High-flow nasal oxygen for children's airway surgery to reduce hypoxaemic events: a randomised controlled trial.

BACKGROUND: Tubeless upper airway surgery in children is a complex procedure in which surgeons and anaesthetists share the same operating field. These procedures are often interrupted for rescue oxygen therapy. The efficacy of nasal high-flow oxygen to decrease the frequency of rescue interruptions in children undergoing upper airway surgery is unknown. METHODS: In this multicentre randomised trial conducted in five tertiary hospitals in Australia, children aged 0-16 years who required tubeless upper airway surgery were randomised (1:1) by a web-based randomisation tool to either nasal high-flow oxygen delivery or standard oxygen therapy (oxygen flows of up to 6 L/min). Randomisation was stratified by site and age (<1 year, 1-4 years, and 5-16 years). Subsequent tubeless upper airway surgery procedures in the same child could be included if there were more than 2 weeks between the procedures, and repeat surgical procedures meeting this condition were considered to be independent events. The oxygen therapy could not be masked, but the investigators remained blinded until outcome data were locked. The primary outcome was successful anaesthesia without interruption of the surgical procedure for rescue oxygenation. A rescue oxygenation event was defined as an interruption of the surgical procedure to deliver positive pressure ventilation using either bag mask technique, insertion of an endotracheal tube, or laryngeal mask to improve oxygenation. There were ten secondary outcomes, including the proportion of procedures with a hypoxaemic event (SpO2 <90%). Analyses were done on an intention-to-treat (ITT) basis. Safety was assessed in all enrolled participants. This trial is registered in the Australian New Zealand Clinical Trials Registry, ACTRN12618000949280, and is completed. FINDINGS: From Sept 4, 2018, to April 12, 2021, 581 procedures in 487 children were randomly assigned to high-flow oxygen (297 procedures) or standard care (284 procedures); after exclusions, 528 procedures (267 assigned to high-flow oxygen and 261 assigned to standard care) in 483 children (293 male and 190 female) were included in the ITT analysis. The primary outcome of successful anaesthesia without interruption for tubeless airway surgery was achieved in 236 (88%) of 267 procedures on high-flow oxygen and in 229 (88%) of 261 procedures on standard care (adjusted risk ratio [RR] 1·02, 95% CI 0·96-1·08, p=0·82). There were 51 (19%) procedures with a hypoxaemic event in the high-flow oxygen group and 57 (22%) in the standard care group (RR 0·86, 95% CI 0·58-1·24). Of the other prespecified secondary outcomes, none showed a significant difference between groups. Adverse events of epistaxis, laryngospasm, bronchospasm, hypoxaemia, bradycardia, cardiac arrest, hypotension, or death were similar in both study groups. INTERPRETATION: Nasal high-flow oxygen during tubeless upper airway surgery did not reduce the proportion of interruptions of the procedures for rescue oxygenation compared with standard care. There were no differences in adverse events between the intervention groups. These results suggest that both approaches, nasal high-flow or standard oxygen, are suitable alternatives to maintain oxygenation in children undergoing upper airway surgery. FUNDING: Thrasher Research Fund, the Australian and New Zealand College of Anaesthetists, the Society for Paediatric Anaesthesia in New Zealand and Australia.

Host movement dominates the predicted effects of climate change on parasite transmission between wild and domestic mountain ungulates.

Climate change is shifting the transmission of parasites, which is determined by host density, ambient temperature and moisture. These shifts can lead to increased pressure from parasites, in wild and domestic animals, and can impact the effectiveness of parasite control strategies. Understanding the interactive effects of climate on host movement and parasite life histories will enable targeted parasite management, to ensure livestock productivity and avoid additional stress on wildlife populations. To assess complex outcomes under climate change, we applied a gastrointestinal nematode transmission model to a montane wildlife-livestock system, based on host movement and changes in abiotic factors due to elevation, comparing projected climate change scenarios with the historic climate. The wildlife host, Alpine ibex (Capra ibex ibex), undergoes seasonal elevational migration, and livestock are grazed during the summer for eight weeks. Total parasite infection pressure was more sensitive to host movement than to the direct effect of climatic conditions on parasite availability. Extended livestock grazing is predicted to increase parasite exposure for wildlife. These results demonstrate that movement of different host species should be considered when predicting the effects of climate change on parasite transmission, and can inform decisions to support wildlife and livestock health.

Predisposing, enabling and reinforcing factors associated with opioid addiction helping behaviour in tri-state Appalachian counties: application of the PRECEDE-PROCEED model-cross-sectional analysis.

OBJECTIVES: The overdose epidemic was designated a 'Public Health Emergency' in the USA on 26 October 2017, bringing attention to the severity of this public health problem. The Appalachian region remains substantially impacted by the effects from years of overprescription of opioids, and subsequently opioid non-medical use and addiction. This study aims to examine the utility of the PRECEDE-PROCEED model constructs (ie, predisposing, reinforcing and enabling factors) to explain opioid addiction helping behaviour (ie, helping someone who has an opioid addiction) among members of the public living in tri-state Appalachian counties. DESIGN: Cross-sectional study. SETTING: Rural county in the Appalachian region of the USA. PARTICIPANTS: A total of 213 participants from a retail mall in a rural Appalachian Kentucky county completed the survey. Most participants were between the ages of 18 and 30 years (n=68; 31.9%) and identified as men (n=139; 65.3%). PRIMARY OUTCOME MEASURE: Opioid addiction helping behaviour. RESULTS: The regression model was significant (F (6, 180)=26.191, p<0.001) and explained 44.8% of the variance in opioid addiction helping behaviour (R2=0.448). Attitude towards helping someone with opioid addiction (B=0.335; p<0.001), behavioural skills (B=0.208; p=0.003), reinforcing factors (B=0.190; p=0.015) and enabling factors (B=0.195; p=0.009) were all significantly associated with opioid addiction helping behaviour. CONCLUSIONS: PRECEDE-PROCEED model constructs have utility to explain opioid addiction helping behaviour among individuals in a region greatly impacted by the overdose epidemic. This study provides an empirically tested framework for future programmes addressing helping behaviour related to opioid non-medical use.

Drivers of the changing abundance of European birds at two spatial scales.

Detecting biodiversity change and identifying its causes is challenging because biodiversity is multifaceted and temporal data often contain bias. Here, we model temporal change in species' abundance and biomass by using extensive data describing the population sizes and trends of native breeding birds in the United Kingdom (UK) and the European Union (EU). In addition, we explore how species' population trends vary with species' traits. We demonstrate significant change in the bird assemblages of the UK and EU, with substantial reductions in overall bird abundance and losses concentrated in a relatively small number of abundant and smaller sized species. By contrast, rarer and larger birds had generally fared better. Simultaneously, overall avian biomass had increased very slightly in the UK and was stable in the EU, indicating a change in community structure. Abundance trends across species were positively correlated with species' body mass and with trends in climate suitability, and varied with species' abundance, migration strategy and niche associations linked to diet. Our work highlights how changes in biodiversity cannot be captured easily by a single number; care is required when measuring and interpreting biodiversity change given that different metrics can provide very different insights. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Model selection in occupancy models: Inference versus prediction.

Occupancy models are a vital tool for ecologists studying the patterns and drivers of species occurrence, but their use often involves selecting among models with different sets of occupancy and detection covariates. The information-theoretic approach, which employs information criteria such as Akaike's information criterion (AIC) is arguably the most popular approach for model selection in ecology and is often used for selecting occupancy models. However, the information-theoretic approach risks selecting models that produce inaccurate parameter estimates due to a phenomenon called collider bias, a type of confounding that can arise when adding explanatory variables to a model. Using simulations, we investigated the consequences of collider bias (using an illustrative example called M-bias) in the occupancy and detection processes of an occupancy model, and explored the implications for model selection using AIC and a common alternative, the Schwarz criterion (or Bayesian information criterion, BIC). We found that when M-bias was present in the occupancy process, AIC and BIC selected models that inaccurately estimated the effect of the focal occupancy covariate, while simultaneously producing more accurate predictions of the site-level occupancy probability than other models in the candidate set. In contrast, M-bias in the detection process did not impact the focal estimate; all models made accurate inferences, while the site-level predictions of the AIC/BIC-best model were slightly more accurate. Our results show that information criteria can be used to select occupancy covariates if the sole purpose of the model is prediction, but must be treated with more caution if the purpose is to understand how environmental variables affect occupancy. By contrast, detection covariates can usually be selected using information criteria regardless of the model's purpose. These findings illustrate the importance of distinguishing between the tasks of parameter inference and prediction in ecological modeling. Furthermore, our results underline concerns about the use of information criteria to compare different biological hypotheses in observational studies.

Orthobiologic Interventions for Muscle Injuries.

Muscle injuries represent a common problem in active populations. Orthobiologics continue to be studied for their ability to improve muscle healing. To date, the basic science research for treating muscle injuries with platelet-rich plasma or stem cell remains novel. Furthermore, there are even fewer clinical studies on these topics, and their findings are inconclusive. Reviewing the literature, muscle injuries treated with ultrasound-guided leukocyte-rich PRP injections appear to have the strongest evidence. Scar formation remains a major barrier in muscle injury healing, and there is optimism for future orthobiologic treatments that target the downregulation of TGF-B, resulting in decreased scar development.

A Case of Invasive Pulmonary Aspergillosis vs. Pulmonary Aspergilloma in Immunocompromised Patient With Preexisting Lung Cavity.

Subacute invasive aspergillosis (SAIA) occurs in immunocompromised patients and/or patients with preexisting pulmonary pathology. An aspergilloma is a fungus ball that occurs in preexisting lung cavities and can be relatively asymptomatic without tissue invasion. In contrast to an aspergilloma, SAIA invades local tissue and parenchyma, resulting in tissue necrosis. We present a case of a 68-year-old immunocompromised female with a past medical history of hypertension, hyperlipidemia, chronic obstructive pulmonary disease (COPD), stage IIIA adenocarcinoma, and a preexisting pulmonary cavity with chronic invasive aspergillosis vs. pulmonary aspergilloma treated with oral (PO) voriconazole. This case demonstrates that invasive aspergillosis should be considered in the differential diagnosis of any pulmonary lung lesion showing tissue invasion and expansion in an immunocompromised patient.

Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with a combination of cetuximab and nivolumab. PATIENTS AND METHODS: Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 i.v. on day 14 as a lead-in followed by cetuximab 500 mg/m2 i.v. and nivolumab 240 mg i.v. on day 1 and day 15 of each 28-day cycle. Expression of p16 and programmed cell death-ligand 1 (PD-L1) in archived tumors were determined. Tumor-tissue-modified human papillomavirus (TTMV) DNA was quantified in plasma. RESULTS: Ninety-five patients were enrolled, and 88 patients were evaluable for OS with a median follow-up of 15.9 months. Median OS in the 45 patients who had prior therapy for R/M HNSCC (cohort A) was 11.4 months, with a 1 year OS 50% [90% confidence interval (CI), 0.43-0.57]. Median OS in the 43 patients who had no prior therapy (cohort B) was 20.2 months, with a 1-year OS 66% (90% CI, 0.59-0.71). In the combined cohorts, the p16-negative immunostaining was associated with higher response rate (RR; P = 0.02) but did not impact survival while higher PD-L1 combined positive score was associated with higher RR (P = 0.03) and longer OS (log-rank P = 0.04). In the p16-positive patients, lower median (1,230 copies/mL) TTMV DNA counts were associated with higher RR (P = 0.01) and longer OS compared with higher median (log-rank P = 0.05). CONCLUSIONS: The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.

The importance of direct and indirect trophic interactions in determining the presence of a locally rare day-flying moth.

Ecosystem engineers affect other organisms by creating, maintaining or modifying habitats, potentially supporting species of conservation concern. However, it is important to consider these interactions alongside non-engineering trophic pathways. We investigated the relative importance of trophic and non-trophic effects of an ecosystem engineer, red deer, on a locally rare moth, the transparent burnet (Zygaena purpuralis). This species requires specific microhabitat conditions, including the foodplant, thyme, and bare soil for egg-laying. The relative importance of grazing (i.e., trophic effect of modifying microhabitat) and trampling (i.e., non-trophic effect of exposing bare soil) by red deer on transparent burnet abundance is unknown. We tested for these effects using a novel method of placing pheromone-baited funnel traps in the field. Imago abundance throughout the flight season was related to plant composition, diversity and structure at various scales around each trap. Indirect effects of red deer activity were accounted for by testing red deer pellet and trail presence against imago abundance. Imago abundance was positively associated with thyme and plant diversity, whilst negatively associated with velvet grass and heather species cover. The presence of red deer pellets and trails were positively associated with imago abundance. The use of these sites by red deer aids the transparent burnet population via appropriate levels of grazing and the provision of a key habitat condition, bare soil, in the form of deer trails. This study shows that understanding how both trophic and non-trophic interactions affect the abundance of a species provides valuable insights regarding conservation objectives.

Limitations of using surrogates for behaviour classification of accelerometer data: refining methods using random forest models in Caprids.

BACKGROUND: Animal-attached devices can be used on cryptic species to measure their movement and behaviour, enabling unprecedented insights into fundamental aspects of animal ecology and behaviour. However, direct observations of subjects are often still necessary to translate biologging data accurately into meaningful behaviours. As many elusive species cannot easily be observed in the wild, captive or domestic surrogates are typically used to calibrate data from devices. However, the utility of this approach remains equivocal. METHODS: Here, we assess the validity of using captive conspecifics, and phylogenetically-similar domesticated counterparts (surrogate species) for calibrating behaviour classification. Tri-axial accelerometers and tri-axial magnetometers were used with behavioural observations to build random forest models to predict the behaviours. We applied these methods using captive Alpine ibex (Capra ibex) and a domestic counterpart, pygmy goats (Capra aegagrus hircus), to predict the behaviour including terrain slope for locomotion behaviours of captive Alpine ibex. RESULTS: Behavioural classification of captive Alpine ibex and domestic pygmy goats was highly accurate (> 98%). Model performance was reduced when using data split per individual, i.e., classifying behaviour of individuals not used to train models (mean ± sd = 56.1 ± 11%). Behavioural classifications using domestic counterparts, i.e., pygmy goat observations to predict ibex behaviour, however, were not sufficient to predict all behaviours of a phylogenetically similar species accurately (> 55%). CONCLUSIONS: We demonstrate methods to refine the use of random forest models to classify behaviours of both captive and free-living animal species. We suggest there are two main reasons for reduced accuracy when using a domestic counterpart to predict the behaviour of a wild species in captivity; domestication leading to morphological differences and the terrain of the environment in which the animals were observed. We also identify limitations when behaviour is predicted in individuals that are not used to train models. Our results demonstrate that biologging device calibration needs to be conducted using: (i) with similar conspecifics, and (ii) in an area where they can perform behaviours on terrain that reflects that of species in the wild.

Impacts of invasive plants on animal behaviour.

The spread of invasive species is a threat to ecosystems worldwide. However, we know relatively little about how invasive species affect the behaviour of native animals, even though behaviour plays a vital role in the biotic interactions which are key to understanding the causes and impacts of biological invasions. Here, we explore how invasive plants - one of the most pervasive invasive taxa - impact the behaviour of native animals. To promote a mechanistic understanding of these behavioural impacts, we begin by introducing a mechanistic framework which explicitly considers the drivers and ecological consequences of behavioural change, as well as the moderating role of environmental context. We then synthesise the existing literature within this framework. We find that while some behavioural impacts of invasive plants are relatively well-covered in the literature, others are supported by only a handful of studies and should be explored further in the future. We conclude by identifying priority topics for future research, which will benefit from an interdisciplinary approach uniting invasion ecology with the study of animal behaviour and cognition.

Erratum: Author Correction: Deep learning for automated sleep staging using instantaneous heart rate.

[This corrects the article DOI: 10.1038/s41746-020-0291-x.].

Deep learning for automated sleep staging using instantaneous heart rate.

Clinical sleep evaluations currently require multimodal data collection and manual review by human experts, making them expensive and unsuitable for longer term studies. Sleep staging using cardiac rhythm is an active area of research because it can be measured much more easily using a wide variety of both medical and consumer-grade devices. In this study, we applied deep learning methods to create an algorithm for automated sleep stage scoring using the instantaneous heart rate (IHR) time series extracted from the electrocardiogram (ECG). We trained and validated an algorithm on over 10,000 nights of data from the Sleep Heart Health Study (SHHS) and Multi-Ethnic Study of Atherosclerosis (MESA). The algorithm has an overall performance of 0.77 accuracy and 0.66 kappa against the reference stages on a held-out portion of the SHHS dataset for classifying every 30 s of sleep into four classes: wake, light sleep, deep sleep, and rapid eye movement (REM). Moreover, we demonstrate that the algorithm generalizes well to an independent dataset of 993 subjects labeled by American Academy of Sleep Medicine (AASM) licensed clinical staff at Massachusetts General Hospital that was not used for training or validation. Finally, we demonstrate that the stages predicted by our algorithm can reproduce previous clinical studies correlating sleep stages with comorbidities such as sleep apnea and hypertension as well as demographics such as age and gender.

A global assessment of the drivers of threatened terrestrial species richness.

High numbers of threatened species might be expected to occur where overall species richness is also high; however, this explains only a proportion of the global variation in threatened species richness. Understanding why many areas have more or fewer threatened species than would be expected given their species richness, and whether that is consistent across taxa, is essential for identifying global conservation priorities. Here, we show that, after controlling for species richness, environmental factors, such as temperature and insularity, are typically more important than human impacts for explaining spatial variation in global threatened species richness. Human impacts, nevertheless, have an important role, with relationships varying between vertebrate groups and zoogeographic regions. Understanding this variation provides a framework for establishing global conservation priorities, identifying those regions where species are inherently more vulnerable to the effects of threatening human processes, and forecasting how threatened species might be distributed in a changing world.

Burning savanna for avian species richness and functional diversity.

Prescribed fire is used throughout fire-prone landscapes to conserve biodiversity. Current best practice in managing savanna systems advocates methods based on the assumption that increased fire-mediated landscape heterogeneity (pyrodiversity) will promote biodiversity. However, considerable knowledge gaps remain in our understanding of how savanna wildlife responds to the composition and configuration of pyrodiverse landscapes. The effects of pyrodiversity on functional diversity have rarely been quantified and assessing this relationship at a landscape scale that is commensurate with fire management is important for understanding mechanisms underlying ecosystem resilience. Here, we assess the impact of spatiotemporal variation in a long-term fire regime on avian diversity in North West Province, South Africa. We examined the relationship between (1) species richness, (2) three indices of functional diversity (i.e., functional richness, functional evenness, and functional dispersion) and four measures of pyrodiversity, the spatial extents of fire age classes, and habitat type at the landscape scale. We then used null models to assess differences between observed and expected functional diversity. We found that the proportion of newly burned (<1-yr post-fire), old, unburned (≥10 yr post-fire), and woodland habitat on the landscape predicted species and functional richness. Species richness also increased with the degree of edge contrast between patches of varying fire age, while functional dispersion increased with the degree of patch shape complexity. Lower than expected levels of functional richness suggest that habitat filtering is occurring, resulting in functional redundancy across our study sites. We demonstrate that evaluating functional diversity and redundancy is an important component of conservation planning as they may contribute to previously reported fire resilience. Our findings suggest that it is the type and configuration, rather than the diversity, of fire patches on the landscape that promote avian diversity and conserve ecological functions. A management approach is needed that includes significant coverage of adjacent newly burned and older, unburned savanna habitat; the latter, in particular, is inadequately represented under current burning practices.

Innovations in Camera Trapping Technology and Approaches: The Integration of Citizen Science and Artificial Intelligence.

Camera trapping has become an increasingly reliable and mainstream tool for surveying a diversity of wildlife species. Concurrent with this has been an increasing effort to involve the wider public in the research process, in an approach known as 'citizen science'. To date, millions of people have contributed to research across a wide variety of disciplines as a result. Although their value for public engagement was recognised early on, camera traps were initially ill-suited for citizen science. As camera trap technology has evolved, cameras have become more user-friendly and the enormous quantities of data they now collect has led researchers to seek assistance in classifying footage. This has now made camera trap research a prime candidate for citizen science, as reflected by the large number of camera trap projects now integrating public participation. Researchers are also turning to Artificial Intelligence (AI) to assist with classification of footage. Although this rapidly-advancing field is already proving a useful tool, accuracy is variable and AI does not provide the social and engagement benefits associated with citizen science approaches. We propose, as a solution, more efforts to combine citizen science with AI to improve classification accuracy and efficiency while maintaining public involvement.

Quantifying neurologic disease using biosensor measurements in-clinic and in free-living settings in multiple sclerosis.

Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p = 0.0070), several aspects of turning including turn angle (0.437; p = 0.0372), and maximum angular velocity (0.653; p = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting.

High-flow oxygen for children's airway surgery: randomised controlled trial protocol (HAMSTER).

INTRODUCTION: Hypoxaemia during anaesthesia for tubeless upper airway surgery in children with abnormal airways is common due to the complexity of balancing adequate depth of anaesthesia with maintenance of spontaneous breathing and providing an uninterrupted field of view of the upper airway for the surgeon. High-flow nasal oxygenation (HIGH-FLOW) can prolong safe apnoea time and be used in children with abnormal airways but to date has not been compared with the alternative technique of low-flow nasal oxygenation (LOW-FLOW). The aim is to investigate if use of HIGH-FLOW can reduce the number of hypoxaemic events requiring rescue oxygenation compared with LOW-FLOW. METHODS AND ANALYSIS: High-flow oxygen for children's airway surgery: randomised controlled trial (HAMSTER) is a multicentre, unmasked, randomised controlled, parallel group, superiority trial comparing two oxygenation techniques during anaesthesia. Children (n=530) aged >37 weeks to 16 years presenting for elective tubeless upper airway surgery who fulfil inclusion but not exclusion criteria will be randomised prior to surgery to HIGH-FLOW or LOW-FLOW post induction of anaesthesia. Maintenance of anaesthesia with HIGH-FLOW requires Total IntraVenous Anaesthesia (TIVA) and with LOW-FLOW, either inhalational or TIVA at discretion of anaesthetist. The primary outcome is the incidence of hypoxaemic events requiring interruption of procedure for rescue oxygenation by positive pressure ventilation and the secondary outcome includes total hypoxaemia time, adverse cardiorespiratory events and unexpected paediatric intensive care admission admission. Hypoxaemia is defined as Sp02 <90%. Analysis will be conducted on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethical approval has been obtained by Children's Health Queensland Human Research Ethics Committee (HREC/18/QRCH/130). The trial commenced recruitment in 2018. The primary manuscript will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: The HAMSTER is registered with the Australia and New Zealand Clinical TrialsRegistry: ACTRN12618000949280.