Prescribing of pancreatic enzyme therapy for malabsorption in unresectable pancreatic cancer: Cross-sectional survey across New Zealand and Australia.

OBJECTIVE: To investigate the practices of clinicians prescribing pancreatic enzyme replacement therapy (PERT) for unresectable pancreatic cancer in Aotearoa New Zealand and Australia. METHODS: A mixed media advertising campaign was used to recruit appropriate clinicians to complete a questionnaire that collected demographic data, information regarding prescribed medication, and awareness of PERT guidelines. RESULTS: The study recruited 161 clinicians, with 93 and 68 respondents from Aotearoa New Zealand and Australia respectively. Most respondents from both countries were experienced gastrointestinal surgeons and dietitians. Aotearoa New Zealand clinicians and dietitians used faecal elastase more frequently to diagnose PEI than other groups. Clinicians had a tendency to under-prescribe PERT, and to advise incorrectly on the timing of the medication. The majority of clinicians from Aotearoa New Zealand and Australia were not aware of any best practice clinical guidelines for PERT (70 % and 77 %, respectively). CONCLUSION: This study suggests clinicians are over-reliant on faecal elastase to diagnose PEI and are uncertain about the correct dose and timing of PERT for optimal patient benefit in those with unresectable pancreatic cancer. Most clinicians were not aware of best practice guidelines.

The care of older patients with cancer across the United Kingdom in 2024: A narrative review by the International Society of Geriatric Oncology UK Country Group.

The worldwide population is ageing, alongside an increase in cancer incidence rates. Over the past 10 years, there has been huge progress in the field of oncology with earlier diagnosis and an expansion of treatment options, leading to a growing number of older people living with cancer. That has meant that caring for older patients with cancer is now part of day-to-day oncology practices. This cohort often has geriatric syndromes and a higher prevalence of frailty and complex needs and preparing our clinical services to optimise care for these patients is essential. Whilst it is widely accepted that comprehensive geriatric assessments are of benefit to patients, only a small proportion of patients can access these through specialised teams during their cancer care. In the past few years there has been significant progress in this field throughout the United Kingdom (UK). The goal of this review is to inform other health care systems how to learn from what has been done in the UK. This paper provides an update from our previous review in 2020, detailing the new services being implemented and made available to patients and an expansion in the number of new pilot teams and research projects/trials throughout the four nations of the UK.

Doctors' experience providing primary care for refugee women living with chronic pain: a qualitative study.

BACKGROUND: The experiences of GPs in Australia highlight key considerations regarding workload demands, remuneration incentives and the practical implications of working in regions with high ethnic density. This exploration helps to understand the elements that influence GPs delivery of care, particular for refugee women who exhibit disproportionately higher rates of chronic pain. This qualitative study explored the experiences of GPs providing care for refugee women living with chronic pain. METHODS: Semi-structured interviews were undertaken with 10 GPs (9 female and 1 male) practicing across metropolitan Melbourne, Australia. GPs were recruited via purposive sampling and a snowballing strategy. Participants work experience ranged from one to 32 years. Audio recordings of the interviews were transcribed verbatim and stored in qualitative data Nvivo 12 software for coding. Transcripts of interviews were analysed thematically using a phenomenological approach. RESULTS: Three overarching themes were identified: (1) meeting the needs of refugee women living with chronic pain; (2) the role of the GP; and (3) the challenges of the health care system. These themes reflected the complexity of consultations which arose, in part, from factors such as trust, the competencies of clinician's and the limitations posed by time, funding and interpreter use. CONCLUSION: GPs acknowledged the uniqueness of refugee women's chronic pain needs and whilst doctors welcomed care, many were often challenged by the complex nature of consultations. Those that worked in settings that aligned with refugee women's needs highlighted the importance of cultivating culturally safe clinical environments and listening to their patients' stories. However, system level challenges such as time, funding and resource constraints created significant challenges for GPs. Exploring GPs experiences allows for a better understanding of how vectors of disadvantage intersect in health care and highlights the need to better support doctors to improve health care provision for refugee women living with chronic pain.

Tracking Ovine Pulmonary Adenocarcinoma Development Using an Experimental Jaagsiekte Sheep Retrovirus Infection Model.

Ovine pulmonary adenocarcinoma (OPA) is an infectious, neoplastic lung disease of sheep that causes significant animal welfare and economic issues throughout the world. Understanding OPA pathogenesis is key to developing tools to control its impact. Central to this need is the availability of model systems that can monitor and track events after Jaagsiekte sheep retrovirus (JSRV) infection. Here, we report the development of an experimentally induced OPA model intended for this purpose. Using three different viral dose groups (low, intermediate and high), localised OPA tumour development was induced by bronchoscopic JSRV instillation into the segmental bronchus of the right cardiac lung lobe. Pre-clinical OPA diagnosis and tumour progression were monitored by monthly computed tomography (CT) imaging and trans-thoracic ultrasound scanning. Post mortem examination and immunohistochemistry confirmed OPA development in 89% of the JSRV-instilled animals. All three viral doses produced a range of OPA lesion types, including microscopic disease and gross tumours; however, larger lesions were more frequently identified in the low and intermediate viral groups. Overall, 31% of JSRV-infected sheep developed localised advanced lesions. Of the sheep that developed localised advanced lesions, tumour volume doubling times (calculated using thoracic CT 3D reconstructions) were 14.8 ± 2.1 days. The ability of ultrasound to track tumour development was compared against CT; the results indicated a strong significant association between paired CT and ultrasound measurements at each time point (R2 = 0.799, p < 0.0001). We believe that the range of OPA lesion types induced by this model replicates aspects of naturally occurring disease and will improve OPA research by providing novel insights into JSRV infectivity and OPA disease progression.

One health: a structured review and commentary on trends and themes.

BACKGROUND: One Health (OH) is defined as a unifying approach aiming to sustainably balance and optimise the health of people, animals and the ecosystem. It recognises that the health of humans, animals (both domestic and wild), plants and the wider ecosystem are both interdependent and linked. As a concept, it aims to address complex problems requiring input from multiple disciplines. Suitable issues for OH approaches typically include global issues which can widely impact not only the health of humans and animals, but also have a significant environmental impact. Examples include emerging zoonotic diseases and antimicrobial resistance (AMR). Interpretations and use of the term OH differ in the literature and have the potential to dilute its impact. The meaning of OH among the research community has evolved over time. Here, we collate the OH relevant literature from the last two decades, identifying major themes and trends and considering how OH has been embraced differently across various geographical regions. METHODS AND RESULTS: Bibliographic databases were searched using the term "One Health" AND ("Veterinary" OR "Animal") AND ("Medicine" OR "Human") AND ("Environment" OR "Ecosystem") during the period between 1980 and 2022. Data analysis and narrative synthesis identified themes, similarities, and differences within literature. Web of Science and PubMed returned 948 and 1250 results for the period mentioned above. The predominant literature focused on human health, with veterinary health second, although often to benefit human health. It was found that OH is often utilised as a public health approach, generally towards the end of disease surveillance and control. Interestingly, while authors from low- and middle-income countries were well-represented within studies using the term OH, they were less well-represented as corresponding authors. CONCLUSIONS: The predominant focus of the literature was on human and veterinary health, implying OH approach is human-orientated, despite its suggestion that all domains share a common 'health'. Potential improvement to OH could be achieved through greater incorporation of the environmental and social sciences for a more encompassing approach.

Impact of antiretroviral therapy during primary HIV infection on T-cell immunity after treatment interruption.

This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.

Beyond individual factors: a critical ethnographic account of urban residential fire risks, experiences, and responses in single-room occupancy (SRO) housing.

BACKGROUND: Burn injuries are a significant public health concern, closely linked to housing conditions and socioeconomic status. Residents in socioeconomically deprived neighbourhoods are at increased risk of exposure to hazards due to older and poorer housing conditions and limited access to fire protection measures. Individual behaviours such as substance use, smoking, and hoarding are often highlighted as primary causes of residential fires, overshadowing the broader socioeconomic and structural factors that also play a significant role in housing safety. This paper explores the correlation between inadequate housing conditions and heightened fire risks leading to burn injuries, focusing on the contextual factors shaping everyday urban fire risks, experiences, and responses of residents living in Single-Room Occupancy (SRO) housing in Vancouver's Downtown East Side (DTES) and staff working in the fire, health, housing (social and private), and non-profit sectors. METHODS: As part of an ongoing ethnographic study, we partnered with the Vancouver Fire Rescue Services (VFRS) to conduct participant observations in private, non-profit, and government-owned SROs, modular homes, and a temporary shelter. This paper synthesizes insights from participant observations from the first author's self-reflexive journals, including informal conversations with approximately fifty-nine individuals such as SRO tenants, SRO managers/caretakers, health workers, burn survivors, municipal staff, not-for-profit staff, and firefighters. RESULTS: Urgent housing-related issues contributing to inequitable everyday urban fire risks were identified, such as structural deficiencies in SRO buildings and systems, inadequate waste management and storage, and inequitable approaches to addressing hoarding. Additionally, disparities in access to information and the interaction between interpersonal and structural stigmas were significant factors, underscoring the pressing need for intervention. CONCLUSION: Communities like DTES, facing precarious housing conditions, disadvantaged neighbourhoods, and complex health and social challenges, necessitate a comprehensive and holistic approach to fire prevention and safety. Recognizing the interplay between housing instability, mental and physical health issues, unregulated toxic drug supply, drug criminalization, and structural inequities allows practitioners from various sectors to develop contextually driven fire prevention strategies. This multifaceted approach transcends individual-level behaviour change and is crucial for addressing the complex issues contributing to fire risks in underserved communities.

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.

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.

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.

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).

"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.

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.

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.

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.