Distinguishing Mechanisms for Reactive Uptake at Liquid Surfaces via Angular Distributions of Inelastically Scattered Molecules.

Angular distributions of OH inelastically scattered from the surfaces of the reactive hydrocarbon liquids squalane (fully saturated) and squalene (partially unsaturated) have been measured. A pulsed, rotationally cold molecular beam (Ei = 35 kJ mol-1) of OH was scattered from refreshed liquid surfaces in a vacuum. Spatially and temporally resolved OH number densities were measured by pulsed, planar laser-induced fluorescence. Results are compared with those for the inert liquid perfluoropolyether. The clearly asymmetric distributions for 45° incidence add to the weight of evidence for predominantly impulsive scattering from all three liquids. However, we propose that significant differences in their shapes may be diagnostic of contrasting reaction mechanisms. Direct, near-specular trajectories survive preferentially on squalene, consistent with an addition mechanism removing those at more backward angles. This trend is reversed for squalane, as expected for direct abstraction. The results reinforce the need to consider the effects of composition-dependent contributions from different reaction mechanisms in the modeling of OH-aging of atmospheric aerosol particles.

Achieving large-scale clinician adoption of AI-enabled decision support.

Computerised decision support (CDS) tools enabled by artificial intelligence (AI) seek to enhance accuracy and efficiency of clinician decision-making at the point of care. Statistical models developed using machine learning (ML) underpin most current tools. However, despite thousands of models and hundreds of regulator-approved tools internationally, large-scale uptake into routine clinical practice has proved elusive. While underdeveloped system readiness and investment in AI/ML within Australia and perhaps other countries are impediments, clinician ambivalence towards adopting these tools at scale could be a major inhibitor. We propose a set of principles and several strategic enablers for obtaining broad clinician acceptance of AI/ML-enabled CDS tools.

Pathways from research to sustainable development: Insights from ten research projects in sustainability and resilience.

Drawing on collective experience from ten collaborative research projects focused on the Global South, we identify three major challenges that impede the translation of research on sustainability and resilience into better-informed choices by individuals and policy-makers that in turn can support transformation to a sustainable future. The three challenges comprise: (i) converting knowledge produced during research projects into successful knowledge application; (ii) scaling up knowledge in time when research projects are short-term and potential impacts are long-term; and (iii) scaling up knowledge across space, from local research sites to larger-scale or even global impact. Some potential pathways for funding agencies to overcome these challenges include providing targeted prolonged funding for dissemination and outreach, and facilitating collaboration and coordination across different sites, research teams, and partner organizations. By systematically documenting these challenges, we hope to pave the way for further innovations in the research cycle.

Systematic review and longitudinal analysis of implementing Artificial Intelligence to predict clinical deterioration in adult hospitals: what is known and what remains uncertain.

OBJECTIVE: To identify factors influencing implementation of machine learning algorithms (MLAs) that predict clinical deterioration in hospitalized adult patients and relate these to a validated implementation framework. MATERIALS AND METHODS: A systematic review of studies of implemented or trialed real-time clinical deterioration prediction MLAs was undertaken, which identified: how MLA implementation was measured; impact of MLAs on clinical processes and patient outcomes; and barriers, enablers and uncertainties within the implementation process. Review findings were then mapped to the SALIENT end-to-end implementation framework to identify the implementation stages at which these factors applied. RESULTS: Thirty-seven articles relating to 14 groups of MLAs were identified, each trialing or implementing a bespoke algorithm. One hundred and seven distinct implementation evaluation metrics were identified. Four groups reported decreased hospital mortality, 1 significantly. We identified 24 barriers, 40 enablers, and 14 uncertainties and mapped these to the 5 stages of the SALIENT implementation framework. DISCUSSION: Algorithm performance across implementation stages decreased between in silico and trial stages. Silent plus pilot trial inclusion was associated with decreased mortality, as was the use of logistic regression algorithms that used less than 39 variables. Mitigation of alert fatigue via alert suppression and threshold configuration was commonly employed across groups. CONCLUSIONS: : There is evidence that real-world implementation of clinical deterioration prediction MLAs may improve clinical outcomes. Various factors identified as influencing success or failure of implementation can be mapped to different stages of implementation, thereby providing useful and practical guidance for implementers.

Impact of 1-hour and 3-hour sepsis time bundles on antibiotic use in emergency departments in Queensland, Australia: a before-and-after cohort study.

OBJECTIVE: To determine if the introduction of an emergency department (ED) sepsis screening tool and management bundle affects antibiotic prescribing and use. DESIGN: Multicentre, cohort, before-and-after study design. SETTING: Three tertiary hospitals in Queensland, Australia (median bed size 543, range 520-742). PARTICIPANTS: Adult patients, presenting to the ED with symptoms and signs suggestive of sepsis who had blood cultures collected. These participants were further assessed and stratified as having septic shock, sepsis or infection alone, using Sepsis-3 definitions. The study dates were 1 July 2017-31 March 2020. INTERVENTION: The breakthrough series collaborative 'Could this be Sepsis?' Programme, aimed at embedding a sepsis screening tool and treatment bundle with weighted-incidence syndromic combined antibiogram-derived antibiotic guidelines in EDs. MAIN OUTCOME MEASURES: The primary outcome was the rate of empirical prescriptions adherent to antibiotic guidelines during the ED encounter. Secondary outcomes included the empirical prescriptions considered appropriate, effective antibiotics administered within 3 hours and assessment of harm measures. RESULTS: Of 2591 eligible patients, 721 were randomly selected: 241 in the baseline phase and 480 in the post-intervention phase. The rates of guideline adherence were 54.0% and 59.5%, respectively (adjusted OR (aOR) 1.41 (95% CI 1.00, 1.98)). As compared with baseline, there was an increase in the rates of appropriate antibiotic prescription after bundle implementation (69.9% vs 57.1%, aOR 1.92 (95% CI 1.37, 2.68)). There were no differences between the baseline and post-intervention groups with respect to time to effective antibiotics, adverse effects or ED rates of broad-spectrum antibiotic use. CONCLUSION AND RELEVANCE: The use of an ED sepsis screening tool and management bundle was associated with an improvement in the rates of appropriate antibiotic prescription without evidence of adverse effects.

Understanding the Liquid Structure in Mixtures of Ionic Liquids with Semiperfluoroalkyl or Alkyl Chains.

By mixing ionic liquids (ILs), it is possible to fine-tune their bulk and interfacial structure. This alters their physical properties and solvation behavior and is a simple way to prepare a collection of ILs whose properties can be tuned to optimize a specific application. In this study, mixtures of perfluorinated and alkylated ILs have been prepared, and links between composition, properties, and nanostructure have been investigated. These different classes of ILs vary substantially in the flexibility and polarizability of their chains. Thus, a range of useful structural and physical property variations are accessible through mixing that will expand the library of IL mixtures available in an area that to this point has received relatively little attention. In the experiments presented herein, the physical properties and bulk structure of mixtures of 1-methyl-3-octylimidazolium bis(trifluoromethylsulfonyl)imide [C8MIM][Tf2N] and 1-(1H,1H,2H,2H-perfluorooctyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C8MIM-F13][Tf2N] have been prepared. The bulk liquid structure was investigated using a combination of small-angle X-ray and neutron scattering (SAXS and SANS, respectively) experiments in combination with atomistic molecular dynamics simulations and the measurement of density and viscosity. We observed that the addition of [C8MIM-F13][Tf2N] to [C8MIM][Tf2N] causes changes in the nanostructure of the IL mixtures that are dependent on composition so that variation in the characteristic short-range correlations is observed as a function of composition. Thus, while the length scales associated with the apolar regions (polar non-polar peak─PNPP) increase with the proportion of [C8MIM-F13][Tf2N] in the mixtures, perhaps surprisingly given the greater volume of the fluorocarbon chains, the length scale of the charge-ordering peak decreases. Interestingly, consideration of the contact peak shows that its origins are both in the direct anion···cation contact length scale and the nature (and hence volume) of the chains appended to the imidazolium cation.

Archaeological science, globalisation, and local agency: gold in Great Zimbabwe.

Great Zimbabwe (CE1000-1600) is world famous for outstanding cultural innovations and localised and globalised entanglement with trans-Africa and trans-Indian Ocean exchange. New excavations yielded fragments of over a hundred gold processing vessels comprising reused pottery and purpose-made crucibles from stratified contexts in the Eastern Ridge Ruins and adjacent areas. Selected samples were studied using archaeological, microscopic, and compositional (SEM-EDS) techniques. All ceramics were made of alumina-rich clays and contain minerals common to granite-derived lithologies typical of the area, although it is possible that particularly refractory clays were selected to make crucibles locally. These technical ceramics were used for refining and collecting gold at high temperature, most likely producing not only relatively standardised ingots but also finished objects. The composition of the gold prills set in crucible slag is consistent with that of natural, unalloyed gold, while the variability in silver levels and minor impurities point to heterogeneous sources of the gold. Considering these finds in their multiple site and regional contexts, and together with complementary threads of information from early reports of antiquarians and looters, we argue that local agency and gold consumption were much more significant than generally assumed. The conclusion to the paper is that Great Zimbabwe's famous participation in local and global exchanges was backed by internally driven but improvisation laden production and consumption occurring in homesteads located throughout its various settlements. We end by raising a word of caution about oversimplified narratives of globalisation and their archaeological expressions (see Supplementary Material S0 for the abstract in Shona). Supplementary Information: The online version contains supplementary material available at 10.1007/s12520-023-01811-7.

The Value of Different Experimental Observables: A Transient Absorption Study of the Ultraviolet Excitation Dynamics Operating in Nitrobenzene.

Excess energy redistribution dynamics operating in nitrobenzene under hexane and isopropanol solvation were investigated using ultrafast transient absorption spectroscopy (TAS) with a 267 nm pump and a 340-750 nm white light continuum probe. The use of a nonpolar hexane solvent provides a proxy to the gas-phase environment, and the findings are directly compared with a recent time-resolved photoelectron imaging (TRPEI) study on nitrobenzene using the same excitation wavelength [L. Saalbach et al., J. Phys. Chem. A 2021, 125, 7174-7184]. Of note is the observation of a 1/e lifetime of 3.5-6.7 ps in the TAS data that was absent in the TRPEI measurements. This is interpreted as a dynamical signature of the T2 state in nitrobenzene─analogous to observations in the related nitronaphthalene system, and additionally supported by previous quantum chemistry calculations. The discrepancy between the TAS and TRPEI measurements is discussed, with the overall findings providing an example of how different spectroscopic techniques can exhibit varying sensitivity to specific steps along the overall reaction coordinate connecting reactants to photoproducts.

Inelastic scattering of OH from a liquid PFPE surface: Resolution of correlated speed and angular distributions.

Inelastic collisions of OH with an inert liquid perfluoropolyether (PFPE) surface have been studied experimentally. A pulsed molecular beam of OH with a kinetic energy distribution peaking at 35 kJ mol-1 was directed at a continually refreshed PFPE surface. OH molecules were detected state-selectively with spatial and temporal resolution by pulsed, planar laser-induced fluorescence. The scattered speed distributions were confirmed to be strongly superthermal, regardless of the incidence angle (0° or 45°). Angular scattering distributions were measured for the first time; their reliability was confirmed through extensive Monte Carlo simulations of experimental averaging effects, described in Paper II [A. G. Knight et al., J. Chem. Phys. 158, 244705 (2023)]. The distributions depend markedly on the incidence angle and are correlated with scattered OH speed, consistent with predominantly impulsive scattering. For 45° incidence, the angular distributions are distinctly asymmetric to the specular side but peak at sub-specular angles. This, along with the breadth of the distributions, is incompatible with scattering from a surface that is flat on a molecular scale. New molecular dynamics simulations corroborate the roughness of the PFPE surface. A subtle but unexpected systematic dependence of the angular distribution on the OH rotational state was found, which may be dynamical in origin. The OH angular distributions are similar to those for kinematically similar Ne scattering from PFPE and hence not strongly perturbed by OH being a linear rotor. The results here are broadly compatible with prior predictions from independent quasiclassical trajectory simulations of OH scattering from a model-fluorinated self-assembled monolayer surface.

Quantifying the dynamical information content of pulsed, planar laser-induced fluorescence measurements.

We have analyzed the effects of the spreads in experimental parameters on the reliability of speeds and angular distributions extracted from a generic surface-scattering experiment based on planar laser-induced fluorescence detection. The numerical model assumes a pulsed beam of projectile molecules is directed at a surface. The spatial distribution of the scattered products is detected by imaging the laser-induced fluorescence excited by a thin, pulsed sheet of laser light. Monte Carlo sampling is used to select from realistic distributions of the experimental parameters. The key parameter is found to be the molecular-beam diameter, expressed as a ratio to the measurement distance from the point of impact. Measured angular distributions are negligibly distorted when this ratio is <∼10%. Measured most-probable speeds are more tolerant, being undistorted when it is <∼20%. In contrast, the spread of speeds or of corresponding arrival times in the incident molecular beam has only very minor systematic effects. The thickness of the laser sheet is also unimportant within realistic practical limits. These conclusions are broadly applicable to experiments of this general type. In addition, we have analyzed the specific set of parameters designed to match the experiments on OH scattering from a liquid perfluoropolyether (PFPE) surface in the Paper I [Roman et al., J. Chem. Phys. 158, 244704 (2023)]. This reveals that the detailed form of the molecular-beam profile is important, particularly on apparent angular distributions, for geometric reasons that we explain. Empirical factors have been derived to correct for these effects.

Superthermal Al Atoms as a Reactive-Atom Probe of Fluorinated Surfaces.

We demonstrate a proof-of-concept of a new analytical technique to measure relative F atom exposure at the surfaces of fluorinated materials. The method is based on reactive-atom scattering (RAS) of Al atoms, produced by pulsed laser ablation of solid Al at 532 nm. The properties of the incident ground-state Al were characterized by laser-induced fluorescence (LIF); at typical ablation fluences, the speed distribution is approximately Maxwellian at ∼45000 K, with a most-probable kinetic energy of 187 kJ mol-1 and a mean of 560 kJ mol-1 When these Al atoms impact the surfaces of perfluorinated solids (poly(tetrafluorethylene), PTFE) or liquids (perfluoropolyether, PFPE), gas-phase AlF products are clearly detectable by LIF on the AlF A-X band. Quantitative AlF yields were compared for a small representative set of a widely studied family of ionic liquids based on the common 1-alkyl-3-methylimidazolium ([Cnmim]+) cation. Yields of (1.9 ± 0.2):1 were found from [C2mim][Tf2N] and [C8mim][Tf2N], containing the common fluorinated bis(trifluoromethylsulfonyl)imide anion ([Tf2N]-). This is in quantitative agreement with previous independent low-energy ion scattering (LEIS) measurements and consistent with other independent results indicating that the longer cationic alkyl chains cover a larger fraction of the liquid surface and hence reduce anion exposure. The expected null result was obtained for the ionic liquid [C2mim][EtSO4] which contains no fluorine. These results open the way for further characterization and the potential application of this new variant of the RAS-LIF method.

Deployment of machine learning algorithms to predict sepsis: systematic review and application of the SALIENT clinical AI implementation framework.

OBJECTIVE: To retrieve and appraise studies of deployed artificial intelligence (AI)-based sepsis prediction algorithms using systematic methods, identify implementation barriers, enablers, and key decisions and then map these to a novel end-to-end clinical AI implementation framework. MATERIALS AND METHODS: Systematically review studies of clinically applied AI-based sepsis prediction algorithms in regard to methodological quality, deployment and evaluation methods, and outcomes. Identify contextual factors that influence implementation and map these factors to the SALIENT implementation framework. RESULTS: The review identified 30 articles of algorithms applied in adult hospital settings, with 5 studies reporting significantly decreased mortality post-implementation. Eight groups of algorithms were identified, each sharing a common algorithm. We identified 14 barriers, 26 enablers, and 22 decision points which were able to be mapped to the 5 stages of the SALIENT implementation framework. DISCUSSION: Empirical studies of deployed sepsis prediction algorithms demonstrate their potential for improving care and reducing mortality but reveal persisting gaps in existing implementation guidance. In the examined publications, key decision points reflecting real-word implementation experience could be mapped to the SALIENT framework and, as these decision points appear to be AI-task agnostic, this framework may also be applicable to non-sepsis algorithms. The mapping clarified where and when barriers, enablers, and key decisions arise within the end-to-end AI implementation process. CONCLUSIONS: A systematic review of real-world implementation studies of sepsis prediction algorithms was used to validate an end-to-end staged implementation framework that has the ability to account for key factors that warrant attention in ensuring successful deployment, and which extends on previous AI implementation frameworks.

Implementation frameworks for end-to-end clinical AI: derivation of the SALIENT framework.

OBJECTIVE: To derive a comprehensive implementation framework for clinical AI models within hospitals informed by existing AI frameworks and integrated with reporting standards for clinical AI research. MATERIALS AND METHODS: (1) Derive a provisional implementation framework based on the taxonomy of Stead et al and integrated with current reporting standards for AI research: TRIPOD, DECIDE-AI, CONSORT-AI. (2) Undertake a scoping review of published clinical AI implementation frameworks and identify key themes and stages. (3) Perform a gap analysis and refine the framework by incorporating missing items. RESULTS: The provisional AI implementation framework, called SALIENT, was mapped to 5 stages common to both the taxonomy and the reporting standards. A scoping review retrieved 20 studies and 247 themes, stages, and subelements were identified. A gap analysis identified 5 new cross-stage themes and 16 new tasks. The final framework comprised 5 stages, 7 elements, and 4 components, including the AI system, data pipeline, human-computer interface, and clinical workflow. DISCUSSION: This pragmatic framework resolves gaps in existing stage- and theme-based clinical AI implementation guidance by comprehensively addressing the what (components), when (stages), and how (tasks) of AI implementation, as well as the who (organization) and why (policy domains). By integrating research reporting standards into SALIENT, the framework is grounded in rigorous evaluation methodologies. The framework requires validation as being applicable to real-world studies of deployed AI models. CONCLUSIONS: A novel end-to-end framework has been developed for implementing AI within hospital clinical practice that builds on previous AI implementation frameworks and research reporting standards.

Surface Structure of Alkyl/Fluoroalkylimidazolium Ionic-Liquid Mixtures.

The gas-liquid interface of ionic liquids (ILs) is critically important in many applications, for example, in supported IL phase (SILP) catalysis. Methods to investigate the interfacial structure in these systems will allow their performance to be improved in a rational way. In this study, reactive-atom scattering (RAS), surface tension measurements, and molecular dynamics (MD) simulations were used to study the vacuum interface of mixtures of partially fluorinated and normal alkyl ILs. The underlying aim was to understand whether fluorinated IL ions could be used as additives to modify the surface structure of one of the most widely used families of alkyl ILs. The series of ILs 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Cnmim][Tf2N]) with n = 4-12 were mixed with a fixed-length, semiperfluorinated analogue (1H,1H,2H,2H-perfluorooctyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C8mimF13][Tf2N]), forming [Cnmim](1-x)[C8mimF13]x[Tf2N] mixtures, where x is the bulk mole fraction of the fluorinated component. The RAS-LIF method combined O-atom projectiles with laser-induced fluorescence (LIF) detection of the product OH as a measure of surface exposure of the alkyl chains. For [C8mim](1-x)[C8mimF13]x[Tf2N] mixtures, RAS-LIF OH yields are below those expected from stoichiometry. There are quantitatively consistent negative deviations from linearity of the surface tension. Both results imply that the lower-surface-tension fluoroalkyl material dominates the surface. A similar deficit is found for alkyl chain lengths n = 4, 6, 8, and 12 and for all (nonzero) x investigated by RAS-LIF. Accessible-surface-area (ASA) analyses of the MD simulations for [Cnmim](1-x)[C8mimF13]x[Tf2N] mixtures qualitatively reproduce the same primary effect of fluoro-chain predominance of the surface over most of the range of n. However, there are significant quantitative discrepancies between MD ASA predictions and experiment relating to the strength of any n-dependence of the relative alkyl coverage at fixed x, and on the x-dependence at fixed n. These discrepancies are discussed in the context of detailed examinations of the surface structures predicted in the MD simulations. Potential explanations, beyond experimental artifacts, include inadequacies in the classical force fields used in the MD simulations or the inability of simple ASA algorithms to capture dynamical factors that influence RAS-LIF yields.

Impact of 1-hour and 3-hour sepsis time bundles on patient outcomes and antimicrobial use: A before and after cohort study.

BACKGROUND: Sepsis bundles, promulgated by Surviving Sepsis Campaign have not been widely adopted because of variability in sepsis identification strategies, implementation challenges, concerns about excess antimicrobial use, and limited evidence of benefit. METHODS: A 1-hour septic shock and a 3-hour sepsis bundle were implemented using a Breakthrough Series Collaborative in 14 public hospitals in Queensland, Australia. A before (baseline) and after (post-intervention) study evaluated its impact on outcomes and antimicrobial prescription in patients with confirmed bacteremia and sepsis. FINDINGS: Between 01 July 2017 to 31 March 2020, of 6976 adults presenting to the Emergency Departments and had a blood culture taken, 1802 patients (732 baseline, 1070 post-intervention) met inclusion criteria. Time to antibiotics in 1-hour 73.7% vs 85.1% (OR 1.9 [95%CI 1.1-3.6]) and the 3-hour bundle compliance (48.2% to 63.3%, OR 1.7, [95%CI 1.4 to 2.1]) improved post-intervention, accompanied by a significant reduction in Intensive Care Unit (ICU) admission rates (26.5% vs 17.5% (OR 0.5, [95%CI 0.4 to 0.7]). There were no significant differences in-hospital and 30-day post discharge mortality between the two phases. In a post-hoc analysis of the post-intervention phase, sepsis pathway compliance was associated with lower in-hospital mortality (9.7% vs 14.9%, OR 0.6, 95%CI 0.4 to 0.8). The proportions of appropriate antimicrobial prescription at baseline and post-intervention respectively were 55.4% vs 64.1%, (OR 1.4 [95%CI 0.9 to 2.1]). INTERPRETATION: Implementing 1-hour and 3-hour sepsis bundles for patients presenting with bacteremia resulted in improved bundle compliance and a reduced need for ICU admission without adversely influencing antimicrobial prescription.

Late Holocene environmental change and anthropogenic: Ecosystem interaction on the Laikipia Plateau, Kenya.

East African ecosystems have been shaped by long-term socio-ecological-environmental interactions. Although much previous work on human-environment interrelationships have emphasised the negative impacts of human interventions, a growing body of work shows that there have also often been strong beneficial connections between people and ecosystems, especially in savanna environments. However, limited information and understanding of past interactions between humans and ecosystems of periods longer than a century hampers effective management of contemporary environments. Here, we present a late Holocene study of pollen, fern spore, fungal spore, and charcoal analyses from radiocarbon-dated sediment sequences and assess this record against archaeological and historical data to describe socio-ecological changes on the Laikipia Plateau in Rift Valley Province, Kenya. The results suggest a landscape characterised by closed forests between 2268 years before present (cal year BP) and 1615 cal year BP when there was a significant change to a more open woodland/grassland mosaic that continues to prevail across the study area. Increased amounts of charcoal in the sediment are observed for this same period, becoming particularly common from around 900 cal year BP associated with fungal spores commonly linked to the presence of herbivores. It is likely these trends reflect changes in land use management as pastoral populations improved and extended pasture, using fire to eradicate disease-prone habitats. Implications for contemporary land use management are discussed in the light of these findings.

Creating a healthcare variant CYNEFIN framework to improve leadership and urgent decision-making in times of crisis.

PURPOSE: The complex and occasionally chaotic nature of health care has been previously described in the literature, as has the broadening recognition that different management approaches are required for different types of problems rather than a "one size fits all" approach. The CYNEFIN framework from Snowden outlines a consistent cognitive approach that offers the leader and leadership team an ability to urgently apply the correct actions to a given situation. This paper proposes a variant CYNEFIN approach for healthcare. DESIGN/METHODOLOGY/APPROACH: Consistent and accurate decision-making within health care is the hallmark of an effective and pragmatic leader and leadership team. An awareness of how one's cognitive biases and heuristics may adversely impact on this cognitive process is paramount, as is an understanding of the calibration between fast and slow thinking. FINDINGS: The authors propose a variant CYNEFIN approach for health care of "act-probe-sense-respond" to resolve complex and time-critical emergency scenarios, using the differing contexts of a cardiac arrest and an evolving crisis management problem as examples. The variant serves as a pragmatic sense-making framework for the health-care leader and leadership team that can be adopted for many time-critical crisis situations. ORIGINALITY/VALUE: The variant serves as a pragmatic sense-making framework for the health-care leader that can be adopted for many crisis situations.

Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial.

BACKGROUND: During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0-4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin. RESULTS: All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only ('sapropterin extension' group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period ('sapropterin continuous' group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the 'sapropterin continuous' group (95% CI 28.9, 48.6; p < 0.0001). In the 'sapropterin extension' group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI - 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. CONCLUSIONS: Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .

Sustainment of a patient flow intervention in an intensive care unit in a regional hospital in Australia: a mixed-method, 5-year follow-up study.

OBJECTIVE: In 2014, an escalation plan and morning handover meetings were implemented in an intensive care unit (ICU) to reduce access block for post-operative care. In this study, the improvement intervention is revisited 5 years on with the objective to see if the changes are sustained and to understand factors contributing to sustainability. DESIGN: A mixed-method approach was used, with quantitative analysis of ICU administrative data and qualitative analysis of interviews with hospital management and ICU staff. SETTING: ICU with mixed surgical and non-surgical cases in a regional hospital in Australia. PARTICIPANTS: Interview participants: ICU nurses (four), ICU doctors (four) and hospital management (four). MAIN OUTCOME MEASURES: Monthly number of elective surgeries were cancelled due to unavailability of ICU beds. Staff perceptions of the interventions and factors contributed to sustainability. RESULTS: After a decline in elective surgeries being cancelled in the first year after the intervention, there was an increase in cancellations in the following years (χ2=16.38, p=0.003). Lack of knowledge about the intervention and competitive interests in the management of patient flow were believed to be obstacles for sustained effects of the original intervention. So were communication deficiencies that were reported within the ICU and between ICU and other departments. There are discrepancies between how nurses and doctors use the escalation plan and regard the availability of ICU beds. CONCLUSION: Improvement interventions in healthcare that appear initially to be successful are not necessarily sustained over time, as was the case in this study. In healthcare, there is no such thing as a 'fix and forget' solution for interventions. Management commitment to support communication within and between microsystems, and to support healthcare staff understanding of the underlying reasons for intervention, are important implications for change and change management across healthcare systems.

Health economic burden of patients with phenylketonuria (PKU) - A retrospective study of German health insurance claims data.

This retrospective matched-cohort analysis compared health-economic burdens of adults (≥18 years; n = 377) with phenylketonuria (PKU) and age/gender-matched non-PKU controls (n = 3770) in Germany. Healthcare costs and resource-utilization were analyzed for the year 2015. Differences between groups were tested using 95% CI of mean differences (MD). PKU patients had significantly higher mean costs in total (MD €3307, 95% CI €1736-€4879), for pharmaceuticals (MD €1912, 95% CI €1195-€2629) [including dietary amino-acid supplements (MD €1268, 95% CI €864-€1672)], and outpatient costs (MD €395, 95% CI €115-€675). Inpatient costs (MD €904, 95% CI -€293 to €2100) and costs for aids and remedies (MD €97, 95% CI -€10 to €203) were also higher in PKU patients. PKU patients had more outpatient visits and stayed longer in hospital. Adult PKU patients incur higher total healthcare costs than non-PKU controls, especially regarding pharmaceuticals and outpatient costs, and more frequent resource-utilization, resulting in higher health-economic burden for the statutory healthcare system.