Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Patient-reported use of pancreatic enzyme replacement treatment (PERT) in pancreatic cancer in New Zealand and Australia: a cross-sectional survey study.

PURPOSE: This study investigated pancreatic enzyme replacement therapy (PERT) use in people diagnosed with pancreatic cancer in New Zealand (NZ) and Australia (AU). METHODS: A cross-sectional survey study was conducted using a mixed-media campaign to recruit people with pancreatic cancer and collect information about current PERT use. The questionnaire gathered data on participant demographics, awareness of PERT, prescribing practices and efficacy of enzyme replacement. RESULTS: Over 300 people with pancreatic cancer were recruited, 135 from New Zealand and 199 from Australia. Every region, state and territory was represented except for the West Coast (NZ) and the Northern Territory (AU), the lowest populated areas in both countries. In New Zealand, 60% of participants had heard about PERT, compared to 69.3% in Australia. Dosing regimens were inconsistent in both countries, with 18% and 27% of participants being prescribed PERT considered best practice in New Zealand and Australia, respectively. Before PERT commencement, 70% of participants experienced symptoms of malabsorption, with all symptoms improving after therapy was established. The majority of participants were compliant with their medication. CONCLUSION: PERT use in pancreatic cancer in New Zealand and Australia was highly variable and not compliant with international guidelines in which PERT is recommended as standard therapy. Enzyme replacement is effective for improving the symptoms of malabsorption in patients with pancreatic cancer. Clinician education may be needed to help improve the use of PERT in people with pancreatic cancer.

Raising the barcode: improving medication safety behaviours through a behavioural science-informed feedback intervention. A quality improvement project and difference-in-difference analysis.

Barcode medication administration (BCMA) technology can improve patient safety by using scanning technology to ensure the right drug and dose are given to the right patient. Implementation can be challenging, requiring adoption of different workflows by nursing staff. In one London National Health Service trust scanning rates were lower than desired at around 0-20% of doses per ward. Our objective was to encourage patient safety behaviours in the form of medication scanning through implementation of a feedback intervention. This was informed by behavioural science, codesigned with nurses and informed by known barriers to use. Five wards were selected to trial the intervention over an 18-week period beginning August 2021. The remaining 14 hospital wards acted as controls. Intervention wards had varying uptake of BCMA at baseline and represented a range of specialties. A bespoke feedback intervention comprising three behavioural science constructs (gamification, the messenger effect and framing) was delivered to each intervention ward each week. A linear difference-in-difference analysis was used to evaluate the impact of our intervention on scan rates, both for the overall 18-week period and at two weekly intervals within this timeframe. We identified a 23.1 percentage point increase in medication scan rates (from an average baseline of 15.0% to 38.1%) on the intervention wards compared with control (p<0.001) following implementation of the intervention. Feedback had most impact in the first 6 weeks, with an initial percentage point increase of 26.3 (p<0.001), which subsequently plateaued. Neither clinical specialty nor number of beds on each ward were significant factors in our models. Our study demonstrated that a feedback intervention, codesigned with end users and incorporating behavioural science constructs, can lead to a significant increase in the adoption of BCMA scanning.

Prevalence of resistance-associated viral variants to the HIV-specific broadly neutralising antibody 10-1074 in a UK bNAb-naïve population.

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Cost-effectiveness of reducing children's sedentary time and increasing physical activity at school: the Transform-Us! intervention.

BACKGROUND: Improving physical activity and reducing sedentary behavior represent important areas for intervention in childhood in order to reduce the burden of chronic disease related to obesity and physical inactivity in later life. This paper aims to determine the cost-effectiveness of a multi-arm primary school-based intervention to increase physical activity and/or reduce sedentary time in 8-9 year old children (Transform-Us!). METHODS: Modelled cost-utility analysis, using costs and effects from a cluster randomized controlled trial of a 30-month intervention that used pedagogical and environmental strategies to reduce and break up sedentary behaviour (SB-I), promote physical activity (PA-I), or a combined approach (PA + SB-I), compared to current practice. A validated multiple-cohort lifetable model (ACE-Obesity Policy model) estimated the obesity and physical activity-related health outcomes (measured as change in body mass index and change in metabolic equivalent task minutes respectively) and healthcare cost-savings over the cohort's lifetime from the public-payer perspective, assuming the intervention was delivered to all 8-9 year old children attending Australian Government primary schools. Sensitivity analyses tested the impact on cost-effectiveness of varying key input parameters, including maintenance of intervention effect assumptions. RESULTS: Cost-effectiveness results demonstrated that, when compared to control schools, the PA-I and SB-I intervention arms were "dominant", meaning that they resulted in net health benefits and healthcare cost-savings if the intervention effects were maintained. When the costs and effects of these intervention arms were extrapolated to the Australian population, results suggested significant potential as obesity prevention measures (PA-I: 60,780 HALYs saved (95% UI 15,007-109,413), healthcare cost-savings AUD641M (95% UI AUD165M-$1.1B); SB-I: 61,126 HALYs saved (95% UI 11,770 - 111,249), healthcare cost-savings AUD654M (95% UI AUD126M-1.2B)). The PA-I and SB-I interventions remained cost-effective in sensitivity analysis, assuming the full decay of intervention effect after 10 years. CONCLUSIONS: The PA-I and SB-I Transform-Us! intervention arms represent good value for money and could lead to health benefits and healthcare cost-savings arising from the prevention of chronic disease in later life if intervention effects are sustained. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN83725066). Australia and New Zealand Clinical Trials Registry Number (ACTRN12609000715279).

Composing adult lives with a ventilator at the intersection of developmental and neoliberal discourses of time.

This paper explores temporalities and experiences of time drawn from an analysis of interview data from a critical narrative inquiry of the experiences of young adults living with home mechanical ventilation (HMV). The analysis centers the ideological effects of dominant discourses that shape understandings of time in the Euro-Western world and the ways in which young adults' stories prompt a rethinking of time in health research and praxis. Data generation involved interviews and photo-elicitation with five young adults (ages 18-40). A critical narrative analysis of participants' stories surfaced the influence of ableist, developmentalist, and neoliberal discourses of time and the creative resistance that points to the potential of crip orientations to time in opening up possibilities for living. Implications for practice and research are offered.

"Shared experience makes this all possible": documenting the guiding principles of peer-led services for people released from prison.

BACKGROUND: There is a growing body of evidence demonstrating the effectiveness of peer-led services in supporting community reintegration for people released from prison. This study aims to document the guiding principle of a peer-led service for people released from prison, from the perspective of peer mentors. METHODS: Data were collected using focus groups (N = 10; 2 groups with 5 participants each) and one-on-one interviews (N = 5) including a total of 13 people, representing all UTGSS staff at the time of the study. An inductive thematic analysis was used to identify patterns in the data. Initial coding was done by using "in-vivo" codes (i.e. applying codes to terms used by participants). This informed the direction of the next stage of analysis, which focused on identifying categories that synthesized the codes and data across transcripts. In this stage, broad themes and sub-themes were developed. FINDINGS: Six themes were constructed to reflect the guiding principles of UTGSS staff. This includes four central themes: 1) Offering hope; 2) Building respectful relationships; 3) Providing consistent support; 4) Meeting people where they are at. Two connected themes are also reported: 1) Relying on shared experience, which participants reported serves as the foundation for practicing these guiding principles and 2) Bridging connections to services, which reflects the outcome of practicing these guiding principles. CONCLUSION: The principles identified in this study can be used by UTGSS staff as a guide for checking-in on progress with clients and may be considered as a model for reflection on practice by staff providing similar peer-led services. These principles should not be applied in a prescriptive way, as relationship building is at the centre of peer support, and different applications will be required depending on clients' goals and the range of supports available within their community.

Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study.

PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.

Industry perspective on a holistic container closure integrity approach to parenteral combination products.

Biologics are being developed more and more as parenteral combination products with drug delivery devices. The maintenance of sterility is imperative for such medical devices throughout their life cycle. Therefore, the container closure integrity (CCI) should, preferably, be built into the overall process, and not just demonstrated during the final testing of the combination product. The integrity is an important Critical Quality Attribute (CQA) and in the scope of specific considerations and studies during the combination product life cycle i.e., design robustness, assembly processes, storage (to end of shelf life), and shipping prior to patient use. The goal of this paper is to summarize an industry holistic approach to ensure CCI, for a combination product, and to build a scientifically based justification that Quality (in terms of CCI) is built into the overall process. Current analytical approaches used for characterization or Good Manufacturing Practice (GMP) CCI testing during combination product development will be described. However, the use of quality by design (QbD) during product development can reduce or eliminate routine batch level or stability testing of the combination product.

Rapid antiretroviral therapy in primary HIV-1 infection enhances immune recovery.

OBJECTIVE: We present findings from a large cohort of individuals treated during primary HIV infection (PHI) and examine the impact of time from HIV-1 acquisition to antiretroviral therapy (ART) initiation on clinical outcomes. We also examine the temporal changes in the demographics of individuals presenting with PHI to inform HIV-1 prevention strategies. METHODS: Individuals who fulfilled the criteria of PHI and started ART within 3 months of confirmed HIV-1 diagnosis were enrolled between 2009 and 2020. Baseline demographics of those diagnosed between 2009 and 2015 (before preexposure prophylaxis (PrEP) and universal ART availability) and 2015-2020 (post-PrEP and universal ART availability) were compared. We examined the factors associated with immune recovery and time to viral suppression. RESULTS: Two hundred four individuals enrolled, 144 from 2009 to 2015 and 90 from 2015 to 2020; median follow-up was 33 months. At PHI, the median age was 33 years; 4% were women, 39% were UK-born, and 84% were MSM. The proportion of UK-born individuals was 47% in 2009-2015, compared with 29% in 2015-2020. There was an association between earlier ART initiation after PHI diagnosis and increased immune recovery; each day that ART was delayed was associated with a lower likelihood of achieving a CD4 + cell count more than 900 cells/µl [hazard ratio 0.99 (95% confidence interval, 95% CI 0.98-0.99), P  = 0.02) and CD4/CD8 more than 1.0 (hazard ratio 0.98 (95% CI 0.97-0.99). CONCLUSION: Early initiation of ART at PHI diagnosis is associated with enhanced immune recovery, providing further evidence to support immediate ART in the context of PHI. Non-UK-born MSM accounts for an increasing proportion of those with primary infection; UK HIV-1 prevention strategies should better target this group.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Recruitment of participants with pancreatic cancer to a mixed media study for optimal recruitment in an Australasian survey of pancreatic enzyme replacement.

BACKGROUND: Pancreatic cancer is relatively rare and aggressive, with digestion and malabsorption issues often leading to significant weight loss. Recruitment of people with this malignancy into studies can be challenging, and innovative methods need to be explored to improve recruitment rates. AIM: To describe a mixed media methodology and the outcomes used to recruit patients to participate in a binational survey. METHODS: The details of the mixed media method used to identify and recruit people with pancreatic cancer are described. This method was used to investigate pancreatic enzyme replacement therapy use in people with pancreatic cancer across Australia and Aotearoa New Zealand. RESULTS: The mixed media approach was successful in reaching 334 participants from a range of ethnicities and regions. Results showed that social media platforms were notably more efficient and cost-effective than radio and newspaper but required additional expertise, including graphic design and media strategy knowledge. CONCLUSIONS: Social media is an effective and efficient method of recruiting people with pancreatic cancer to a national survey. Studies using media to recruit patients may need to include team members with a range of skills.

Scaling up a school-based intervention to increase physical activity and reduce sedentary behaviour in children: protocol for the TransformUs hybrid effectiveness-implementation trial.

INTRODUCTION: Efficacious programmes require implementation at scale to maximise their public health impact. TransformUs is an efficacious behavioural and environmental intervention for increasing primary (elementary) school children's (5-12 years) physical activity and reducing their sedentary behaviour within school and home settings. This paper describes the study protocol of a 5-year effectiveness-implementation trial to assess the scalability and effectiveness of the TransformUs programme. METHODS AND ANALYSIS: A type II hybrid implementation-effectiveness trial, TransformUs is being disseminated to all primary schools in the state of Victoria, Australia (n=1786). Data are being collected using mixed methods at the system (state government, partner organisations), organisation (school) and individual (teacher, parent and child) levels. Evaluation is based on programme Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. RE-AIM domains are being measured using a quasi-experimental, pre/post, non-equivalent group design, at baseline, 12 and 24 months. Effectiveness will be determined in a subsample of 20 intervention schools (in Victoria) and 20 control schools (in New South Wales (NSW), Australia), at baseline, 12 and 24 months. Primary outcomes include TransformUs Reach, Adoption, Implementation and organisational Maintenance (implementation trial), and children's physical activity and sedentary time assessed using accelerometers (effectiveness trial). Secondary outcomes include average sedentary time and moderate to vigorous-intensity physical activity on weekdays and during school hours, body mass index z-scores and waist circumference (effectiveness trial). Linear mixed-effects models will be fitted to compare outcomes between intervention and control participants accounting for clustering of children within schools, confounding and random effects. ETHICS AND DISSEMINATION: The trial was approved by the Deakin University Human Research Ethics Committee (HEAG-H 28_2017), Victorian Department of Education, the NSW Department of Education, Australian Catholic University (2017-145R), Melbourne Archdiocese Catholic Schools and Catholic Schools NSW. Partners, schools/teachers and parents will provide an informed signed consent form prior to participating. Parents will provide consent for their child to participate in the effectiveness trial. Findings will be disseminated via peer-reviewed publications, scientific conferences, summary reports to schools and our partner organisations, and will inform education policy and practice on effective and sustainable ways to promote physical activity and reduce sedentary behaviours population-wide. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registration Registry (ACTRN12617000204347).

Estimating County Level Health Indicators Using Spatial Microsimulation.

Given the importance of understanding health outcomes at fine spatial scales, iterative proportional fitting (IPF), a form of small area estimation, was applied to a fixed number of health-related variables (obesity, overweight, diabetes) taken from regionalized 2019 survey responses (n = 5474) from the Idaho Behavioral Risk Factor Surveillance System (BRFSS). Using associated county-level American Community Survey (ACS) census data, a set of constraints, which included age categorization, race, sex, and education level, were used to create county-level weighting matrices for each variable, for each of the seven (7) Idaho public health districts. Using an optimized modeling construction technique, we identified significant constraints and grouping splits for each variable/region, resulting in estimates that were internally and externally validated. Externally validated model results for the most populated counties showed correlations ranging from .79 to .85, with p values all below .05. Estimates indicated higher levels of obesity and overweight individuals for midsouth and southwestern Idaho counties, with a cluster of higher diabetes estimates in the center of the state (Gooding, Lincoln, Minidoka, and Jerome counties). Alternative external sources for health outcomes aligned extremely well with our estimates, with wider confidence intervals in more rural counties with sparse populations.

Analysis of Escherichia coli O157 strains in cattle and humans between Scotland and England & Wales: implications for human health.

For the last two decades, the human infection frequency of Escherichia coli O157 (O157) in Scotland has been 2.5-fold higher than in England and Wales. Results from national cattle surveys conducted in Scotland and England and Wales in 2014/2015 were combined with data on reported human clinical cases from the same time frame to determine if strain differences in national populations of O157 in cattle could be associated with higher human infection rates in Scotland. Shiga toxin subtype (Stx) and phage type (PT) were examined within and between host (cattle vs human) and nation (Scotland vs England and Wales). For a subset of the strains, whole genome sequencing (WGS) provided further insights into geographical and host association. All three major O157 lineages (I, II, I/II) and most sub-lineages (Ia, Ib, Ic, IIa, IIb, IIc) were represented in cattle and humans in both nations. While the relative contribution of different reservoir hosts to human infection is unknown, WGS analysis indicated that the majority of O157 diversity in human cases was captured by isolates from cattle. Despite comparable cattle O157 prevalence between nations, strain types were localized. PT21/28 (sub-lineage Ic, Stx2a+) was significantly more prevalent in Scottish cattle [odds ratio (OR) 8.7 (2.3-33.7; P<0.001] and humans [OR 2.2 (1.5-3.2); P<0.001]. In England and Wales, cattle had a significantly higher association with sub-lineage IIa strains [PT54, Stx2c; OR 5.6 (1.27-33.3); P=0.011] while humans were significantly more closely associated with sub-lineage IIb [PT8, Stx1 and Stx2c; OR 29 (4.9-1161); P<0.001]. Therefore, cattle farms in Scotland were more likely to harbour Stx2a+O157 strains compared to farms in E and W (P<0.001). There was evidence of limited cattle strain migration between nations and clinical isolates from one nation were more similar to cattle isolates from the same nation, with sub-lineage Ic (mainly PT21/28) exhibiting clear national association and evidence of local transmission in Scotland. While we propose the higher rate of O157 clinical cases in Scotland, compared to England and Wales, is a consequence of the nationally higher level of Stx2a+O157 strains in Scottish cattle, we discuss the multiple additional factors that may also contribute to the different infection rates between these nations.

Rapid mechanosensitive migration and dispersal of newly divided mesenchymal cells aid their recruitment into dermal condensates.

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour.

Synthesis and Catalytic Activity for 2, 3, and 4-Nitrophenol Reduction of Green Catalysts Based on Cu, Ag and Au Nanoparticles Deposited on Polydopamine-Magnetite Porous Supports.

This work reports on the synthesis of nine materials containing Cu, Ag, Au, and Ag/Cu nanoparticles (NPs) deposited on magnetite particles coated with polydopamine (PDA). Ag NPs were deposited on two PDA@Fe3O4 supports differing in the thickness of the PDA film. The film thickness was adjusted to impart a textural porosity to the material. During synthesis, Ag(I) was reduced with ascorbic acid (HA), photochemically, or with NaBH4, whereas Au(III), with HA, with the PDA cathecol groups, or NaBH4. For the material characterization, TGA, XRD, SEM, EDX, TEM, STEM-HAADF, and DLS were used. The catalytic activity towards reduction of 4-, 3- and 2-nitrophenol was tested and correlated with the synthesis method, film thickness, metal particle size and NO2 group position. An evaluation of the recyclability of the materials was carried out. In general, the catalysts prepared by using soft reducing agents and/or thin PDA films were the most active, while the materials reduced with NaBH4 remained unchanged longer in the reactor. The activity varied in the direction Au > Ag > Cu. However, the Ag-based materials showed a higher recyclability than those based on gold. It is worth noting that the Cu-containing catalyst, the most environmentally friendly, was as active as the best Ag-based catalyst.

The effectiveness of alcohol label information for increasing knowledge and awareness: a rapid evidence review.

BACKGROUND: Consumers have difficulty understanding alcoholic units and low risk drinking guidelines (LRDG). Labelling may improve comprehension. The aims of this rapid evidence review were to establish the effectiveness of on-bottle labelling for (i) improving comprehension of health risks; (ii) improving comprehension of unit and/or standard drink information and/or LRDG, and (iii) reducing self-reported intentions to drink/actual drinking. METHODS: Electronic database searches were carried out (January 2008-November 2018 inclusive). Papers were included if they were: published in English; from an Organization for Economic Co-operation and Development country; an experimental/quasi-experimental design. Papers were assessed for quality using the Effective Public Health Practice Project Quality Assessment tool. Ten papers were included. Most studies were moderate quality (n = 7). RESULTS: Five themes emerged: comprehension of health risks; self-reported drinking intentions; comprehension of unit/standard drink information and/or LRDG; outcome expectancies; and label attention. Labelling can improve awareness, particularly of health harms, but is unlikely to change behaviour. Improved comprehension was greatest for labels with unit information and LRDG. CONCLUSIONS: Alcohol labelling can be effective in improving people's comprehension of the health risks involved in drinking alcohol enabling them to make informed consumption decisions, and perhaps thereby provide a route to changing behaviour. Thus, effective alcohol labelling is an intervention that can be added to the broader suite of policy options. That being said, the literature reviewed here suggests that the specific format of the label matters, so careful consideration must be given to the design and placement of labels.