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Abstract Background Hypertension, or high blood pressure, is a key modifiable risk factor for heart disease and stroke. International guidelines have highlighted ‘poor adherence to treatment’ and ‘physician inertia’ as major barriers to effective blood pressure management. The Maximising Adherence, Minimising Inertia (MIAMI) intervention, a theory-based complex intervention, supports General Practitioners (GPs) and people with hypertension in maximising medication use to manage blood pressure. This pilot cluster randomised control trial (RCT) aimed to collect and analyse feasibility data to refine the MIAMI intervention and assess the feasibility of a definitive RCT. Method A pilot cluster RCT with a MIAMI intervention arm and usual care control arm was conducted. Quantitative data collection consisting of clinical measures and a self-report questionnaire took place at baseline and twelve week follow up. Semi-structured interviews with GP and patient participants were conducted. Fidelity (as measured by a protocol checklist and through qualitative interviews) and health economics costings were assessed. Results Six GP practices (intervention arm n = 3, control arm n = 3) and 52 patients (intervention arm n = 25, control arm n = 27) took part. All six GP practices and 92% of patients were retained. Fidelity, as measured by a checklist and through qualitative interviews, was good but three deviations from protocol were identified. Outcomes and measures used were acceptable. The implementation cost of the MIAMI intervention was estimated at €490 per participant. The qualitative data demonstrated that the intervention was considered acceptable and feasible by both GP and patient participants, except for the urine test component, which GPs found difficult to incorporate into practice due to logistical challenges. Conclusions The MIAMI intervention was considered largely acceptable and feasible. Some changes to both intervention components and trial processes are required but with these in place a definitive RCT could be considered worthwhile. Trial registration ISRCTN registry, ISRCTN85009436, registered 17/1/23.

Background: Hypertension remains one of the most important modifiable risk factors for stroke and heart disease. Anti-hypertensive medications are effective, but are often not used to maximum benefit. Sub-optimal dosing by prescribers and challenges with medication-taking for patients remain barriers to effective blood pressure control.Objectives: We aimed to systematically develop a theory-based complex intervention to support General Practitioners (GPs) and people with hypertension to maximise medication use to control blood pressure.Methods: We used the three-phase Behaviour Change Wheel (BCW) as the overarching intervention development framework. Collective Intelligence methodology was used to operationalise the stakeholder input to Phases 2 and 3 of the BCW. This took the form of a Collective Intelligence workshop with 19 stakeholders from diverse backgrounds including lived experience, general practice, nursing, pharmacy and health psychology. Techniques such as barrier identification, idea-writing and scenario-based design were used to generate possible intervention options. Intervention options were then selected and refined using the Acceptability, Practicability, Effectiveness, Affordability, Side-effects and Equity (APEASE) criteria and guidance from the MIAMI Public and Patient Involvement Panel.Results: The finalised MIAMI intervention consists of both GP and patient supports. GP supports include a 30-minute online training, information booklet and consultation guide (drop-down menu) embedded within the patient electronic health system. Patient supports include a pre-consultation plan, website, and a structured GP consultation with results from an Ambulatory Blood Pressure Monitor and urine chemical adherence test. The intervention components have been mapped to the intervention functions of the BCW and Behaviour Change Technique Ontology.Conclusion: Collective Intelligence offered a novel method to operationalise stakeholder input to Phases 2 and 3 of the BCW. The MIAMI intervention is now at pilot evaluation stage.

BackgroundDespite growing use, questions remain surrounding the utility, acceptability and feasibility of chemical adherence testing (CAT) as part of hypertension management in clinical practice.ObjectivesThis scoping review aimed to (i) identify and summarise studies using CAT in hypertension management, and (ii) describe and critically evaluate how CAT is currently being used in the clinical management of hypertension.Eligibility criteriaPeer-reviewed and published studies in English, reporting original research in any setting, with any study design, were included. Search concepts included hypertension, medication adherence, CAT, and their synonyms.Sources of evidenceSearches were carried out using Ovid Medline, EMBASE, and PsycInfo (EBSCO), alongside manual searching of reference lists. Using Covidence software, we screened titles and abstracts, followed by full-text articles. Data from the included articles were tabulated and summarised.ResultsOf the 618 studies identified, 48 were included. The studies cover diverse clinical settings, and were mostly observational in design. 7 studies reporting adherence analyses within clinical trials for hypertension therapies. The use of theoretical frameworks to guide reporting was rare, and there was considerable variation in key terminology and definitions, most notably in the definition of adherence.ConclusionThe current body of evidence demonstrates considerable variability in the approach to implementing CAT for hypertension management in clinical practice, and a paucity of randomised controlled trials to evaluate its impact. Future research could (i) adopt a cohesive theoretical framework including clear operational definitions to standardise the approach to this important topic; (ii) further explore the impact of CAT on clinical outcomes using RCTs.

IntroductionNeonatal encephalopathy (NE) is a condition with multifactorial etiology that causes multiorgan injury to neonates. The severity of multiorgan dysfunction (MOD) in NE varies, with therapeutic hypothermia (TH) as the standard of care. The aim is to identify current approaches used to assess and determine an optimum scoring system for MOD in NE.MethodsThe systematic review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search was conducted using PubMed, EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus, and CINAHL for studies of scoring systems for MOD in NE.ResultsThe search yielded 628 articles of which 12 studies were included for data extraction and analysis. Five studies found a positive correlation between the severity of NE and MOD. There was significant heterogeneity across the scoring systems, including the eligibility criteria for participants, the methods assessing specific organ systems, the length of follow-up, and adverse outcomes. The neurological, hepatic, cardiovascular, respiratory, hematological, and renal systems were included in most studies while the gastrointestinal system was only in three studies. The definitions for hepatic, renal, and respiratory systems dysfunction were most consistent while the cardiovascular system varied the most.DiscussionA NE multiorgan scoring system should ideally include the renal, hepatic, respiratory, neurological, hematological, and cardiovascular systems. Despite the heterogeneity between the studies, these provide potential candidates for the standardization of MOD scoring systems in NE. Validation is needed for the parameters with adequate length of follow-up beyond the neonatal period. Additionally, the evaluation of MOD may be affected by TH considering its multiorgan effects.

Introduction At least 10% of hospital admissions in high-income countries, including Australia, are associated with patient safety incidents, which contribute to patient harm (‘adverse events’). When a patient is seriously harmed, an investigation or review is undertaken to reduce the risk of further incidents occurring. Despite 20 years of investigations into adverse events in healthcare, few evaluations provide evidence of their quality and effectiveness in reducing preventable harm.This study aims to develop consistent, informed and robust best practice guidance, at state and national levels, that will improve the response, learning and health system improvements arising from adverse events.Methods and analysis The setting will be healthcare organisations in Australian public health systems in the states of New South Wales, Queensland, Victoria and the Australian Capital Territory. We will apply a multistage mixed-methods research design with evaluation and in-situ feasibility testing. This will include literature reviews (stage 1), an assessment of the quality of 300 adverse event investigation reports from participating hospitals (stage 2), and a policy/procedure document review from participating hospitals (stage 3) as well as focus groups and interviews on perspectives and experiences of investigations with healthcare staff and consumers (stage 4). After triangulating results from stages 1–4, we will then codesign tools and guidance for the conduct of investigations with staff and consumers (stage 5) and conduct feasibility testing on the guidance (stage 6). Participants will include healthcare safety systems policymakers and staff (n=120–255) who commission, undertake or review investigations and consumers (n=20–32) who have been impacted by adverse events.Ethics and dissemination Ethics approval has been granted by the Northern Sydney Local Health District Human Research Ethics Committee (2023/ETH02007 and 2023/ETH02341).The research findings will be incorporated into best practice guidance, published in international and national journals and disseminated through conferences.

Abstract Background This study estimated the prevalence of evidence-based care received by a population-based sample of Australian residents in long-term care (LTC) aged ≥ 65 years in 2021, measured by adherence to clinical practice guideline (CPG) recommendations. Methods Sixteen conditions/processes of care amendable to estimating evidence-based care at a population level were identified from prevalence data and CPGs. Candidate recommendations (n = 5609) were extracted from 139 CPGs which were converted to indicators. National experts in each condition rated the indicators via the RAND-UCLA Delphi process. For the 16 conditions, 236 evidence-based care indicators were ratified. A multi-stage sampling of LTC facilities and residents was undertaken. Trained aged-care nurses then undertook manual structured record reviews of care delivered between 1 March and 31 May 2021 (our record review period) to assess adherence with the indicators. Results Care received by 294 residents with 27,585 care encounters in 25 LTC facilities was evaluated. Residents received care for one to thirteen separate clinical conditions/processes of care (median = 10, mean = 9.7). Adherence to evidence-based care indicators was estimated at 53.2% (95% CI: 48.6, 57.7) ranging from a high of 81.3% (95% CI: 75.6, 86.3) for Bladder and Bowel to a low of 12.2% (95% CI: 1.6, 36.8) for Depression. Six conditions (skin integrity, end-of-life care, infection, sleep, medication, and depression) had less than 50% adherence with indicators. Conclusions This is the first study of adherence to evidence-based care for people in LTC using multiple conditions and a standardised method. Vulnerable older people are not receiving evidence-based care for many physical problems, nor care to support their mental health nor for end-of-life care. The six conditions in which adherence with indicators was less than 50% could be the focus of improvement efforts.

Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants’ genetic profiles.Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms.Ethics and dissemination To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).

Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1’s interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1’s access to the nucleus may explain RSV’s suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV’s respiratory disease progression.

Abstract MIS-C is a systemic inflammation disorder with poorly characterised immunopathological mechanisms. We compared changes in the systemic immune response in children with MIS-C (n = 12, 5–13 years) to healthy controls (n = 14, 5–15 years). Analysis was done in whole blood treated with LPS. Expression of CD11b and Toll-like receptor-4 (TLR4) in neutrophils and monocytes were analysed by flow cytometry. Serum cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-Ira, TNF-α, TNF-β, IFN-Υ, VEGF, EPO and GM-CSF) and mRNA levels of inflammasome molecules (NLRP3, ASC and IL-1β) were evaluated. Subpopulations of lymphocytes (CD3+, CD19+, CD56+, CD4+, CD8+, TCR Vδ1+, TCR Vδ2+) were assessed at basal levels. Absolute counts of neutrophils and NLR were high in children with MIS-C while absolute counts of lymphocytes were low. Children with MIS-C had increased levels of IL-6, IL-10, TNF-β and VEGF serum cytokines at the basal level, and significantly increased TNF-β post-LPS, compared to controls. IL-1RA and EPO decreased at baseline and post-LPS in MIS-C patients compared to controls. The percentage of CD3+ cells, NK cells and Vδ1 was lower while B cells were higher in children with MIS-C than in controls. Dysregulated immune response in children with MIS-C was evident and may be amenable to immunomodulation.

Abstract Background Delphi surveys are commonly used to prioritise critical outcomes in core outcome set (COS) development. This trial aims to compare a three-round (Multi-Round) Delphi (MRD) with a Real-Time Delphi (RTD) in the prioritisation of outcomes for inclusion in a COS for neonatal encephalopathy treatments and explore whether ‘feedback’, ‘iteration’, and ‘initial condition’ effects may occur in the two survey methods. Methods We recruited 269 participants (parents/caregivers, healthcare providers and researchers/academics) of which 222 were randomised to either the MRD or the RTD. We investigated the outcomes prioritised in each survey and the ‘feedback’, ‘iteration’, and ‘initial condition’ effects to identify differences between the two survey methods. Results In the RTD, n = 92 participants (83%) fully completed the survey. In the MRD, n = 60 participants (54%) completed all three rounds. Of the 92 outcomes presented, 26 (28%) were prioritised differently between the RTD and MRD. Significantly fewer participants amended their scores when shown stakeholder responses in the RTD compared to the MRD (‘feedback effect’). The ‘iteration effect’ analysis found most experts appeared satisfied with their initial ratings in the RTD and did not amend their scores following stakeholder response feedback. Where they did amend their scores, ratings were amended substantially, suggesting greater convergence. Variance in scores reduced with subsequent rounds of the MRD (‘iteration effect’). Whilst most participants did not change their initial scores in the RTD, of those that did, later recruits tended to align their final score more closely to the group mean final score than earlier recruits (an ‘initial condition’ effect). Conclusion The feedback effect differed between the two Delphi methods but the magnitude of this difference was small and likely due to the large number of observations rather than because of a meaningfully large difference. It did not appear to be advantageous to require participants to engage in three rounds of a survey due to the low change in scores. Larger drop-out through successive rounds in the MRD, together with a lesser convergence of scores and longer time to completion, indicate considerable benefits of the RTD approach. Trial registration NCT04471103. Registered on 14 July 2020.

Background:. Hip resurfacing arthroplasty (HRA) provides an attractive alternative to total hip arthroplasty (THA) for the management of osteoarthritis in younger, more active patients; however, concerns persist over complications specific to HRA. The aims of this systematic review were to assess the documented long-term survival rates of the metal-on-metal BIRMINGHAM HIP Resurfacing System at a follow-up of at least 10 years and to analyze the functional outcomes and cause of failures. Methods:. A systematic review was undertaken of all published cohort studies available in the MEDLINE, Cochrane, Embase, and PubMed research databases up to December 2021, as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction was focused on survival rates, causes of failure, and functional outcomes. Survival estimates at 10 years were pooled in a meta-analysis, with each series weighted by its variance. Causes of failure were presented as a percentage of the pooled revisions. Results:. A total of 11 studies were identified, encompassing 3,129 cases. Across the 9 studies that had reported a mean follow-up, the mean follow-up was 11.7 years (range, 9.55 to 13.7 years). We found a pooled 10-year survival rate of 95.5% (95% confidence interval, 93.4% to 97.1%). There were 149 revisions among the studies (range, 4 to 38 revisions per study), a rate of 4.8% of the total procedures performed. The 2 main causes of revision were aseptic loosening (20.1% of revisions) and adverse reactions to metal debris (20.1%). There were no revisions for dislocation. Of the studies that reported preoperative functional scores, all reported significant improvement in mean scores postoperatively except for 1 study in which the mean Tegner activity score did not significantly improve. Conclusions:. When performed for appropriate indications, patients undergoing an HRA with use of the BIRMINGHAM HIP Resurfacing System can expect good implant survivorship at 10 years with acceptable functional results and low rates of dislocation and infection. This systematic review, however, confirms concerns regarding adverse reactions to metal debris as a leading cause of revision. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

AimRetinopathy of prematurity is a significant global cause of childhood blindness. This study aims to identify serum biomarkers that are associated with the development of ROP.MethodsA systematic review and meta-analysis was conducted using PRISMA guidelines. Three databases were searched (Pubmed, Scopus and Web of Science) from 2003 to March 2023. Only studies investigating serum biomarker levels in preterm infants (

Abstract The heritability of intelligence or general cognitive ability is estimated at 41% and 66% in children and adults respectively. Many rare copy number variants are associated with neurodevelopmental and neuropsychiatric conditions (ND-CNV), including schizophrenia and autism spectrum disorders, and may contribute to the observed variability in cognitive ability. Here, we reviewed studies of intelligence quotient or cognitive function in ND-CNV carriers, from both general population and clinical cohorts, to understand the cognitive impact of ND-CNV in both contexts and identify potential genotype-specific cognitive phenotypes. We reviewed aggregate studies of sets ND-CNV broadly linked to neurodevelopmental and neuropsychiatric conditions, and genotype-first studies of a subset of 12 ND-CNV robustly associated with schizophrenia and autism. Cognitive impacts were observed across ND-CNV in both general population and clinical cohorts, with reports of phenotypic heterogeneity. Evidence for ND-CNV-specific impacts were limited by a small number of studies and samples sizes. A comprehensive understanding of the cognitive impact of ND-CNVs would be clinically informative and could identify potential educational needs for ND-CNV carriers. This could improve genetic counselling for families impacted by ND-CNV, and clinical outcomes for those with complex needs.

Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.

Objective: Adherence to inhaled corticosteroids (ICS) among young adults living with asthma is low and in need of appropriate intervention. Digital health interventions (DHIs) have demonstrated potential to improve ICS adherence; however, young adult preferences for these DHIs and how their use could support adherence in this population remain understudied. Therefore, this study aimed to explore young adult preferences for ICS adherence supports and potential DHI features to deliver these supports, in order to improve adherence behaviour throughout this critical developmental stage of the lifespan.Methods: Qualitative, semi-structured interviews were conducted with 13 young adults living with asthma. Analysis followed an inductive, reflexive thematic approach.Results: Participant’s age ranged from 18 to 30 years (M = 24.7; 8 female). Three themes were developed from the analysis: ‘Enabling young adults to find their ‘own way of knowing', ‘Support for making a habit of adherence’, and ‘Providing accessible information’ which included the sub-themes: ‘Education on asthma self-management and medication’, ‘Self-monitoring information’ and ‘Personal feedback on outcomes of adherence’. Suggested features to deliver these supports included a medication and prescription refill reminder, adherence charts, symptom and trigger monitoring, rewards for adherence, visual representations of lungs demonstrating the impact of adherence and lung function monitoring.Conclusion: DHIs may offer an appropriate solution to improve suboptimal adherence to ICS in young adults. However, it is crucial that young adult preferences for adherence supports and features are integrated into these interventions in order to optimise engagement and support adherence behaviour in this population.

Abstract 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.

Abstract Background For older populations with multimorbidity, polypharmacy (use of multiple medications) is a standard practice. PolyPrime is a theory-based intervention developed to improve appropriate polypharmacy in older people in primary care. This pilot study aims to assess the feasibility of the PolyPrime intervention in primary care in Northern Ireland (NI) and the Republic of Ireland (ROI). Methods This external pilot cluster randomised controlled trial (cRCT) aimed to recruit 12 general practitioner (GP) practices (six in NI; six in the ROI counties that border NI) and ten older patients receiving polypharmacy (≥ 4 medications) per GP practice (n = 120). Practices allocated to the intervention arm watched an online video and scheduled medication reviews with patients on two occasions. We assessed the feasibility of collecting GP record (medication appropriateness, health service use) and patient self-reported data [health-related quality of life (HRQoL), health service use)] at baseline, 6 and 9 months. HRQoL was measured using the EuroQol-5 dimension-5 level questionnaire (EQ-5D-5L) and medication-related burden quality-of-life (MRB-QoL) tool. An embedded process evaluation and health economics analysis were also undertaken. Pre-specified progression criteria were used to determine whether to proceed to a definitive cRCT. Results Twelve GP practices were recruited and randomised. Three GP practices withdrew from the study due to COVID-related factors. Sixty-eight patients were recruited, with 47 (69.1%) being retained until the end of the study. GP record data were available for 47 patients for medication appropriateness analysis at 9 months. EQ-5D-5L and MRB-QoL data were available for 46 and 41 patients, respectively, at 9 months. GP record and patient self-reported health service use data were available for 47 patients at 9 months. Health service use was comparable in terms of overall cost estimated from GP record versus patient self-reported data. The intervention was successfully delivered as intended; it was acceptable to GPs, practice staff, and patients; and potential mechanisms of action have been identified. All five progression criteria were met (two ‘Go’, three ‘Amend’). Conclusion Despite challenges faced during the COVID-19 pandemic, this study has demonstrated that it may be feasible to conduct an intervention to improve appropriate polypharmacy in older people in primary care across two healthcare jurisdictions. Trial registration ISRCTN, ISRCTN41009897 . Registered 19 November 2019. Clinicaltrials.gov, NCT04181879 . Registered 02 December 2019.

Around 5 % of anthropogenic radiative forcing (RF) is attributed to aviation CO2 and non-CO2 impacts. This paper quantifies aviation emissions and contrail climate forcing in the North Atlantic, one of the world's busiest air traffic corridors, over 5 years. Between 2016 and 2019, growth in CO2 (+3.13 % yr−1) and nitrogen oxide emissions (+4.5 % yr−1) outpaced increases in flight distance (+3.05 % yr−1). Over the same period, the annual mean contrail cirrus net RF (204–280 mW m−2) showed significant inter-annual variability caused by variations in meteorology. Responses to COVID-19 caused significant reductions in flight distance travelled (−66 %), CO2 emissions (−71 %) and the contrail net RF (−66 %) compared with the prior 1-year period. Around 12 % of all flights in this region cause 80 % of the annual contrail energy forcing, and the factors associated with strongly warming/cooling contrails include seasonal changes in meteorology and radiation, time of day, background cloud fields, and engine-specific non-volatile particulate matter (nvPM) emissions. Strongly warming contrails in this region are generally formed in wintertime, close to the tropopause, between 15:00 and 04:00 UTC, and above low-level clouds. The most strongly cooling contrails occur in the spring, in the upper troposphere, between 06:00 and 15:00 UTC, and without lower-level clouds. Uncertainty in the contrail cirrus net RF (216–238 mW m−2) arising from meteorology in 2019 is smaller than the inter-annual variability. The contrail RF estimates are most sensitive to the humidity fields, followed by nvPM emissions and aircraft mass assumptions. This longitudinal evaluation of aviation contrail impacts contributes a quantified understanding of inter-annual variability and informs strategies for contrail mitigation.

Introduction In-bed leg cycling with critically ill patients is a promising intervention aimed at minimising immobility, thus improving physical function following intensive care unit (ICU) discharge. We previously completed a pilot randomised controlled trial (RCT) which supported the feasibility of a large RCT. In this report, we describe the protocol for an international, multicentre RCT to determine the effectiveness of early in-bed cycling versus routine physiotherapy (PT) in critically ill, mechanically ventilated adults.Methods and analysis We report a parallel group RCT of 360 patients in 17 medical-surgical ICUs and three countries. We include adults (≥18 years old), who could ambulate independently before their critical illness (with or without a gait aid), ≤4 days of invasive mechanical ventilation and ≤7 days ICU length of stay, and an expected additional 2-day ICU stay, and who do not fulfil any of the exclusion criteria. After obtaining informed consent, patients are randomised using a web-based, centralised system to either 30 min of in-bed cycling in addition to routine PT, 5 days per week, up to 28 days maximum, or routine PT alone. The primary outcome is the Physical Function ICU Test-scored (PFIT-s) at 3 days post-ICU discharge measured by assessors blinded to treatment allocation. Participants, ICU clinicians and research coordinators are not blinded to group assignment. Our sample size estimate was based on the identification of a 1-point mean difference in PFIT-s between groups.Ethics and dissemination Critical Care Cycling to improve Lower Extremity (CYCLE) is approved by the Research Ethics Boards of all participating centres and Clinical Trials Ontario (Project 1345). We will disseminate trial results through publications and conference presentations.Trial registration number NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot).

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.

Abstract 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.

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Abstract Asthma is the most common chronic condition of childhood. Self-management is integral to good asthma control. This qualitative paper explores how children with asthma and their parents perceive asthma, their experience with asthma, and how they manage symptoms, preventions and medications within and outside the home. We undertook 15 focus groups with 41 school-aged (6–11 years) children with asthma and 38 parents. Parents and their children attended the same focus groups. We used thematic analysis to analyse the transcripts. Our findings show the impact asthma can have on children’s social and emotional wellbeing and highlight how reliant school-aged children are on their parents to effectively manage their asthma. Parents reported being unsure when their child’s symptoms warranted visiting their doctor or hospital. Schools were identified as a source of difficulty regarding asthma management; families reported that children may be self-conscious about their asthma and using their inhaler at school. School policies and teachers’ lack of asthma knowledge were reported to exacerbate children’s reluctance to use their inhaler at school. Our results have implications for the design and implementation of children’s self-management interventions for their asthma, particularly when they are at school and away from their parents.

Abstract 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.gov ISRCTN41009897 . Registered on 19 November 2019. ClinicalTrials.gov NCT04181879 . Registered 02 December 2019.

The strong reduction of air traffic during the COVID-19 pandemic provides a unique test case for the relationship between air traffic density, contrails, and their radiative forcing of climate change. Here, air traffic and contrail cirrus changes are quantified for a European domain for March to August 2020 and compared to the same period in 2019. Traffic data show a 72 % reduction in flight distance compared with 2019. This paper investigates the induced contrail changes in a model study. The contrail model results depend on various methodological details as discussed in parameter studies. In the reference case, the reduced traffic caused a reduction in contrail length. The reduction is slightly stronger than expected from the traffic change because the weather conditions in 2020 were less favorable for contrail formation than in 2019. Contrail coverage over Europe with an optical depth larger than 0.1 decreased from 4.6 % in 2019 to 1.4 % in 2020; the total cirrus cover amount changed by 28 % to 25 %. The reduced contrail coverage caused 70 % less longwave and 73 % less shortwave radiative forcing but, because of various nonlinearities, only 54 % less net forcing in this case. The methods include recently developed models for performance parameters and soot emissions. The overall propulsion efficiency of the aircraft is about 20 % smaller than estimated in earlier studies, resulting in 3 % fewer contrails. Considerable sensitivity to soot emissions is found, highlighting fuel and engine importance. The contrail model includes a new approximate method to account for water vapor exchange between contrails and background air and for radiative forcing changes due to contrail–contrail overlap. The water vapor exchange reduces available ice supersaturation in the atmosphere, which is critical for contrail formation. Contrail–contrail overlap changes the computed radiative forcing considerably. Comparisons to satellite observations are described and discussed in a parallel publication.

Abstract Background Minor injuries are very common in the pediatric population and often occur in the home environment. Despite its prevalence, little is known about outcomes in children following minor injury at home. Understanding the impact of these injuries on children and their families is important for treatment, prevention, and policy. The objectives of our study were (1) To describe the distribution of short-term outcomes following pediatric minor injuries sustained at home and (2) To explore the relationship of injury type and patient and household demographics with these outcomes. Methods Children (n = 102) aged 0–7 years with a minor injury sustained at home were recruited in an urban pediatric emergency department as part of the Child Housing Assessment for a Safer Environment (CHASE) observational study. Each patient had a home visit following the emergency department visit, where five parent-reported outcomes were assessed. Relationships were explored with logistic regression. Results The most common type of injury was soft tissue (57.8 %). 13.2 % of children experienced ≥ 7 days of pain, 21.6 % experienced ≥ 7 days of abnormal activity, 8.9 % missed ≥ 5 days of school, 17.8 % of families experienced ≥ 7 days of disruption, and 9.1 % of parents missed ≥ 5 days of work. Families reported a total of 120 missed school days and 120 missed work days. Children who sustained a burn had higher odds of experiencing pain (OR 6.97), abnormal activity (OR 8.01), and missing school (OR 8.71). The parents of children who sustained a burn had higher odds of missing work (OR 14.97). Conclusions Families of children suffering a minor injury at home reported prolonged pain and changes in activity as well as significant school and work loss. In this cohort, burns were more likely than other minor injuries to have these negative short-term outcomes reported and represent an important target for interventions. The impact of these injuries on missed school and disruption of parental work warrants further consideration.

Abstract Gastro-oesophageal reflux (GOR) is a common physiological state in infants and young children, with gastro-oesophageal reflux disease (GORD) its pathological manifestation. Management of GOR/GORD requires elimination of possible underlying causes, parental reassurance, modification of feeding and symptom mitigation, monitoring, and referral to paediatricians if warning signs are present. Published clinical practice guidelines (CPGs) seek to support clinicians and improve management. This study aimed to measure the proportion of Australian GOR/GORD paediatric care that was in line with CPG recommendations. National and international CPGs for GOR/GORD were systematically identified and candidate indicators extracted; a Delphi process selected 32 indicators relevant to Australian paediatric care in 2012 and 2013. Medical records were identified in General Practices, the offices of general paediatricians, Emergency Departments and inpatient settings. Adherence to indicators was assessed by nine trained paediatric nurses undertaking retrospective medical record review. Medical records were reviewed in 115 healthcare sites; identifying 285 children, three-quarters aged

Abstract Two 3-oxo-Δ4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ4-3-oxo-steroid 5β-reductase (AKR1D1). Relatively little is known about 1 and 2 in adult patients with liver disease. The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). Highly statistically significant correlations (P

Abstract Background The use of multiple medications (polypharmacy) is a concern in older people (≥65 years) and is associated with negative health outcomes. For older populations with multimorbidity, polypharmacy is the reality and the key challenge is ensuring appropriate polypharmacy (as opposed to inappropriate polypharmacy). This external pilot cluster randomised controlled trial (cRCT) aims to further test a theory-based intervention to improve appropriate polypharmacy in older people in primary care in two jurisdictions, Northern Ireland (NI) and the Republic of Ireland (ROI). Methods Twelve GP practices across NI (n=6) and the six counties in the ROI that border NI will be randomised to either the intervention or usual care group. Members of the research team have developed an intervention to improve appropriate polypharmacy in older people in primary care using the Theoretical Domains Framework of behaviour change. The intervention consists of two components: (1) an online video which demonstrates how a GP may prescribe appropriate polypharmacy during a consultation with an older patient and (2) a patient recall process, whereby patients are invited to scheduled medication review consultations with GPs. Ten older patients receiving polypharmacy (≥4 medications) will be recruited per GP practice (n=120). GP practices allocated to the intervention arm will be asked to watch the online video and schedule medication reviews with patients on two occasions; an initial and a 6-month follow-up appointment. GP practices allocated to the control arm will continue to provide usual care to patients. The study will assess the feasibility of recruitment, retention and study procedures including collecting data on medication appropriateness (from GP records), quality of life and health service use (i.e. hospitalisations). An embedded process evaluation will assess intervention fidelity (i.e. was the intervention delivered as intended), acceptability of the intervention and potential mechanisms of action. Discussion This pilot cRCT will provide evidence of the feasibility of a range of study parameters such as recruitment and retention, data collection procedures and the acceptability of the intervention. Pre-specified progression criteria will also be used to determine whether or not to proceed to a definitive cRCT. Trial registration ISRCTN, ISRCTN41009897 . Registered 19 November 2019. ClinicalTrials.gov, NCT04181879 . Registered 02 December 2019.

Abstract Background Neonatal encephalopathy is a complex syndrome in infants that predominantly affects the brain and other organs. The leading cause is a lack of oxygen in the blood reaching the brain. Neonatal encephalopathy can result in mortality or complications later in life, including seizures, movement disorders and cerebral palsy. Treatment options for neonatal encephalopathy are limited mainly to therapeutic hypothermia, although other potential treatments are emerging. However, evaluations of the effectiveness of treatments are challenging because of heterogeneity and inconsistency in outcomes measured and reported between trials. In this paper, we detail how we will develop a core outcome set to standardise outcomes measured and reported upon for interventions for the treatment of neonatal encephalopathy. Methods We will systematically review the literature to identify outcomes reported previously in randomised trials and systematic reviews of randomised trials. We will identify outcomes important to parents or caregivers of infants diagnosed with and who have received treatment for neonatal encephalopathy. We will do this by conducting in person or by video teleconferencing interviews with parents or caregivers in high-income and low- to middle-income countries. Stakeholders with expertise in neonatal encephalopathy (parents/caregivers, healthcare providers and researchers) will rate the importance of identified outcomes in an online Delphi survey using either a three-round Delphi survey or a “Real-Time” Delphi survey to which stakeholders will be allocated at random. Consensus meetings will take place by video conference to allow for an international group of stakeholder representatives to discuss and vote on the outcomes to include in the final core outcome set (COS). Discussion More research is needed on treatments for neonatal encephalopathy. Standardising outcomes measured and reported in evaluations of the effectiveness of interventions for the treatment of neonatal encephalopathy will improve evidence synthesis and improve results reported in systematic reviews and meta-analysis in this area. Overall, this COS will allow for improved treatments to be identified, heterogeneity in research to be reduced, and overall patient care to be enhanced. Trial registration This study is registered in the Core Outcome Measures for Effectiveness (COMET) database http://www.comet-initiative.org/Studies/Details/1270 .

Abstract Background The Delphi method is used in a wide variety of settings as a method of building consensus on important issues. Traditionally, the Delphi method uses multiple rounds of a survey to allow for feedback of other participants’ survey responses in between rounds. By informing participants about how others answer a question or prioritise specific topics, it allows for diverse opinions to inform the consensus process. For this reason, the Delphi method is popular as a consensus building approach in developing core outcome sets (COS), i.e. the minimum agreed set of standardised outcomes that should be measured and reported in studies on a specific health condition. In a COS setting, participants prioritise the importance of outcomes for inclusion in a COS. This usually involves participating in multiple rounds of a survey that can span several weeks or months. Challenges with participant retention have been highlighted in previous COS. We will compare a three-round with a Real-Time Delphi approach on prioritised outcomes. This trial is embedded within the COHESION study which is developing a COS for interventions treating neonatal encephalopathy. Methods One hundred and eighty stakeholders (parents/caregivers of infants diagnosed and treated with neonatal encephalopathy, healthcare providers and researchers) will be randomised using stratified randomisation to take part in either the Multi-Round or Real-Time Delphi. Stakeholders will rate the importance of the same set of outcomes in both arms. We will compare the prioritised outcomes at the end of both surveys as well as other parameters such as feedback, initial condition and iteration effects. Discussion This trial will provide evidence to inform decisions on the use of Multi-Round compared to Real-Time Delphi survey methods. Trial registration NCT04471103 . Registered on 14 July 2020.

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.

Australia harbours a rich and highly endemic orchid flora with over 90% of native species found nowhere else. However, little is known about the assembly and evolution of Australia’s orchid flora. Here, we used a phylogenomic approach to infer evolutionary relationships, divergence times and range evolution in Pterostylidinae (Orchidoideae), the second largest subtribe in the Australian orchid flora, comprising the genera Pterostylis and Achlydosa. Phylogenetic analysis of 75 plastid genes provided well-resolved and supported phylogenies. Intrageneric relationships in Pterostylis were clarified and monophyly of eight of 10 sections supported. Achlydosa was found to not form part of Pterostylidinae and instead merits recognition at subtribal level, as Achlydosinae. Pterostylidinae were inferred to have originated in eastern Australia in the early Oligocene, coinciding with the complete separation of Australia from Antarctica and the onset of the Antarctic Circumpolar Current, which led to profound changes in the world’s climate. Divergence of all major lineages occurred during the Miocene, accompanied by increased aridification and seasonality of the Australian continent, resulting in strong vegetational changes from rainforest to more open sclerophyllous vegetation. The majority of extant species were inferred to have originated in the Quaternary, from the Pleistocene onwards. The rapid climatic oscillations during the Pleistocene may have acted as important driver of speciation in Pterostylidinae. The subtribe underwent lineage diversification mainly within its ancestral range, in eastern Australia. Long-distance dispersals to southwest Australia commenced from the late Miocene onwards, after the establishment of the Nullarbor Plain, which constitutes a strong edaphic barrier to mesic plants. Range expansions from the mesic into the arid zone of eastern Australia (Eremaean region) commenced from the early Pleistocene onwards. Extant distributions of Pterostylidinae in other Australasian regions, such as New Zealand and New Caledonia, are of more recent origin, resulting from long-distance dispersals from the Pliocene onwards. Temperate eastern Australia was identified as key source area for dispersals to other Australasian regions.

Abstract Background Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results GM-CSF, TNF-β, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.

Abstract Background People with dementia (PwD) face unique challenges with medicines management, yet little is known about these challenges from the perspectives of primary healthcare professionals, particularly general practitioners (GPs) and community pharmacists. Few medicines management interventions have been developed which are aimed at community-dwelling PwD. This study sought to develop an intervention to improve medicines management for PwD in primary care using a theory-informed approach. Methods Semi-structured interviews were conducted with GPs (n = 15) and community pharmacists (n = 15) to explore participants’ views and experiences of medicines management for PwD, and their perceptions of barriers and facilitators to successful medicines management for PwD. The 14-domain Theoretical Domains Framework was the underpinning theoretical guide, allowing key theoretical domains to be identified and mapped to behaviour change techniques (BCTs) which are considered the ‘active ingredients’ of an intervention. Draft interventions were developed to operationalise selected BCTs and were presented to GPs and community pharmacists during task groups. Final selection of an intervention for feasibility testing was guided by feedback provided during these task groups and through application of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria. Results Participants expressed a number of concerns about medicines management for PwD, particularly monitoring adherence to medication regimens and conducting medication review. Two draft interventions comprising selected BCTs (‘Modelling or demonstration of behaviour’; ‘Salience of consequences’; ‘Health consequences’; ‘Social and environmental consequences’; ‘Action planning’; Social support or encouragement’, ‘Self-monitoring of behaviour’) were developed, each targeting GPs and community pharmacists. Following the task groups and discussions within the research team, the community pharmacy-based intervention was selected for future feasibility testing. The intervention will target community pharmacists to conduct a medication review (incorporating an adherence check) with a PwD, delivered as an online video demonstrating key behaviours. The video will include feedback emphasising positive outcomes of performing the behaviours. Action planning and a quick reference guide will be used as complementary intervention components. Conclusions A community pharmacist-based intervention has been developed targeting medicines management for PwD in primary care using a systematic, theory-informed approach. Future work will determine the usability and acceptability of implementing this intervention in clinical practice.

Acute kidney injury (AKI) is a common problem in the neonatal intensive care unit (NICU). Neonates born at

Protein C plays a major role in the physiological regulation of coagulation pathways through inactivation of factor Va, factor VIIIa, and plasminogen activator inhibitor. Protein C is involved in the control of inflammation during sepsis, by inhibiting release of pro-inflammatory cytokines, thereby controlling neutrophil, and monocyte effects on injured tissue. Recombinant human activated protein C (rhAPC) reduced mortality in adult sepsis in earlier studies but had no significant benefit in more recent trials. Protein C levels are reduced during paediatric and neonatal sepsis, which may play a major role in the development of disseminated intravascular thrombosis, purpura fulminans, and multiorgan dysfunction. The role of protein C in paediatric sepsis requires further clinical and immunological evaluation to define the patient subgroups who may benefit from this therapy. Newer versions of rhAPC are under development with less risk of haemorrhage potentially broadening the scope of this intervention.

Synaptic gene conditions, i.e., “synaptopathies,” involve disruption to genes expressed at the synapse and account for between 0.5 and 2% of autism cases. They provide a unique entry point to understanding the molecular and biological mechanisms underpinning autism-related phenotypes. Phelan-McDermid Syndrome (PMS, also known as 22q13 deletion syndrome) and NRXN1 deletions (NRXN1ds) are two synaptopathies associated with autism and related neurodevelopmental disorders (NDDs). PMS often incorporates disruption to the SHANK3 gene, implicated in excitatory postsynaptic scaffolding, whereas the NRXN1 gene encodes neurexin-1, a presynaptic cell adhesion protein; both are implicated in trans-synaptic signaling in the brain. Around 70% of individuals with PMS and 43–70% of those with NRXN1ds receive a diagnosis of autism, suggesting that alterations in synaptic development may play a crucial role in explaining the aetiology of autism. However, a substantial amount of heterogeneity exists between conditions. Most individuals with PMS have moderate to profound intellectual disability (ID), while those with NRXN1ds have no ID to severe ID. Speech abnormalities are common to both, although appear more severe in PMS. Very little is currently known about the neurocognitive underpinnings of phenotypic presentations in PMS and NRXN1ds. The Synaptic Gene (SynaG) study adopts a gene-first approach and comprehensively assesses these two syndromic forms of autism. The study compliments preclinical efforts within AIMS-2-TRIALS focused on SHANK3 and NRXN1. The aims of the study are to (1) establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1ds, (2) to compare the clinical profile of PMS, NRXN1ds, and individuals with ‘idiopathic’ autism (iASD), (3) to identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles, and (4) investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles. In the current paper we describe our methodology for phenotyping the sample and our planned comparisons, with information on the necessary adaptations made during the global COVID-19 pandemic. We also describe the demographics of the data collected thus far, including 25 PMS, 36 NRXN1ds, 33 iASD, and 52 NTD participants, and present an interim analysis of autistic features and adaptive functioning.

Neonatal encephalopathy is a syndrome characterised by abnormal neurological function often caused by a hypoxic insult during childbirth. Triggers such as hypoxia-ischaemia result in the release of cytokines and chemokines inducing the infiltration of neutrophils, natural killer cells, B cells, T cells and innate T cells into the brain. However, the role of these cells in the development of the brain injury is poorly understood. We review the mechanisms by which lymphocytes contribute to brain damage in NE. NK, T and innate T cells release proinflammatory cytokines contributing to the neurodegeneration in the secondary and tertiary phase of injury, whereas B cells and regulatory T cells produce IL-10 protecting the brain in NE. Targeting lymphocytes may have therapeutic potential in the treatment of NE in terms of management of inflammation and brain damage, particularly in the tertiary or persistent phases.

Abstract Morgellons disease (MD) is a rare dermatopathy characterized by nonspecific symptoms and the production of multicolored fibers and granular tissue from diffuse skin ulcerations which are described as being either pruritic or painful. The etiology of MD is currently unknown; previous studies have suggested both psychiatric and infectious causes, with increasing interest over the previous decade in elaborating a possible pathogenesis for the disease secondary to infection by Borrelia species. We report a middle‐aged Caucasian female who developed symptoms of MD in the days following exposure to a tick bite after spending an afternoon hiking through a wooded area. She was subsequently treated with a course of Doxycycline and found on two‐week follow‐up to have complete remission of her symptoms. This case report further supports the theory for an infectious etiology of MD and encourages future studies into its pathophysiology.

Background: Neonatal encephalopathy (NE) is associated with adverse neurodevelopmental outcome and is linked with systemic inflammation. Pro-inflammatory and anti-inflammatory cytokines are known to play a role in the pathology of NE by activating innate immune cells.Methods: Eighty-seven infants were enrolled including 53 infants with NE of whom 52 received therapeutic hypothermia (TH) and 34 term infant healthy controls (TC). Whole blood sampling was performed in the first 4 days of life, and a 14-spot ELISA Multiplex Cytokine Array was carried out on baseline samples or after stimulation with lipopolysaccharide (LPS) as an additional inflammatory stimulus. The cytokine medians were examined for differences between infants with NE and healthy TC; and then short-term outcomes of Sarnat stage, seizures, and MRI brain were examined within the NE group. The potential of LPS stimulation to predict abnormal MRI was explored using receiver operating characteristic (ROC) curves.Results: At baseline, infants with NE had significantly higher levels of erythropoietin (Epo), interleukin (IL)-6, and IL-1ra and significantly lower vascular endothelial growth factor (VEGF) than had controls. All cytokines were increased after LPS stimulation in infants with NE with an excessive Epo and IL-1ra response than in controls. Infants with NE had lower IL-8, IL-2, IL-6, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), VEGF, and interferon (IFN)-γ than controls had following LPS. GM-CSF and IFN-γ, IL-1β, IL-1ra, and VEGF were higher on days 1–2 in NE infants with abnormal neuroimaging. GM-CSF, IFN-γ, and TNF-α levels with LPS stimulation were different upon stimulation between normal and abnormal neuroimaging. TNF-α is the only strong cytokine predictor both pre- and post-LPS stimulation of abnormal brain imaging.Conclusions: Altered cytokine responses are found in infants with NE vs. controls, and more significant differences are unmasked by the additional stimulus of LPS, which potentially improves the predictive power of these cytokines for the detection of abnormal MRIs. Infants with NE undergoing TH demonstrate both trained immunity and tolerance, and understanding these responses will facilitate adjunctive immunomodulatory treatments.

BackgroundYoung adults with asthma often report low adherence to inhaled corticosteroids (ICS), leading to uncontrolled symptoms and poor disease outcomes. Technology-enabled digital supports such as mobile health (mHealth) asthma smartphone apps have the potential to support adherence to ICS and asthma self-management. There is a need for feasibility studies to determine the usability, acceptability, and feasibility of these interventions. In addition, it is essential to determine the feasibility of recruiting and retaining young adults to plan future efficacy and effectiveness trials and therefore, establish evidence-based asthma apps. ObjectiveThis study aimed to determine (1) the feasibility of recruiting and retaining young adults to a trial and (2) the usability, acceptability, and feasibility of using the AsthmaMD app to support adherence to ICS in a population of young adults living with asthma. MethodsA multi-methods feasibility study was conducted. Young adults aged 18-30 years with asthma and current prescription for ICS were eligible and invited to take part through a university circular email, social media, and general practice sites. Participation involved completing a baseline self-report questionnaire, downloading and using the AsthmaMD app for 2 weeks, and completing the follow-up assessment, including self-report and open-ended questions about participants’ experience of using the app. Primary outcomes included participant recruitment and retention and the usability, acceptability, and feasibility of using AsthmaMD. Quantitative self-report data were analyzed using descriptive statistics, and qualitative open-ended data were analyzed using inductive reflexive thematic analysis. ResultsA total of 122 young adults (females, n=101, 82.8%) with a mean age of 24.4 (SD 3.8) years were recruited and they completed baseline measures. Of the 122 young adults, 59 (48.4%) completed the study. The AsthmaMD app received a mean score of 63.1/100 (SD 20.1) on the System Usability Scale (ie, a standardized measure of usability for technology-based apps), and an overall user satisfaction score of 5.8/10 (SD 2.2). Of the 59 participants who completed the study, 49 (83%) participants used the app ≥1 day per week. Two main themes were identified in the qualitative analysis of user experiences: (1) learning how to use the app to suit the individual and (2) benefits and relevance of using the app. ConclusionsThe findings from this study indicate that it is feasible to recruit and retain young adults to examine efficacy and effectiveness in a future trial and that young adults living with asthma may find AsthmaMD to be usable, acceptable, and feasible to support adherence to ICS. Our findings also identified opportunities to further optimize the usability of AsthmaMD and similar apps. Based on our findings, we recommend providing more accessible information on how to use the app and replacing medical terminology with simplified language within the app to improve usability. Trial RegistrationISRCTN Registry ISRCTN11295269; https://www.isrctn.com/ISRCTN11295269

Background: Evidence suggests that earlier diagnosis and initiation of treatment immediately after birth is critical for improved neurodevelopmental outcomes following neonatal encephalopathy (NE). Current diagnostic tests are, however, mainly restricted to clinical diagnosis with no molecular tests available. Purines including adenosine are released during brain injury such as hypoxia and are also present in biofluids. Whether blood purine changes can be used to diagnose NE has not been investigated to date.Methods: Blood purines were measured in a mouse model of neonatal hypoxia and infants with NE using a novel point-of-care diagnostic technology (SMARTChip) based on the summated electrochemical detection of adenosine and adenosine metabolites in the blood.Results: Blood purine concentrations were ∼2–3-fold elevated following hypoxia in mice [2.77 ± 0.48 μM (Control) vs. 7.57 ± 1.41 μM (post-hypoxia), p = 0.029]. Data in infants with NE had a 2–3-fold elevation when compared to healthy controls [1.63 ± 0.47 μM (Control, N = 5) vs. 4.87 ± 0.92 μM (NE, N = 21), p = 0.0155]. ROC curve analysis demonstrates a high sensitivity (81%) and specificity (80%) for our approach to identify infants with NE. Moreover, blood purine concentrations were higher in infants with NE and seizures [8.13 ± 3.23 μM (with seizures, N = 5) vs. 3.86 ± 0.56 μM (without seizures, N = 16), p = 0.044].Conclusion: Our data provides the proof-of-concept that measurement of blood purine concentrations via SMARTChip technology may offer a low-volume bedside test to support a rapid diagnosis of NE.

Objectives This 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.Methods A 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.Results The 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%, p

Cerebral Palsy (CP) describes a heterogenous group of non-progressive disorders of posture or movement, causing activity limitation, due to a lesion in the developing brain. CP is an umbrella term for a heterogenous condition and is, therefore, descriptive rather than a diagnosis. Each case requires detailed consideration of etiology. Our understanding of the underlying cause of CP has developed significantly, with areas such as inflammation, epigenetics and genetic susceptibility to subsequent insults providing new insights. Alongside this, there has been increasing recognition of the multi-organ dysfunction (MOD) associated with CP, in particular in children with higher levels of motor impairment. Therefore, CP should not be seen as an unchanging disorder caused by a solitary insult but rather, as a condition which evolves over time. Assessment of multi-organ function may help to prevent complications in later childhood or adulthood. It may also contribute to an improved understanding of the etiology and thus may have an implication in prevention, interventional methods and therapies. MOD in CP has not yet been quantified and a scoring system may prove useful in allowing advanced clinical planning and follow-up of children with CP. Additionally, several biomarkers hold promise in assisting with long-term monitoring. Clinicians should be aware of the multi-system complications that are associated with CP and which may present significant diagnostic challenges given that many children with CP communicate non-verbally. A step-wise, logical, multi-system approach is required to ensure that the best care is provided to these children. This review summarizes multi-organ dysfunction in children with CP whilst highlighting emerging research and gaps in our knowledge. We identify some potential organ-specific biomarkers which may prove useful in developing guidelines for follow-up and management of these children throughout their lifespan.

Background: Physical distancing measures (e.g., keeping a distance of two metres from others, avoiding crowded areas, and reducing the number of close physical contacts) continue to be among the most important preventative measures used to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Therefore, it is important to understand barriers and facilitators of physical distancing to help inform future public health campaigns. Methods: The current study aimed to qualitatively explore barriers and facilitators of physical distancing in the context of the COVID-19 pandemic using a qualitative interpretative design. Semi-structured one-to-one phone interviews were conducted with 25 participants aged 18+ years and living in the Republic of Ireland between September and October 2020. A purposive sampling strategy was used to maximise diversity in terms of age, gender, and socioeconomic status. Interviews were analysed using inductive thematic analysis. Results: Analysis resulted in the development of six main themes related to barriers and facilitators of physical distancing: (1) Maintaining and negotiating close relationships; (2) Public environments support or discourage physical distancing; (3) Habituation to threat; (4) Taking risks to protect well-being; (5) Personal responsibility to control the “controllables”; and (6) Confusion and uncertainty around government guidelines. Conclusions: Physical distancing measures were judged to be more or less difficult based on a number of internal and external psychosocial factors. Barriers to distancing included difficulties maintaining and negotiating close relationships, habituation to COVID-19-related threat, risk compensation, and confusion and uncertainty around government guidelines. Having a sense of personal responsibility to prevent COVID-19 transmission through distancing was an important facilitator. The structure of public environments was viewed as both barrier and facilitator. Barriers and facilitators may vary depending on context and life stage, which should be considered in the design of interventions to target physical distancing behaviour.

Abstract Background Variable and poor care quality are important causes of preventable patient harm. Many patients receive less than recommended care, but the extent of the problem remains largely unknown. The CareTrack Kids (CTK) research programme sought to address this evidence gap by developing a set of indicators to measure the quality of care for common paediatric conditions. In this study, we focus on one clinical area, ‘preventive care’ for pre-school aged children. Our objectives were two-fold: (i) develop and validate preventive care quality indicators and (ii) apply them in general medical practice to measure adherence. Methods Clinical experts (n = 6) developed indicator questions (IQs) from clinical practice guideline (CPG) recommendations using a multi-stage modified Delphi process, which were pilot tested in general practice. The medical records of Australian children (n = 976) from general practices (n = 80) in Queensland, New South Wales and South Australia identified as having a consultation for one of 17 CTK conditions of interest were retrospectively reviewed by trained paediatric nurses. Statistical analyses were performed to estimate percentage compliance and its 95% confidence intervals. Results IQs (n = 43) and eight care ‘bundles’ were developed and validated. Care was delivered in line with the IQs in 43.3% of eligible healthcare encounters (95% CI 30.5–56.7). The bundles of care with the highest compliance were ‘immunisation’ (80.1%, 95% CI 65.7–90.4), ‘anthropometric measurements’ (52.7%, 95% CI 35.6–69.4) and ‘nutrition assessments’ (38.5%, 95% CI 24.3–54.3), and lowest for ‘visual assessment’ (17.9%, 95% CI 8.2–31.9), ‘musculoskeletal examinations’ (24.4%, 95% CI 13.1–39.1) and ‘cardiovascular examinations’ (30.9%, 95% CI 12.3–55.5). Conclusions This study is the first known attempt to develop specific preventive care quality indicators and measure their delivery to Australian children in general practice. Our findings that preventive care is not reliably delivered to all Australian children and that there is substantial variation in adherence with the IQs provide a starting point for clinicians, researchers and policy makers when considering how the gap between recommended and actual care may be narrowed. The findings may also help inform the development of specific improvement interventions, incentives and national standards.

Abstract Background Clinical trials management can be studied using project management theory. The CYCLE pilot randomized controlled trial (RCT) was conducted to determine the feasibility of a future rehabilitation trial of early in-bed cycling in the intensive care unit (ICU). In-bed cycling is a novel intervention, not typically available in ICUs. Implementation of this intervention requires personnel with specialized clinical expertise caring for critically ill patients and use of the in-bed cycle. Our objective was to describe the implementation and conduct of our pilot RCT using a project management approach. Methods We retrospectively reviewed activities, timelines, and personnel involved in the trial. We organized activities into four project management phases: initiation, planning, execution, and monitoring and controlling. Data sources included Methods Centre documents used for trial coordination and conduct, and the trial data set. We report descriptive statistics as counts and proportions and also medians and quartiles, and we summarize the lessons learned. Results Seven ICUs in Canada participated in the trial. Time from research ethics board and contracts submission to first enrolment was a median (first quartile, third quartile) of 185 (146, 209) and 162 (114, 181) days, respectively. We trained 128 personnel on the CYCLE pilot RCT protocol, and 80 (63%) completed trial-related activities. Four sites required additional training after start-up due to staff turnover and leaves of absence. Over 15 months, we screened 864 patients: 256 were eligible and 66 were enrolled. Despite an 85% consent rate, 74% (190/256) of eligible patients were not randomized, largely (80% [152/190]) due to physiotherapist availability. Thirteen percent of recruitment weeks were lost due to physiotherapist staffing shortages. We highlight five key lessons learned: (1) prepare and anticipate site needs; (2) communicate regularly; (3) proactively analyse and act on process measure data; (4) develop contingency plans; (5) express appreciation to participating sites. Conclusions Our analysis highlights the scope of relevant activities, rigorous training and monitoring, number and types of required personnel, and time required to conduct a multicentre ICU rehabilitation intervention trial. Our lessons learned can help others interested in implementing complex intervention trials, such as rehabilitation. Trial registration ClinicalTrials.gov, NCT02377830. Registered prospectively on 4 March 2015.

Neutrophils are the most abundant innate immune cell with critical anti-microbial functions. Since the discovery of granulocytes at the end of the nineteenth century, the cells have been given many names including phagocytes, polymorphonuclear neutrophils (PMN), granulocytic myeloid derived suppressor cells (G-MDSC), low density neutrophils (LDN) and tumor associated neutrophils (TANS). This lack of standardized nomenclature for neutrophils suggest that biologically distinct populations of neutrophils exist, particularly in disease, when in fact these may simply be a manifestation of the plasticity of the neutrophil as opposed to unique populations. In this review, we profile the surface markers and granule expression of each stage of granulopoiesis to offer insight into how each stage of maturity may be identified. We also highlight the remarkable surface marker expression profiles between the supposed neutrophil populations.