Analysis of Philip Morris International's 'aspirational' target for its 2025 cigarette shipments.

BACKGROUND: Philip Morris International (PMI) claims to be transforming and has committed to a 'smoke-free' future. In 2020, it announced an 'aspirational' target for reduced cigarette shipments by 2025. METHODS: PMI cigarette shipment data are taken from PMI quarterly financial reports 2008-2023. Trends in these data before and after the 2020 announcement are analysed using linear regression, and auto regressive integrated moving average and error, trend, seasonal time-series models to assess if PMI's 2025 target would be met on pre-existing trends, and if the trend changed after the announcement. These trends are also compared with the global retail market for cigarettes, using sales data from Euromonitor. RESULTS: Findings were consistent across all three models. PMI's shipment target of 550 billion cigarette sticks by 2025 would readily have been met given pre-existing shipment trends. Following the 2020 announcement, the decline in PMI cigarette shipments stalled markedly with a statistically significant change in trend (p<0.001). The current and projected trend to 2025 is consistent with no further decline in cigarette volumes, meaning PMI is unlikely to hit its target. This mirrors a global pattern in which declines in cigarette sales have stalled since 2020. CONCLUSIONS: PMI's 2025 target was not 'aspirational' but highly conservative-it would have been met based on pre-existing trends in declining cigarette shipments. Yet PMI will nonetheless fail to meet that target providing evidence it is not transforming. Stalling of the decline of PMI and global cigarette sales raises significant concerns about progress in global tobacco control.

Advanced Solid Geopolymer Formulations for Refractory Applications.

Cement, as a construction material, has low thermal resistance, inherent fire resistance, and is incombustible up to a certain degree. However, the loss of its mechanical performance and spalling are its primary issues, and it thus cannot retain its performance in refractory applications. The present study explores the performance of geopolymer formulations that have excellent fire resistance properties for potential refractory applications. This study is unique, as it investigates advanced solid geopolymer formulations that need only water to activate and bind. Various solid geopolymer formulations with fly ash as a precursor; potassium hydroxide and potassium silicate as activators; and mullite and alumina as refractory aggregates were studied for their compressive strength at up to 1100 °C and compared with their two-part conventional liquid alkaline geopolymer counterparts. Advanced solid geopolymer formulations with mullite and alumina as refractory aggregates had mechanical strength values of 84 MPa and 64 MPa post-1100 °C exposure and were further exposed to ten thermal cycles of 1100 °C to study their fatigue resistance and post-exposure compressive strengths. The geopolymer sample with mullite as a refractory aggregate yielded 115.2 MPa compressive strength after the fourth cycle of exposure. This sample was also studied for its temperature distribution upon direct flame exposure. All the geopolymer formulations displayed a drop in compressive strength at 600 °C due to viscous sintering and then a rise in strength at 1100 °C due to phase transformation. X-ray diffraction studies revealed that the formation of crystalline phases such as leucite, sanidine, and annite were responsible for the superior strengths at 1100 °C for the alumina- and mullite-based geopolymer formulations.

Whole-mitogenome analysis unveils previously undescribed genetic diversity in cane toads across their invasion trajectory.

Invasive species offer insights into rapid adaptation to novel environments. The iconic cane toad (Rhinella marina) is an excellent model for studying rapid adaptation during invasion. Previous research using the mitochondrial NADH dehydrogenase 3 (ND3) gene in Hawai'ian and Australian invasive populations found a single haplotype, indicating an extreme genetic bottleneck following introduction. Nuclear genetic diversity also exhibited reductions across the genome in these two populations. Here, we investigated the mitochondrial genomics of cane toads across this invasion trajectory. We created the first reference mitochondrial genome for this species using long-read sequence data. We combined whole-genome resequencing data of 15 toads with published transcriptomic data of 125 individuals to construct nearly complete mitochondrial genomes from the native (French Guiana) and introduced (Hawai'i and Australia) ranges for population genomic analyses. In agreement with previous investigations of these populations, we identified genetic bottlenecks in both Hawai'ian and Australian introduced populations, alongside evidence of population expansion in the invasive ranges. Although mitochondrial genetic diversity in introduced populations was reduced, our results revealed that it had been underestimated: we identified 45 mitochondrial haplotypes in Hawai'ian and Australian samples, none of which were found in the native range. Additionally, we identified two distinct groups of haplotypes from the native range, separated by a minimum of 110 base pairs (0.6%). These findings enhance our understanding of how invasion has shaped the genetic landscape of this species.

Is developmental plasticity triggered by DNA methylation changes in the invasive cane toad (Rhinella marina)?

Many organisms can adjust their development according to environmental conditions, including the presence of conspecifics. Although this developmental plasticity is common in amphibians, its underlying molecular mechanisms remain largely unknown. Exposure during development to either 'cannibal cues' from older conspecifics, or 'alarm cues' from injured conspecifics, causes reduced growth and survival in cane toad (Rhinella marina) tadpoles. Epigenetic modifications, such as changes in DNA methylation patterns, are a plausible mechanism underlying these developmental plastic responses. Here we tested this hypothesis, and asked whether cannibal cues and alarm cues trigger the same DNA methylation changes in developing cane toads. We found that exposure to both cannibal cues and alarm cues was associated with local changes in DNA methylation patterns. These DNA methylation changes affected genes putatively involved in developmental processes, but in different genomic regions for different conspecific-derived cues. Genetic background explains most of the epigenetic variation among individuals. Overall, the molecular mechanisms triggered by exposure to cannibal cues seem to differ from those triggered by alarm cues. Studies linking epigenetic modifications to transcriptional activity are needed to clarify the proximate mechanisms that regulate developmental plasticity in cane toads.

Commercial Tobacco Endgame Goals: Early experiences from six countries.

INTRODUCTION: Tobacco use is a major threat to health globally. A number of countries have adopted 'endgame goals' to minimise smoking prevalence. The INSPIRED project aims to describe and compare the experiences of the first six countries to adopt an endgame goal. METHODS: Data were collected on the initial experiences of endgame goals in Canada, Finland, Ireland, New Zealand (Aotearoa), Scotland, and Sweden up to 2018. Information was collated on the nature of the endgame goals, associated interventions and strategies, potential enablers and barriers, and perceived advantages and disadvantages. RESULTS: The INSPIRED countries had relatively low smoking prevalences and moderate to strong smokefree policies. Their endgame goals aimed for smoking prevalences of 5% or less. Target dates ranged from 2025 to 2035. Except for New Zealand (Aotearoa), all countries had an action plan to support their goal by 2018. However, none of the plans incorporated specific endgame measures. Lack of progress in reducing inequities was a key concern, despite the consideration of equity in all of the country's goals and/or action plans. Experience with endgame goals was generally positive, however participants thought additional interventions would be required to equitably meet their endgame goal. CONCLUSIONS: There was variation in the nature and approach to endgame goals. This suggests that countries should consider adopting endgame goals and strategies to suit their social, cultural, and political contexts. The experiences of the INSPIRED countries suggest that further and more significant interventions will be required for the timely and equitable achievement of endgame goals. IMPLICATIONS: By 2018, six countries (Canada, Finland, Ireland, New Zealand (Aotearoa), Scotland, and Sweden) had introduced government-endorsed 'endgame goals', to rapidly reduce smoking prevalence to very low levels by a specified date. The nature and implementation of endgame goals was variable. Early experiences with the goals were generally positive, but progress in reducing smoking prevalence was insufficient, particularly for priority groups. This finding suggests more significant interventions ('endgame interventions') and measures to reduce inequities need to be implemented to achieve endgame goals. Variation in the nature and experience of endgame goals demonstrates the importance of designing endgame strategies that suit distinct social, cultural, and political contexts.

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria.

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.

The impact of racism on subsequent healthcare use and experiences for adult New Zealanders: a prospective cohort study.

BACKGROUND: Racism is an important determinant of health and driver of racial/ethnic health inequities. Experience of racism has been linked to negative healthcare use and experiences although most studies have been cross-sectional. This study examines the relationship between reported experience of racism and subsequent use and experience of health services. METHODS: This is a prospective cohort study design. The 2016/2017 adult New Zealand Health Survey (NZHS) provided the sampling frame and baseline data on exposures, health status and confounders. This stand-alone study invited all exposed individuals to participate when sampled based on their reported experience of racism (ever), stratified by broad ethnic groupings (Maori, Pacific, Asian, European/Other). Equal numbers of unexposed participants were selected for invitation using propensity score matching (propensity to experience racism, based on key available predictive factors). Follow-up was one to two years after NZHS interview. Outcome variables (last 12 months) were: unmet healthcare need (overall, for mental health, for a general practitioner); satisfaction with usual medical centre; and experiences with general practitioners (explaining care, involvement in decision-making, treated with respect/dignity, confidence and trust). Logistic regression models examining the association between experience of racism (at baseline) and health service use and experience (at follow-up) used doubly-robust estimation to weight for propensity scores used in the sampling with additional adjustment for confounders. RESULTS: The study had 2010 participants. Experience of racism (ever) at baseline was associated with higher overall unmet need at follow-up (adjusted OR (aOR) = 1.71, 95% CI 1.31, 2.23), with similar patterns for other unmet need measures. Experience of racism was associated with higher dissatisfaction with a usual medical centre (aOR = 1.41, 95% CI 1.10, 1.81) and with higher reporting of negative patient experiences. CONCLUSION: In line with how racism structures oppression, exposure to racism is largely felt by non-European groups in Aotearoa New Zealand. Experiences of racism potentially lead to poorer healthcare and healthcare inequities through higher unmet need, lower satisfaction and more negative experiences of healthcare. The health system has a critical role to play in addressing racism within healthcare and supporting societal efforts to eliminate racism and ethnic inequities.

Toward genome assemblies for all marine vertebrates: current landscape and challenges.

Marine vertebrate biodiversity is fundamental to ocean ecosystem health but is threatened by climate change, overharvesting, and habitat degradation. High-quality reference genomes are valuable foundational scientific resources that can inform conservation efforts. Consequently, global consortia are striving to produce reference genomes for representatives of all life. Here, we summarize the current landscape of available marine vertebrate reference genomes, including their phylogenetic diversity and geographic hotspots of production. We discuss key logistical and technical challenges that remain to be overcome if we are to realize the vision of a comprehensive reference genome library of all marine vertebrates.

Addressing Intergenerational Inequity in Tobacco-Harm: What Helps Children of Smokers to Remain Nonsmokers?

INTRODUCTION: Children of people who smoke are more likely to take up smoking themselves. In Aotearoa New Zealand (NZ), adolescent smoking declined dramatically between 2000 and 2016 despite limited change in parental smoking, demonstrating that the cycle can be broken. AIMS AND METHODS: This study aimed to identify modifiable factors associated with never smoking in Year 10 students (14-15 years) who had at least one caregiver who smoked. We used data from the Youth Insights Survey (2016 and 2018, pooled, N = 5,422) and identified students with at least one caregiver (mother, father, grandparent, other caregiver) who smoked (N = 2,205). To investigate modifiable factors potentially associated with nonsmoking we used logistic regression with marginally adjusted prevalence estimates. RESULTS: Overall, 41% of students had at least one caregiver who smoked. In this group, the majority (65%) had never smoked themselves. After adjustment, never-smoking was more prevalent among students attending low-deprivation (more affluent) schools (73% had never smoked) compared to high-deprivation schools (44%); students not exposed to others' smoking inside the home (72%) or in cars (70%) in the past week compared to those exposed (59% and 51%, respectively); and students whose parents would be upset if they were caught smoking (68% vs 49% for those whose parents would not be upset), or who had high self-esteem (69% vs 55% for those with low self-esteem). CONCLUSIONS: Modifiable factors independently associated with non-smoking in adolescents with caregiver(s) who smoked were: nonexposure to smoking inside the home and in cars, parental expectations of nonsmoking, and high self-esteem. IMPLICATIONS: Even in countries like NZ with relatively low adult smoking rates, children's exposure to caregiver smoking may be prevalent, particularly in structurally disadvantaged populations. This study suggests that action to promote smokefree homes and cars, build high self-esteem in young people, and communicate expectations of non-smoking are likely to help children of people who smoke to remain nonsmokers. A comprehensive approach that also addresses "upstream" factors (eg, socioeconomic deprivation) and underlying causes of structural inequity (eg, institutional racism) is needed. Such policy and community action may help to break intergenerational cycles of tobacco use and health inequity.

A streamlined, automated workflow to screen and triage large numbers of baculoviruses for protein expression.

The baculovirus expression system is a powerful and widely used method to generate large quantities of recombinant protein. However, challenges exist in workflows utilizing either liquid baculovirus stocks or the Titerless Infected-Cells Preservation and Scale-Up (TIPS) method, including the time and effort to generate baculoviruses, screen for protein expression and store large numbers of baculovirus stocks. To mitigate these challenges, we have developed a streamlined, hybrid workflow which utilizes high titer liquid virus stocks for rapid plate-based protein expression screening, followed by a TIPS-based scale-up for larger protein production efforts. Additionally, we have automated each step in this screening workflow using a custom robotic system. With these process improvements, we have significantly reduced the time, effort and resources required to manage large baculovirus generation and expression screening campaigns.

Low Transvalvular Flow Rate in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI) Is a Predictor of Mortality: The TFR-TAVI Study.

BACKGROUND: Transvalvular flow rate (TFR) represents a better reflection of transvalvular flow than the stroke volume index (SVi), and has recently emerged as a useful prognostic tool in patients undergoing surgical aortic valve replacement. There is a paucity of data investigating the role of TFR and its relationship with other clinical or echocardiographic factors in patients undergoing transcatheter aortic valve implantation (TAVI). METHOD: This was a retrospective single-centre study of 629 consecutive patients who underwent TAVI between March 2009 and September 2020. Pre-TAVI low TFR was defined as <200 c/s. The primary study end point was all-cause mortality. RESULTS: Low TFR was observed in 41.8% (263/629) of included patients and was associated with increasing age, low body surface area, hypertension, diabetes, atrial fibrillation, left ventricular (LV) dysfunction, and significant mitral regurgitation. LV function status and severity of aortic valve disease were independent predictors of low TFR. Low TFR was significantly associated with long-term all-cause mortality even after adjustment for other risk factors (adjusted hazard ratio [aHR] 1.44; 95% confidence interval [CI] 1.02-2.03; p=0.038). When data were stratified according to SVi, low TFR was an independent predictor of long-term all-cause mortality in patients with normal SVi (aHR 1.98; 95% CI 1.06-3.69; p=0.032) but not in patients with low SVi (HR 1.23; 95% CI 0.71-2.11; p=0.46; p=0.016 for interaction). CONCLUSIONS: Low TFR is common in patients undergoing TAVI and is an independent predictor of all-cause mortality, particularly in patients with normal SVi.

Angiographic and Procedural Characteristics in Frail Older Patients with Non-ST Elevation Acute Coronary Syndrome.

Background: Angiographic and procedural characteristics stratified by frailty status are not known in older patients with non-ST elevation acute coronary syndrome (NSTEACS). We evaluated angiographic and procedural characteristics in older adults with NSTEACS by frailty category, as well as associations of baseline and residual SYNTAX scores with long-term outcomes. Methods: In this study, 271 NSTEACS patients aged ≥75 years underwent coronary angiography. Frailty was assessed using the Fried criteria. Angiographic analysis was performed using QAngio® XA Medis in a core laboratory. Major adverse cardiovascular events (MACE) consisted of all-cause mortality, MI, stroke or transient ischaemic attack, repeat unplanned revascularisation and significant bleeding. Results: Mean (±SD) patient age was 80.5 ± 4.9 years. Compared with robust patients, patients with frailty had more severe culprit lesion calcification (OR 5.40; 95% CI [1.75-16.8]; p=0.03). In addition, patients with frailty had a smaller mean improvement in culprit lesion stenosis after percutaneous coronary intervention (50.6%; 95% CI [45.7-55.6]) than robust patients (58.6%; 95% CI [53.5-63.7]; p=0.042). There was no association between frailty phenotype and completeness of revascularisation (OR 0.83; 95% CI [0.36-1.93]; p=0.67). A high baseline SYNTAX score (≥33) was associated with adjusted (age and sex) 5-year MACE (HR 1.40; 95% CI [1.08-1.81]; p=0.01), as was a high residual SYNTAX score (≥8; adjusted HR 1.22; 95% CI [1.00-1.49]; p=0.047). Conclusion: Frail adults presenting with NSTEACS have more severe culprit lesion calcification. Frail adults were just as likely as robust patients to receive complete revascularisation. Baseline and residual SYNTAX score were associated with MACE at 5 years.

A Systematic Review and Meta-Analysis of the Clinical Outcomes of Isolated Tricuspid Valve Surgery.

Patients with isolated tricuspid valve (TV) disease have poor prognosis with no consensus on their management. Transcatheter TV intervention is emerging as a valid option in patients with prohibitive surgical risk. We analyzed studies of patients who underwent isolated TV surgery to identify the features associated with successful clinical outcomes. We performed a systematic review and meta-analysis of studies reporting clinical outcomes of isolated surgical TV intervention, namely TV repair, TV replacement with a bioprosthetic valve (TVR-B), or TV replacement with a mechanical valve (TVR-M). Twenty-seven studies involving 10,478 patients (4,931 TV repair, 3,821 TVR-B, and 1,713 TVR-M) were included. Early mortality occurred in 9% and did not differ between TV surgical approaches. Late mortality was 27% at a median follow-up of 4 (3 to 6) years and was significantly higher for all-TVR (30% vs 25%, rate ratio 1.18, 95% confidence interval 1.05 to 1.31, p = 0.004) and TVR-B (28% vs 24%, rate ratio 1.15, 95% confidence interval 1.02 to 1.30, p = 0.02) compared with TV repair. Late mortality did not differ between TVR-B and TVR-M. Across all studies, early complications included bleeding (7.4%), acute kidney injury (18.7%), permanent pacemaker (13.7%), cerebrovascular accidents (1.2%), and infection (8.9%). Late clinical outcomes included reintervention (3.7%), structural valve deterioration (2.4%), valve thrombosis (2.6%), and TV regurgitation recurrence after 1 year (15.0%). In conclusion, in isolated TV surgeries, TV repair has favorable long-term mortality compared with TV replacement. This supports the development and refinement of transcatheter TV repair approaches. Future research is recommended to provide comparative data for various transcatheter TV interventions.

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111.

Support for and potential impacts of key Smokefree 2025 strategies among Maori who smoke.

AIM: The recently passed Smokefree Environments and Regulated Products (Smoked Tobacco) Amendment Act has the potential to profoundly reduce smoking prevalence and related health inequities experienced among Maori. This study examined support for, and potential impacts of, key measures included within the legislation. METHOD: Data came from Wave 1 (2017-2019) of the Te Ara Auahi Kore longitudinal study, which was conducted in partnership with five primary health organisations serving Maori communities. Participants were 701 Maori who smoked. Analysis included both descriptive analysis and logistic regression. RESULTS: More Maori participants supported than did not support the Smokefree 2025 (SF2025) goal of reducing smoking prevalence to below 5%, and the key associated measures. Support was greatest for mandating very low nicotine cigarettes (VLNCs). Participants also believed VLNCs would prompt high rates of quitting. Participants who had made more quit attempts or reported less control over their life were more likely to support VLNCs. CONCLUSION: There was support for the SF2025 goal and for key measures that could achieve it. In particular, VLNCs may have significant potential to reduce smoking prevalence among Maori. As part of developing and implementing these measures it will be important to engage with Maori who smoke and their communities.