improve adherence among people with multimorbidity should determine for which conditions individuals require most support. The variable levels of medication non-adherence highlight the need for more attention to be paid by healthcare providers to the impact of multimorbidity on chronic disease self-management.PROSPERO registration numberCRD42019133849.

Objective Compared to single diseases, health psychology reflects many areas of medical research by affording relatively less attention to the experiences of people self-managing multiple co-occurring conditions and, in particular, the experience of managing the associated complex medication regimens. This study aimed to explore the experience of self-managing multimorbidity among older adults, with a focus on medication adherence. Design A qualitative approach was taken, using individual semi-structured interviews. Methods Sixteen people with complex multimorbidity aged 65 years or older were recruited through general practice to take part in semi-structured interviews. Data were analysed following guidelines for reflexive thematic analysis. Results Two themes were generated, with each theme comprising three subthemes. Theme one represents the amplified burden arising from multimorbidity that leads to unique challenges for self-management, such as integrating multiple medications into daily life, accumulating new symptoms and treatments, and managing evolving medication regimens. Theme two represents pathways towards relief that reduce this burden and promote medication adherence, such as prioritising certain conditions and treatments, resigning to the need for multiple medications, and identifying and utilising adherence supports. Conclusions We identified factors relevant to medication adherence for older adults with multimorbidity that go beyond single-disease influences and account for the amplified experience of chronic disease that multimorbidity can produce for some people. While evidence of single-disease influences remains fundamental to tailoring behavioural interventions to individuals, the impact of multimorbidity on medication adherence should be accounted for in research and practice.

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.

OBJECTIVESResearchers in recent studies suggest that hospitalized febrile infants aged ≤60 days may be safely discharged if bacterial cultures are negative after 24–36 hours of incubation. We aimed to describe trends and variation in length of stay (LOS) for hospitalized febrile infants across children’s hospitals.METHODSWe conducted a multicenter retrospective cohort study of febrile infants aged ≤60 days hospitalized from 2016 to 2019 at 39 hospitals in the Pediatric Health Information System database. We excluded infants with complex chronic conditions, bacterial infections, lower respiratory tract viral infections, and those who required ICU admission. The primary outcomes were trends in LOS overall and for individual hospitals, adjusted for patient demographics and clinical characteristics. We also evaluated the hospital-level association between LOS and 30-day readmissions.RESULTSWe identified 11 868 eligible febrile infant encounters. The adjusted mean LOS for the study cohort decreased from 44.0 hours in 2016 to 41.9 hours in 2019 (P < .001). There was substantial variation in adjusted mean LOS across children’s hospitals, range 33.5–77.9 hours in 2016 and 30.4–100.0 hours in 2019. The change from 2016 to 2019 in adjusted mean LOS across individual hospitals also varied widely (−23.9 to +26.7 hours; median change −1.8 hours, interquartile range: −5.4 to 0.3). There was no association between hospital-level LOS and readmission rates (P = .70).CONCLUSIONSThe LOS for hospitalized febrile infants decreased marginally between 2016 and 2019, although overall LOS and change in LOS varied substantially across children’s hospitals. Continued quality improvement efforts are needed to reduce LOS for hospitalized febrile infants.

Neonatal encephalopathy (NE) is associated with abnormality of neurological function and involves multiorgan dysfunction. There are long-term complications such as cerebral palsy and developmental delay. Cardiac, renal, neurological and other organ dysfunctions are well described. Haematological dysfunction is relatively common and includes anaemia, thrombocytopenia, monocyte and neutrophil activation, hypofibrinogenemia and coagulopathy. There is a lack of consensus definitions of hematological parameters and optimal levels for intervention due to the lack of interventional studies in term neonates and the lack of knowledge of the optimal values during therapeutic hypothermia. However, derangements in hematological values are also associated with neurodevelopmental outcomes. This article outlines the different hematological complications associated with NE and therapeutic hypothermia and suggests a framework for management.

Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE.

The Nursing and Midwifery Board of Australia's Code of Conduct for Nurses sets out the professional behaviour and conduct expectations for nurses in all practice settings. The publication of a revised version in 2018, which included expectations related to culturally safe and respectful practice and Aboriginal and Torres Strait Islander Peoples' health, caused reverberations beyond the profession of nursing. A controversy that the changes required nurses to verbally apologize for being white before their interactions with Aboriginal and Torres Strait Islander people gained the attention of the mainstream media. This interpretation, which came from outside nursing, was disputed by the Board. Challenged by these events, the authors were interested in understanding the actual impacts of the changes from the perspectives of nurses in practice. This research, carried out nearly three years after publication, has focused specifically on the speciality of mental health nurses in this context. The objective of this research was to undertake a social analysis focused on the impact that changes in the Code have had on the culture of mental health nursing utilizing a qualitative methodology. Eight mental health nurses were interviewed. The research found that there was little evidence of any impact on mental health nursing practice. Many of the participants were unaware of the amendments to the Code, whilst those nurses who were aware did not perceive that it had led to any real change within mental health nursing or service delivery.

BACKGROUND: Cerebral palsy (CP) is a heterogeneous group of non‐progressive disorders of posture or movement, caused by a lesion of the developing brain. Osteoporosis is common in children with cerebral palsy, particularly in children with reduced gross motor function, and leads to an increased risk of fractures. Gross motor function in children with CP can be categorised using a tool called the Gross Motor Function Classification System (GMFCS). Bisphosphonate increases bone mineral density (BMD) and reduces fracture rates. Bisphosphonate is used widely in the treatment of adult osteoporosis. However, the use of bisphosphonate in children with CP remains controversial, due to a paucity of evidence and a lack of recent trials examining the efficacy and safety of bisphosphonate use in this population. OBJECTIVES: To examine the efficacy and safety of bisphosphonate therapy in the treatment of low BMD or secondary osteoporosis (or both) in children with cerebral palsy (GMFCS Levels III to V) who are under 18 years of age. SEARCH METHODS: In September 2020, we searched CENTRAL, MEDLINE, Embase, six other databases, and two trial registers for relevant studies. We also searched the reference lists of relevant systematic reviews, trials, and case studies identified by the search, and contacted the authors of relevant studies in an attempt to identify unpublished literature. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs), and quasi‐RCTs, comparing at least one bisphosphonate (given at any dose, orally or intravenously) with placebo or no drug, for the treatment of low BMD or osteoporosis in children up to 18 years old, with cerebral palsy (GMFCS Levels III to V). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We were unable to conduct any meta‐analyses due to insufficient data, and therefore provide a narrative assessment of the results. MAIN RESULTS: We found two relevant RCTs (34 participants). Both studies included participants with non‐ambulatory CP or CP and osteoporosis. Participants in both studies were similar in severity of CP, age distribution, and sex distribution. The two trials used different bisphosphonate medications and different intervention durations, but further comparison of the interventions was not possible due to a lack of published data from one trial. One trial received funding and support from research, academic, and hospital foundations, with pharmaceutical companies providing components of the calcium and vitamin supplement; the other trial did not report sources of funding. We judged one study at an overall high risk of bias; the other as overall unclear risk of bias. Primary outcome. Compared to placebo or no treatment, both studies provided very low certainty evidence of improved BMD at least four months post‐intervention in children treated with bisphosphonate. Only one study (12 participants) provided sufficient detail to assess a measure of the effect, and reported an improvement at six months post‐intervention in lumbar spine z‐score (mean difference (MD) 18%, 95% confidence interval (CI) 6.57 to 29.43; very low certainty evidence). Secondary outcomes. Very low certainty evidence from one study found that bisphosphonate reduced serum N‐telopeptides (NTX) more than placebo; the other study reported that both bisphosphonate plus alfacalcidol and alfacalcidol alone reduced NTX, but did not compare groups. One study reported inconclusive results between groups for serum bone‐specific alkaline phosphatase (BAP). The other study reported that both bisphosphonate plus alfacalcidol and alfacalcidol alone reduced BAP, but did not compare groups. Neither study reported data for the effect of bisphosphonate treatment on changes in volumetric BMD in the distal radius or tibia, changes in fracture frequency, bone pain, or quality of life. One study reported that two participants had febrile events noted during their first dosing schedule, but no further adverse events were reported in either relevant study. AUTHORS' CONCLUSIONS: Based on the available evidence, there is very low certainty evidence that bisphosphonate treatment may improve bone health in children with cerebral palsy. We could only include one study with 14 participants in the assessment of the effect size; therefore, the precision of the effect estimate is low. We could only evaluate one planned primary outcome, as there was insufficient detail reported in the relevant studies. Further research from RCTs on the effect and safety of bisphosphonate to improve bone health in children with cerebral palsy is required. These studies should clarify the optimal standard treatment regarding weight‐bearing exercises, vitamin D and calcium supplementation, and should include fracture frequency as a primary outcome.

Background The PolyPrime intervention is a theory-based intervention aimed at improving appropriate polypharmacy in older people (aged ≥65 years) in primary care. The intervention consists of an online video which demonstrates how general practitioners (GPs) can prescribe appropriate polypharmacy during a consultation with an older patient and a patient recall process, whereby patients are invited to scheduled medication review consultations with GPs. The aim of the process evaluation is to further examine the implementation of the PolyPrime intervention in primary care. This will involve investigating whether the PolyPrime intervention can be delivered as intended across two healthcare systems, how acceptable the intervention is to GPs, practice staff and patients, and to identify the intervention’s likely mechanisms of action. Methods The PolyPrime study is an external pilot cluster randomised controlled trial (cRCT) which aims to recruit 12 GP practices across Northern Ireland [NI] (n=6) and the six counties in the Republic of Ireland (ROI) that border NI (n=6). Practices have been randomised to intervention or usual care. An embedded process evaluation will assess intervention fidelity (i.e. was the intervention delivered as intended), acceptability of the intervention to GPs, practice staff and patients and potential mechanisms of action (i.e. what components of the intervention were perceived to be effective). Quantitative data will be collected from data collection forms completed by GPs and practice staff and a feedback questionnaire completed by patients from intervention arm practices, which will be analysed using descriptive statistics. Qualitative data will be collected through semi-structured interviews with GPs and practice staff and audio-recordings of medication review appointments from the intervention arm practices which will be transcribed and analysed using the framework method. Quantitative and qualitative data will be triangulated to provide an overall assessment of intervention fidelity, intervention acceptability, and mechanisms of action. Discussion This process evaluation will add to feasibility data from the pilot cRCT by providing evidence on the fidelity of implementing the intervention package across two healthcare systems, the acceptability of the intervention and potential mechanisms of action. Trial registration ClinicalTrials.govISRCTN41009897. Registered on 19 November 2019. ClinicalTrials.govNCT04181879. Registered 02 December 2019.

The implementation of the multidisciplinary Down Syndrome Health Surveillance clinic at Children’s Health Ireland at Tallaght, Dublin has shown significant improvements in the adherence to guidelines as well as providing health promotion strategies such as information on immunisations. Our project provides a framework which would be potentially emulated and used in other medical conditions. The reduction in clinic attendances and co-ordination of same-day appointments has improved parental satisfaction as well as the quality of care.

New cancer incidences worldwide will eclipse 18 million in 2019, with nearly 10 million cancer-related deaths. It is estimated that in the United States, almost 40% of individuals will be diagnosed with cancer in their lifetime. Surgical resection of primary tumors remains a cornerstone of cancer treatment; however, the surgical process can trigger an immune-suppressing sympathetic response, which promotes tumor growth of any residual cancerous cells post surgery. Regional and local anesthesia have become staples of anesthesia and analgesia during and after surgery. Recently, much evidence in the form of retrospective and prospective studies has come to light regarding the protective, antitumor properties of anesthetic and analgesic agents across a wide variety of cancers and patient demographics. It is believed that by blocking afferent pain signals, the body does not mount the sympathetic response that contributes to the perpetuation of disease after surgical treatment. This review, therefore, investigates these studies as they pertain to the treatment and outcomes of cancers treated surgically to elucidate the role of regional anesthesia in the propagation of cancer.

Histological chorioamnionitis (HCA) is associated with preterm birth and adverse neonatal outcomes. We evaluated the rise in C-reactive protein (CRP) in preterm infants as a predictor of HCA severity and outcomes.Consecutive preterm infants, born January 2009 to January 2014 in the National Maternity Hospital, Dublin, under 32 weeks' gestation or1.5 kg birthweight, were included. Histological chorioamnionitis was staged as maternal inflammatory response, foetal inflammatory response and non-HCA.Preterm infants (n = 518) were included with a mean gestational age 28.5 ± 2.8 weeks, birthweight 1.1 ± 0.3 kg, and 53.5% were male. Histological chorioamnionitis was found in 25.4%. Histological chorioamnionitis was present in 93.7% when CRP 5 mg/L, 65.2% when CRP 1-5 mg/L and in 19.4% when CRP 1 mg/L. When both the immature to total neutrophil (IT) ratio was0.2 and the CRP 1 mg/L the positive predictive value and negative predictive value for HCA were 92.5% and 84.9%, respectively. Histological chorioamnionitis was associated with more resuscitation and respiratory distress syndrome (both P .001). A CRP 10 mg/L was associated with a foetal inflammatory response and increased early-onset sepsis.Higher early CRP was a surrogate predictor of HCA and correlated with the severity of HCA. Higher CRP and HCA were associated with adverse early outcomes.