Skin-to-deltoid-muscle distance at three recommended sites for intramuscular vaccination in a population with obesity: an observational study.

AIM: Worldwide, immunisation guidelines variably locate the deltoid injection site based on anatomical landmarks. This may influence the skin-to-deltoid-muscle distance and therefore the needle length required to achieve intramuscular injection. Obesity is associated with increased skin-to-deltoid-muscle distance, but it is unknown whether the injection site location chosen in individuals with obesity impacts the needle length required for intramuscular injection. The aim of the study was to estimate the differences in skin-to-deltoid-muscle distance between three different vaccine injection sites recommended by the national guidelines of the United States of America (USA), Australia and New Zealand, in obese adults. The study also explored i) the associations between skin-to-deltoid-muscle distance across the three recommended sites with sex, body mass index (BMI), and arm circumference, and ii) the proportion of participants with a skin-to-deltoid-muscle distance >20 millimetres (mm), in whom the standard 25mm needle length would not ensure deposition of vaccine within the deltoid muscle. METHOD: Non-interventional cross-sectional study in a single site, non-clinical setting in Wellington, New Zealand. Forty participants (29 females), aged ≥18 years, with obesity (BMI>30 kilograms [km]/m[[2]]). Measurements included distance from acromion to injection sites, BMI, arm circumference, and skin-to-deltoid-muscle distance measured by ultrasound at each recommended injection site. RESULTS: Mean (SD) skin-to-deltoid-muscle distances for USA, Australia and New Zealand sites were 13.96mm (4.54), 17.94mm (6.08) and 20.26mm (5.91) respectively, with a mean (95% confidence interval) for the distance between Australia minus New Zealand -2.7mm (-3.5 to -1.9), P<0.001; and USA minus New Zealand -7.6 mm (-8.5 to -6.7); P<0.001. Skin-to-deltoid-muscle distance was greater in females and was positively associated with BMI and arm circumference. The proportions with a skin-to-deltoid-muscle distance >20 mm were 45%, 40% and 15% for the New Zealand, Australia and USA sites respectively. However, the sample size was relatively small, limiting interpretation in specific sub-groups. CONCLUSION: There were marked differences in the skin-to-deltoid-muscle distance between the three recommended injection sites studied. When choosing the required needle length to achieve intramuscular vaccination in obese vaccine recipients, consideration needs to be given to the injection site location, sex, BMI and/or arm circumference, as these factors all influence the skin-to-deltoid-muscle distance. A standard needle length of 25mm may be insufficient to ensure deposition of vaccine into the deltoid muscle in a substantive proportion of adults with obesity. Research is urgently required to determine anthropometric measurement cut-points that can be used to enable appropriate needle length selection to ensure intramuscular vaccination.

COVID-19 vaccination and the skin to deltoid MUSCLE distance in adults with diabetes.

Objectives: To estimate the proportion of adult diabetics with a skin to deltoid muscle distance (SDMD) of > 25 mm, representing a distance greater than the standard needle length used for intramuscular COVID-19 vaccination, and to assess whether anthropometric measurements predict ultrasound SDMD measurements. Design: Non-interventional cross-sectional study. Setting: Single site, non-clinical setting, Wellington, New Zealand. Participants: One hundred participants (50 females) aged at least 18 years diagnosis with diabetes. All participants completed the study. Main outcome measures: The proportions of participants with a SDMD > 25 mm and a SDMD > 20 mm (indicating that the needle would not have penetrated at least 5 mm into the deltoid, which is considered necessary to ensure deposition of vaccine into muscle); the relationship between anthropometric measurements (body weight, body height, body mass index (BMI), skinfold thickness, arm circumference) and SDMD measured by ultrasound. Results: The proportion (95 %CI) of participants with a SDMD > 25 mm was 6/100; 6 % (2.2 to 12.6), and the proportion with a SDMD > 20 mm was 11 % (5.6 to 18.8), of which 9/11 had a BMI ≥ 30 kg/m2 and 9/11 were female. The strongest relationships between anthropometric measurements and SDMD were with arm circumference (r = 0.76, P < 0.001) and BMI (r = 0.73, P < 0.001). Arm circumference and BMI were the best predictors of SDMD measurements with AUC for ROC curves of 0.99 and 0.94 above the 25 mm cut point, 0.97 and 0.89 above the 20 mm cut point respectively. Conclusions: The standard needle length of 25 mm is likely to be insufficient to ensure deposition of COVID-19 vaccine within the deltoid muscle in a small but important proportion of obese adults with diabetes. Arm circumference and BMI are simple measurements that could identify those that need a long needle to ensure successful intramuscular vaccine administration. Funding: Ruth Maud Ring Spencer Estate; Health Research Council of New Zealand (Independent Research Organisation).

Asthma control with ICS-formoterol reliever versus maintenance ICS and SABA reliever therapy: a post hoc analysis of two randomised controlled trials.

BACKGROUND: In randomised controlled trials, as-needed inhaled corticosteroid (ICS)-formoterol reliever therapy reduces severe exacerbation risk compared with maintenance ICS plus short-acting beta2-agonist (SABA) reliever in adolescent and adult asthma, but results in slightly worse control of asthma symptoms, as measured by mean Asthma Control Questionnaire-5 (ACQ-5) score. OBJECTIVE: To assess the levels and changes in asthma control for as-needed budesonide-formoterol versus maintenance budesonide plus SABA in post hoc analyses from the Novel START and PRACTICAL clinical trials. METHODS: The number and proportion of participants at study end in each ACQ-5 category ('well-controlled', 'partly controlled' or 'inadequately controlled' symptoms), and in each responder category based on the minimal clinically important difference for ACQ-5 of 0.5 (improved, no change and worse) with as-needed budesonide-formoterol and maintenance budesonide plus SABA treatment were calculated. RESULTS: With last observation carried forwards, 189/214 (88.3%) and 354/434 (81.6%) of patients in the budesonide-formoterol group had 'well-controlled' or 'partly controlled' symptoms at the end of the study, vs 183/214 (85.5%) and 358/431 (83.1%) in the budesonide maintenance group, for Novel START and PRACTICAL, respectively. The proportion of patients whose symptom control was either improved or unchanged from baseline was 190/214 (88.8%) and 368/434 (84.8%) for budesonide-formoterol, vs 185/214 (86.4%) and 376/431 (87.2%) for maintenance budesonide, in Novel START and PRACTICAL respectively. CONCLUSIONS: There were no clinically important differences in the proportions of patients with 'well-controlled' or 'partly controlled' asthma symptoms, or proportions who improved or maintained their level of control, with as-needed budesonide-formoterol versus maintenance budesonide plus SABA.

Single dose of budesonide/formoterol turbuhaler compared to salbutamol pMDI for speed of bronchodilator onset in asthma: a randomised cross-over trial.

OBJECTIVE: To compare bronchodilator response after to salbutamol and budesonide/formoterol in adults with stable asthma. METHODS: A double-blind, cross-over, single-centre, placebo-controlled, non-inferiority trial. Adults with stable asthma were randomised to different orders of two treatment regimens: two actuations of placebo via MDI and one actuation of budesonide/formoterol 200/6 µg via turbuhaler; and one actuation of placebo turbuhaler and two actuations of salbutamol 100 µg via MDI. The primary outcome measure was FEV1 after 2 min. Secondary outcome measures included FEV1, mBorg Dyspnoea Scale score and visual analogue score for breathlessness over 30 min. RESULTS: Forty-nine of 50 potential participants were randomised. One participant withdrew following the first intervention visit and another could not be randomised due to COVID-19 restrictions. The mean (SD) change from baseline FEV1 2 min after treatment administration for budesonide/formoterol and salbutamol was 0.08 (0.14) L, n=49, and 0.17 (0.18) L, n=48, respectively, mean (95% CI) paired difference of -0.097 L (-0.147 to -0.047), p=0.07, against a non-inferiority bound of -0.06 L. In the secondary analysis, FEV1 over 30 min was lower for budesonide/formoterol compared with salbutamol, difference (95% CI): -0.10 (-0.12 to -0.08) L, p<0.001. There were no differences in Visual Analogue Scale score or mBorg Dyspnoea Scale score between treatments. CONCLUSION: The results do not support the primary hypothesis of non-inferiority at the boundary of -0.06 L for the difference between budesonide/formoterol 200/6 µg compared with salbutamol 200 µg for FEV1 at 2 min, and could be consistent with inferiority with a p value of 0.07. For the secondary analysis of FEV1 measurements over time, the FEV1 was higher with salbutamol. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN 12619001387112).

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Cannabis in Palliative Care: A Systematic Review of Current Evidence.

CONTEXT: Palliative care aims to improve the quality of life in patients with incurable illness. Medicinal cannabis (MC) has been used in the palliative care setting to address multiple symptoms in patients. OBJECTIVES: To evaluate the full scope of available literature investigating the effects and potential harms of MC on symptom management and quality of life in palliative care. METHODS: PubMed, Embase, The Cochrane Library and clinicaltrials.gov were searched for eligible articles, published between 1960 and September 9, 2021. Quality of the evidence was assessed in accordance with Grading of Recommendations, Assessment, Development and Evaluations. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. RESULTS: Fifty-two studies (20 randomised; 32 non-randomised) with 4786 participants diagnosed with cancer (n = 4491), dementia (n = 43), AIDS (n = 235), spasticity (n = 16), NORSE syndrome (n = 1) were included. The quality of evidence was 'very low' or 'low' for all studies, and low for only two randomised controlled trials. Positive treatment effects (statistical significance with P < 0.05) were seen for some MC products in pain, nausea and vomiting, appetite, sleep, fatigue, chemosensory perception and paraneoplastic night sweats in patients with cancer, appetite and agitation in patients with dementia and appetite, nausea and vomiting in patients with AIDS. Meta-analysis was unable to be performed due to the wide range of cannabis products used and the heterogeneity of the study outcomes. CONCLUSION: While positive treatment effects have been reported for some MC products in the palliative care setting, further high quality evidence is needed to support recommendations for its use in clinical practice.

Prophylaxis in healthcare workers during a pandemic: a model for a multi-centre international randomised controlled trial using Bayesian analyses.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has exposed the disproportionate effects of pandemics on frontline workers and the ethical imperative to provide effective prophylaxis. We present a model for a pragmatic randomised controlled trial (RCT) that utilises Bayesian methods to rapidly determine the efficacy or futility of a prophylactic agent. METHODS: We initially planned to undertake a multicentre, phase III, parallel-group, open-label RCT, to determine if hydroxychloroquine (HCQ) taken once a week was effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in healthcare workers (HCW) aged ≥ 18 years in New Zealand (NZ) and Ireland. Participants were to be randomised 2:1 to either HCQ (800 mg stat then 400 mg weekly) or no prophylaxis. The primary endpoint was time to Nucleic Acid Amplification Test-proven SARS-CoV-2 infection. Secondary outcome variables included mortality, hospitalisation, intensive care unit admissions and length of mechanical ventilation. The trial had no fixed sample size or duration of intervention. Bayesian adaptive analyses were planned to occur fortnightly, commencing with a weakly informative prior for the no prophylaxis group hazard rate and a moderately informative prior on the intervention log hazard ratio centred on 'no effect'. Stopping for expected success would be executed if the intervention had a greater than 0.975 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Final success would be declared if, after completion of 8 weeks of follow-up (reflecting the long half-life of HCQ), the prophylaxis had at least a 0.95 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Futility would be declared if HCQ was shown to have less than a 0.10 posterior probability of reducing acquisition of SARS-CoV-2 infection by more than 20%. DISCUSSION: This study did not begin recruitment due to the marked reduction in COVID-19 cases in NZ and concerns regarding the efficacy and risks of HCQ treatment in COVID-19. Nonetheless, the model presented can be easily adapted for other potential prophylactic agents and pathogens, and pre-established collaborative models like this should be shared and incorporated into future pandemic preparedness planning. TRIAL REGISTRATION: The decision not to proceed with the study was made before trial registration occurred.

Panic or peace - prioritising infant welfare when medicating feverish infants: a grounded theory study of adherence in a paediatric clinical trial.

BACKGROUND: Literature on factors influencing medication adherence within paediatric clinical trials is sparse. The Paracetamol and Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki) trial is an open-label, randomised controlled trial aiming to determine whether paracetamol treatment, compared with ibuprofen treatment, as required for fever and pain in the first year of life, increases the risk of asthma at age six years. To inform strategies for reducing trial medication crossovers, understanding factors influencing the observed ibuprofen-to-paracetamol crossovers (non-protocol adherence) is vital. The aim of this study was to investigate the factors influencing the decision-making process when administering or prescribing ibuprofen to infants that may contribute to the crossover events in the PIPPA Tamariki trial. METHODS: Constructivist grounded theory methods were employed. We conducted semi-structured interviews of caregivers of enrolled PIPPA Tamariki infants and healthcare professionals in various healthcare settings. Increasing theoretical sensitivity of the interviewers led to theoretical sampling of participants who could expand on the teams' early constructed codes. Transcribed interviews were coded and analysed using the constant comparative method of concurrent data collection and analysis. RESULTS: Between September and December 2020, 20 participants (12 caregivers; 8 healthcare professionals) were interviewed. We constructed a grounded theory of prioritising infant welfare that represents a basic social process when caregivers and healthcare professionals medicate feverish infants. This process comprises three categories: historical, trusting relationships and being discerning; and is modified by one condition: being conflicted. Participants bring with them historical ideas. Trusting relationships with researchers, treating clinicians and family play a central role in enabling participants to challenge historical ideas and be discerning. Trial medication crossovers occur when participants become conflicted, and they revert to historical practices that feel familiar and safer. CONCLUSIONS: We identified factors and a basic social process influencing ibuprofen use in infants and trial medication crossover events, which can inform strategies for promoting adherence in the PIPPA Tamariki trial. Future studies should explore the role of trusting relationships between researchers and treating clinicians when conducting research.

Perspectives of mild asthma patients on maintenance versus as-needed preventer treatment regimens: a qualitative study.

OBJECTIVES: As-needed low-dose combination budesonide-formoterol is recommended by asthma guidelines in many countries as an alternative to maintenance inhaled corticosteroids (ICS) for treatment of mild asthma, but there are few data on patient attitudes toward these regimens. This study explored the comparative implementation experiences and future treatment preferences of mild asthma patients who had experienced these two treatment regimens. SETTING: A subgroup of adults randomised to maintenance ICS or as-needed ICS-formoterol in a multinational, 52-week open-label randomised controlled trial (NovelSTART) in mild asthma patients were interviewed to explore their motivations for treatment use during the study and their preferences for future treatment. PARTICIPANTS: Semistructured interviews were conducted with 74 participants (Maintenance group: n=39, As-needed group n=35, mean age 38 (range 19-69)) and thematically analysed from transcribed audiorecordings. RESULTS: Emergent themes from analysis comprised: 'How much my asthma affects me' (how their asthma's impact affected their self-management motivation); 'What I know about asthma' (limited knowledge impeded appropriate self-management decision making); 'How much effort this treatment regimen involves for me' (treatment complexity and/or difficulty establishing a medication routine impeded implementation, particularly in the Maintenance group); and 'My beliefs about the benefits and risks of this treatment' (patients who considered their treatment as ineffective, eg, limited difference in symptoms relative to salbutamol (both groups) or slower onset of relief (As-needed group) had poor motivation to use the treatment). Due to the simplicity of the as-needed combination strategy, this was the preferred future regimen, even by patients who had not yet tried it. CONCLUSIONS: Key patient perspectives on the implementation of preventer treatments for mild asthma included factors relating to perceived asthma burden, disease knowledge, treatment complexity and treatment usefulness or safety. The as-needed budesonide-formoterol regimen was preferred to maintenance ICS treatment in mild asthma though patient education is urgently needed to address implementation motivation. TRIAL REGISTRATION NUMBER: ACTRN12615000999538.

Experiences, patient interactions and knowledge regarding the use of cannabis as a medicine in a cohort of New Zealand doctors in an oncology setting.

PURPOSE OF STUDY: To explore the experiences, patient interactions and knowledge regarding the use of cannabis as a medicine in New Zealand doctors in an oncology setting. STUDY DESIGN: An observational cross-sectional survey undertaken between November 2019 and January 2020 across four secondary-care hospital oncology departments within New Zealand (Auckland, Wellington, Christchurch and Dunedin). Participants were a convenience sample of doctors; consultants, registrars, medical officers of special status and house surgeons working in oncology departments. Of 53 individuals approached, 45 participated (85% Response Rate). The primary outcome was reporteddoctor-patient interactions. Secondary outcomes included knowledge of cannabis-based products, their efficacy, prescribing regulations and educational access. RESULTS: Of 44 doctors, 37 (84%, 95% CI: 70 to 93) reported patient requests to prescribe cannabis-based products and 43 (98%, 95% CI: 88 to 100) reported patients using illicit cannabis for medical symptoms. Primary request reasons were pain, nausea/vomiting and cancer treatment. 33/45 (73%, 95% CI: 58 to 85) cited knowledge of at least one cannabis-based product and 27/45 (60%, 95% CI: 44 to 74) indicated at least one condition that had evidence of efficacy. 36/44 (82%, 95% CI: 67 to 92) expressed future prescribing concerns but all were willing to use a cannabis-based product developed with traditional medical provenance. CONCLUSION: In the oncology setting, patients are asking doctors about symptomatic and curative treatment with cannabis-based products. Doctors are not biased against the use of products showing medical provenance; however, NZ-specific clinical and regulatory guidelines are essential to support patient discussions and appropriate prescribing.

Potential Association Between Dietary Fibre and Humoral Response to the Seasonal Influenza Vaccine.

Influenza vaccination is an effective public health measure to reduce the risk of influenza illness, particularly when the vaccine is well matched to circulating strains. Notwithstanding, the efficacy of influenza vaccination varies greatly among vaccinees due to largely unknown immunological determinants, thereby dampening population-wide protection. Here, we report that dietary fibre may play a significant role in humoral vaccine responses. We found dietary fibre intake and the abundance of fibre-fermenting intestinal bacteria to be positively correlated with humoral influenza vaccine-specific immune responses in human vaccinees, albeit without reaching statistical significance. Importantly, this correlation was largely driven by first-time vaccinees; prior influenza vaccination negatively correlated with vaccine immunogenicity. In support of these observations, dietary fibre consumption significantly enhanced humoral influenza vaccine responses in mice, where the effect was mechanistically linked to short-chain fatty acids, the bacterial fermentation product of dietary fibre. Overall, these findings may bear significant importance for emerging infectious agents, such as COVID-19, and associated de novo vaccinations.

Rhinothermy delivered by nasal high flow therapy in the treatment of the common cold: a randomised controlled trial.

BACKGROUND: The common cold is the most common infectious disease affecting humans and has a substantial economic impact on society. Human rhinoviruses, which cause almost two-thirds of colds, have demonstrated temperature-dependent replication which is optimal between 33°C and 35°C. METHODS: This randomised, single-blind, parallel-group trial completed at a single-centre in New Zealand, recruited 170 participants aged 18-75 years (mean age 27.5 years) who were within 48 hours of common cold symptom onset and had a symptom score (the Modified Jackson Score (MJS)) ≥7 and a negative point-of-care test for influenza. Participants were blinded to the intervention and randomised (1:1) to 5 days of either nasal high flow rhinothermy (rNHF) (100% humidified air delivered at 35 L/min and 41°C for 2 hours daily) (n=85) or 'sham' rhinothermy (100% humidified air delivered at 10 L/min and 31°C for 10 min daily) (n=85) and completed daily symptom diaries, which included the MJS, for 14 days, to investigate whether rNHF reduced common cold symptom severity and duration compared with 'sham' rhinothermy. RESULTS: An intention-to-treat superiority analysis included all randomised participants and showed no difference between treatment groups for the primary outcome, the day 4 MJS analysed by analysis of covariance: mean (SD) 6.33 (3.97) for rNHF vs 5.8 (3.15) for 'sham'; estimated difference (95% CI) 0.37 (-0.69 to 1.42), p=0.49. There was no difference in time until resolution of symptoms: mean (SD) 5.96 (4.47) days for rNHF vs 6.42 (4.09) days for 'sham'; estimated difference (95% CI) 1.02 (0.75 to 1.38), p=0.91. There were no serious adverse events related to the study treatments. CONCLUSIONS: This well-powered, single-blind randomised controlled trial does not provide evidence that 5 days of rNHF (100% humidified air heated to 41°C delivered at 35 L/min for 2 hours daily) reduces common cold symptom severity or duration. However, investigation of rNHF in the treatment of influenza is warranted. TRIAL REGISTRATION NUMBER: ACTRN12617001340325.

The Children's Anti-inflammatory Reliever (CARE) study: a protocol for a randomised controlled trial of budesonide-formoterol as sole reliever therapy in children with mild asthma.

BACKGROUND: Asthma is the most common chronic disease in children, many of whom are managed solely with a short-acting ß2-agonist (SABA). In adults, the evidence that budesonide-formoterol as sole reliever therapy markedly reduces the risk of severe exacerbations compared with SABA alone has contributed to the Global Initiative for Asthma recommending against SABA monotherapy in this population. The current lack of evidence in children means it is unknown whether these findings are also relevant to this demographic. High-quality randomised controlled trials (RCTs) are needed. OBJECTIVE: The aim of this study is to determine the efficacy and safety of as-needed budesonide-formoterol therapy compared with as-needed salbutamol in children aged 5 to 15 years with mild asthma, who only use a SABA. METHODS: A 52-week, open-label, parallel group, phase III RCT will recruit 380 children aged 5 to 15 years with mild asthma. Participants will be randomised 1:1 to either budesonide-formoterol (Symbicort Rapihaler®) 50/3 µg, two actuations as needed, or salbutamol (Ventolin®) 100  µg, two actuations as needed. The primary outcome is asthma attacks as rate per participant per year. Secondary outcomes assess asthma control, lung function, exhaled nitric oxide and treatment step change. A cost-effectiveness analysis is also planned. CONCLUSION: This is the first RCT to assess the safety and efficacy of as-needed budesonide-formoterol in children with mild asthma. The results will provide a much-needed evidence base for the treatment of mild asthma in children.

Determination of oxygen saturation compared to a prescribed target range using continuous pulse oximetry in acutely unwell medical patients.

BACKGROUND: Both inadequate and excessive administration of oxygen to acutely unwell patients results in risk of harm. Guidelines recommend titration of oxygen to achieve a target oxygen saturation (SpO2) range. Information regarding whether this is being achieved is limited. METHODS: In this two-centre non-interventional study we used continuous pulse oximetry in acutely unwell medical patients over a 24-h period to determine the proportion of time spent with SpO2 within the prescribed target range and whether this is influenced by the target range, age, care in a high-dependency area and the number of oxygen adjustments. RESULTS: Eighty participants were included in the analysis. The mean (SD) proportion of time spent in target range was 55.6% (23.6), this was lower in those with a reduced hypercapnic target range (88-92% or below) compared to those with a range of 92-96%; difference - 13.1% (95% CI - 3.0 to - 23.2), P = 0.012. The proportion of time spent above range was 16.2% (22.9); this was higher in those with a reduced hypercapnic range; difference 21.6% (31.4 to 12), P < 0.001. The proportion of time below range was 28.4% (25.2); there was no difference between target ranges. The proportion of time spent in range was higher for those in a high dependency area in the multivariate model; difference 15.5% (95% CI 2.3 to 28.7), P = 0.02. CONCLUSIONS: Medical patients receiving oxygen in a ward setting spend significant periods of time with SpO2 both above and below the prescribed target range while receiving oxygen therapy.

Automatic versus manual oxygen titration using a novel nasal high-flow device in medical inpatients with an acute illness: a randomised controlled trial.

BACKGROUND: Guideline recommendations state oxygen should be administered to acutely unwell patients to achieve a target oxygen saturation (SpO2) range. The current practice of manual oxygen titration frequently results in SpO2 outside of a prescribed range. The aim of this study was to assess the efficacy of automatic oxygen titration using a closed-loop feedback system to achieve SpO2 within a prescribed target range METHODS: An open-label randomised parallel group trial was undertaken comparing automatic oxygen titration using a novel nasal high-flow device to manual oxygen titration using nasal high flow. Medical inpatients requiring oxygen therapy in Wellington Regional Hospital, New Zealand with a prescribed target SpO2 range of 88%-92% or 92%-96% were recruited and randomised equally between the interventions for a period of 24 hours. The primary outcome was the proportion of time spent with SpO2 within the prescribed range. RESULTS: 20 patients were included in the analysis. Automatic oxygen titration resulted in a median (IQR) 96.2% (95.2-97.8) of time within the target range compared with 71% (59.4-88.3) with manual titration; difference (95% CI) 24.2% (7.9% to 35%), p<0.001. There was a reduction in the time spent with SpO2 ≥2% above and ≥2% below range in the automatic titration group, although the point estimate for the differences were small; -1% (-8.2% to -0.04%), p=0.017 and -2.4% (-11.5% to 0.3%), p=0.05 respectively. CONCLUSIONS: Nasal high-flow with automatic oxygen titration resulted in a greater proportion of time spent with SpO2 in target range compared with manual titration. TRIAL REGISTRATION: The trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000901101).

Public engagement with clinical research on social media; which visual medium works best? A 5-year retrospective analysis.

'Public engagement' describes a collaborative relationship between scientists and the public we serve. This has the potential to improve clinical research and is encouraged by key research funding bodies, however the objective evidence base for effective approaches remains limited. Social media algorithms determine what content users see and are known to weight post media differently. While visual content is understood to improve reach and engagement broadly, less is known about which kinds of visuals are most effective for engaging people with clinical research. We present a five year retrospective analysis of public engagement with Facebook posts made by an independent medical research institute, classified by their visual media content. Inclusion of visual post media was associated with positive effects on both reach and engagement. We present medium and strong evidence that this effect was most pronounced for comics compared to other visual media types. This data evidences objective value of using comics and other visual media for public engagement with clinical research. The metrics evaluated are easily accessible on many social media platforms meaning this approach could readily be applied by other researchers to measure the impact of their public engagement efforts, and inform science communication strategies and resource allocation.

Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial.

BACKGROUND: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. OBJECTIVE: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. METHODS: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. RESULTS: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. CONCLUSIONS: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.

ICS-formoterol reliever versus ICS and short-acting ß2-agonist reliever in asthma: a systematic review and meta-analysis.

BACKGROUND: The Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting ß2-agonist (SABA) reliever at step 2 of its stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on prevention of severe exacerbation. METHODS: We performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (identifier number CRD42020154680). RESULTS: Four RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95% CI 0.73-1.00; p=0.048) and reduced daily ICS dose (mean difference -177.3 µg, 95% CI -182.2--172.4 µg). Asthma symptom control was worse in the as-needed group (Asthma Control Questionnaire-5 mean difference 0.12, 95% CI 0.09-0.14), although this did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (OR 1.07, 95% CI 0.84-1.36). CONCLUSION: As-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option when prevention of severe exacerbation is the primary aim of treatment.