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Extant crocodilian jaws are subject to functional demands induced by feeding and hydrodynamics. However, the morphological and ecological diversity of extinct crocodile-line archosaurs is far greater than that of living crocodilians, featuring repeated convergence towards disparate ecologies including armoured herbivores, terrestrial macropredators and fully marine forms. Crocodile-line archosaurs, therefore, present a fascinating case study for morphological and functional divergence and convergence within a clade across a wide range of ecological scenarios. Here, we build performance landscapes of two-dimensional theoretical jaw shapes to investigate the influence of strength, speed and hydrodynamics in the morphological evolution of crocodile-line archosaur jaws, and test whether ecologically convergent lineages evolved similarly optimal jaw function. Most of the 243 sampled jaw morphologies occupy optimized regions of theoretical morphospace for either rotational efficiency, resistance to Von Mises stress, hydrodynamic efficiency or a trade-off between multiple functions, though some seemingly viable shapes remain unrealized. Jaw speed is optimized only in a narrow region of morphospace whereas many shapes possess optimal jaw strength, which may act as a minimum boundary rather than a strong driver for most taxa. This study highlights the usefulness of theoretical morphology in assessing functional optimality, and for investigating form-function relationships in diverse clades.
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Jacarés e Crocodilos , Evolução Biológica , Arcada Osseodentária , Animais , Jacarés e Crocodilos/anatomia & histologia , Jacarés e Crocodilos/fisiologia , Arcada Osseodentária/anatomia & histologia , Arcada Osseodentária/fisiologia , Fenômenos Biomecânicos , Fósseis/anatomia & histologia , Hidrodinâmica , Mandíbula/anatomia & histologia , Mandíbula/fisiologiaRESUMO
Over long spans of geological time, various groups of organisms may wax and wane, experiencing times of apparent success and contraction. These rises and falls are often said to reflect either opportunities created by climate change or the relative success of innovative characteristics. Phylum Brachiopoda was one of the most successful marine clades before the Permian/Triassic mass extinction (PTME), but after this event, they became marginal components of marine communities through to the present day. How brachiopod morphological innovations reacted to swiftly declining diversity has long remained poorly understood. Here we analyse morphological evolution over the 300 Myr (Permian-Quaternary) history of the four major Mesozoic-Cenozoic brachiopod orders (Terebratulida, Rhynchonellida, Spiriferinida, Athyridida). Unexpectedly, their disparities reached or exceeded pre-PTME levels, but were decoupled from generic richness, which was generally low. Distribution of taxa in morphospace and shifts in centroid indicate that all four orders exploited new morphospaces when adapting to post-Permian environments. A comparison of morphospace occupation and diversity evolution suggests that the high extinction rate of brachiopods and the limited diversification of new forms may have accounted for the depauperate nature of modern-day brachiopods.
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OBJECTIVES: This scoping review aimed to identify and critically appraise resources for health professionals to identify, diagnose, refer, and support individuals with fetal alcohol spectrum disorder (FASD)-including the extent to which the resources are appropriate for use in communities with First Nations Peoples. METHOD: Seven peer-reviewed databases (April 2022) and 14 grey literature websites (August 2022) were searched. The reference lists of all sources that underwent full-text review were handsearched, and FASD experts were consulted for additional sources. Resources were assessed using the Appraisal of Guidelines for REsearch and Evaluation II instrument and an adapted version of the National Health and Medical Research Council FORM Framework and iCAHE Guideline Quality Checklist. RESULTS: A total of 41 resources underwent data extraction and critical appraisal, as screening and/or diagnosis guidelines were excluded because they are covered in other reviews. Most were recently published or updated (n=24), developed in the USA (n=15, 36.6%) or Australia (n=12, 29.3%) and assisted with FASD patient referral or support (n=40). Most management guidelines scored 76%-100% on overall quality assessment (n=5/9) and were recommended for use in the Australian context with modifications (n=7/9). Most of the guides (n=15/22) and factsheets (n=7/10) received a 'good' overall score. Few (n=3/41) resources were explicitly designed for or with input from First Nations Australians. CONCLUSION: High-quality resources are available to support health professionals providing referrals and support to individuals with FASD, including language guides. Resources should be codesigned with people living with FASD to capture and integrate their knowledge and preferences.
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Transtornos do Espectro Alcoólico Fetal , Pessoal de Saúde , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/terapia , Humanos , Feminino , Gravidez , Recursos em Saúde , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Countries in the Global South are currently facing momentous economic and social challenges, including major debt service problems. As in previous periods of global financial instability, a growing number of countries have turned to the International Monetary Fund (IMF) for financial assistance. The organization has a long track-record of advocating for extensive fiscal consolidation-commonly known as 'austerity'-for its borrowers. However, in recent years, the IMF has announced major initiatives for ensuring that its loans support social spending, thus aiding countries in meeting their development targets and the Sustainable Development Goals. To assess this track record, we collected spending data on 21 loans signed in the 2020-2022 period, including from all their periodic reviews up to August 2023. RESULTS: We find that austerity measures remain a core part of the organization's mandated policies for its borrowers: 15 of the 21 countries studied here experience a decrease in fiscal space over the course of their IMF programs. Against this fiscal backdrop, social spending floors have failed to live up to their promise. There is no streamlined definition of these floors, thus rendering their application haphazard and inconsistent. But even on their own terms, these floors lack ambition: they often do not foresee trajectories of meaningful social spending increases over time, and, when they do, many of these gains are eaten up by soaring inflation. In addition, a third of social spending floors are not implemented-a much lower implementation rate from that for austerity conditions, which the IMF prioritizes. In several instances, where floors are implemented, they are not meaningfully exceeded, thus-in practice-acting as social spending ceilings. CONCLUSIONS: The IMF's lending programs are still heavily focused on austerity, and its strategy on social spending has not represented the sea-change that the organization advertised. At best, social spending floors act as damage control for the painful budget cuts: they are instruments of social amelioration, underpinned by principles of targeted assistance for highly disadvantaged groups. Alternative approaches rooted in principles of universalism can be employed to build up durable and resilient social protection systems.
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Cooperação Internacional , Humanos , Países em DesenvolvimentoRESUMO
The Triassic was a time of ecological upheaval as life recovered from the Permian-Triassic mass extinction. Archosauromorphs were a key component of the recovery, diversifying substantially during the Triassic and encompassing the origins of dinosaurs, pterosaurs and crocodylomorphs. Here, we explore the evolution of locomotion in Archosauromorpha to test whether dinosaurs show any distinctive locomotory features that might explain their success. We implement geometric morphometrics on limb bone shapes and use limb ratios to calculate bipedality and cursoriality metrics. We find that the Avemetatarsalia (dinosaurs, pterosaurs and relatives) exhibit more variable limb form and limb ratios than any other group, indicating a wider range of locomotory modes. The earliest avemetatarsalians were bipedal and cursorial, and their range of form increased through the Triassic with notable diversification shifts following extinction events. This is especially true of dinosaurs, even though these changes cannot be discriminated from a stochastic process. By contrast, the Pseudosuchia (crocodilians and relatives) were more restricted in limb form and locomotor mode with disparity decreasing through time, suggesting more limited locomotor adaptation and vulnerability to extinction. Perhaps the greater locomotor plasticity of dinosaurs gave them a competitive advantage in the changing climates of the Late Triassic.
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Terrestrial ecosystems evolved substantially through the Palaeozoic, especially the Permian, gaining much new complexity, especially among predators. Key among these predators were non-mammalian synapsids. Predator ecomorphology reflect interactions with prey and competitors, which are key controls on carnivore diversity and ecology. Therefore, carnivorous synapsids may offer insight on wider ecological evolution as the first complex, tetrapod-dominated, terrestrial ecosystems formed through the late Palaeozoic. Using morphometric and phylogenetic comparative methods, we chart carnivorous synapsid trophic morphology from the latest Carboniferous to the earliest Triassic (307-251.2 Ma). We find a major morphofunctional shift in synapsid carnivory between the early and middle Permian, via the addition of new feeding modes increasingly specialised for greater biting power or speed that captures the growing antagonism and dynamism of terrestrial tetrapod predator-prey interactions. The further evolution of new hypo- and hypercarnivorous synapsids highlight the nascent intrinsic pressures and complexification of terrestrial ecosystems across the mid-late Permian.
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Ecossistema , Comportamento Predatório , Animais , Filogenia , Carnivoridade , Estado NutricionalRESUMO
OBJECTIVES: The use of nicotine vaping products (NVPs) has increased in low-income and middle-income countries (LMICs) in the Association of Southeast Asian Nations (ASEAN) region; however, it is uncertain what implications the presence and use of NVPs have for tobacco control. DESIGN: In-depth interviews were conducted to explore ASEAN tobacco control experts' (n=11) views on the rise of NVP use in ASEAN LMICs, current NVP policies, the potential harm reduction and smoking cessation utilities of these devices, and what implications they may have for tobacco control. Data were analysed using inductive, reflexive thematic analysis. RESULTS: Five themes emerged: (1) NVPs threaten tobacco control in ASEAN LMICs; (2) commercial factors influence youth appeal and access: product attributes, marketing, supply chains; (3) opposition to the smoking cessation and harm reduction utilities of NVPs; (4) policies are inconsistent and fragmented in the region; and (5) tobacco industry power and tactics have been used to capture NVP markets. CONCLUSIONS: ASEAN tobacco control experts believe that NVPs pose a threat to youth and non-smokers in LMICs in the region, largely because of tobacco industry NVP marketing activities. They do not support the use of NVPs for smoking cessation or harm reduction and call for more restrictions and consistent policy enforcement across the region to protect young people, while also cautiously recognising that use of NVPs may have some benefits for smokers.
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Países em Desenvolvimento , Controle do Tabagismo , Vaping , Humanos , Nicotina , Sudeste AsiáticoRESUMO
The initial radiation of Eosauropterygia during the Triassic biotic recovery represents a key event in the dominance of reptiles secondarily adapted to marine environments. Recent studies on Mesozoic marine reptile disparity highlighted that eosauropterygians had their greatest morphological diversity during the Middle Triassic, with the co-occurrence of Pachypleurosauroidea, Nothosauroidea and Pistosauroidea, mostly along the margins of the Tethys Ocean. However, these previous studies quantitatively analysed the disparity of Eosauropterygia as a whole without focussing on Triassic taxa, thus limiting our understanding of their diversification and morphospace occupation during the Middle Triassic. Our multivariate morphometric analyses highlight a clearly distinct colonization of the ecomorphospace by the three clades, with no evidence of whole-body convergent evolution with the exception of the peculiar pistosauroid Wangosaurus brevirostris, which appears phenotypically much more similar to nothosauroids. This global pattern is mostly driven by craniodental differences and inferred feeding specializations. We also reveal noticeable regional differences among nothosauroids and pachypleurosauroids of which the latter likely experienced a remarkable diversification in the eastern Tethys during the Pelsonian. Our results demonstrate that the high phenotypic plasticity characterizing the evolution of the pelagic plesiosaurians was already present in their Triassic ancestors, casting eosauropterygians as particularly adaptable animals.
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Fósseis , Fenótipo , Répteis , Animais , Adaptação Fisiológica , Análise Multivariada , Répteis/anatomia & histologia , Répteis/classificação , Fósseis/anatomia & histologia , FilogeniaRESUMO
Neck elongation has appeared independently in several tetrapod groups, including giraffes and sauropod dinosaurs on land, birds and pterosaurs in the air, and sauropterygians (plesiosaurs and relatives) in the oceans. Long necks arose in Early Triassic sauropterygians, but the nature and rate of that elongation has not been documented. Here, we report a new species of pachypleurosaurid sauropterygian, Chusaurus xiangensis gen. et sp. nov., based on two new specimens from the Early Triassic Nanzhang-Yuan'an Fauna in the South China Block. The new species shows key features of its Middle Triassic relatives, but has a relatively short neck, measuring 0.48 of the trunk length, compared to > 0.8 from the Middle Triassic onwards. Comparative phylogenetic analysis shows that neck elongation occurred rapidly in all Triassic eosauropterygian lineages, probably driven by feeding pressure in a time of rapid re-establishment of new kinds of marine ecosystems.
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Dinossauros , Animais , China , Ecossistema , Girafas , Filogenia , RépteisRESUMO
To determine the efficacy of intervention programs for young children (4-9 years) with emerging mental health needs, we conducted a review of meta-analytic and systematic reviews of the intervention literature. Of 41,061 abstracts identified and 15,076 screened, 152 review articles met the inclusion criteria. We reviewed interventions across multiple disciplines targeting: (1) general mental health concerns; (2) internalizing symptoms; (3) externalizing symptoms; (4) anxiety; (5) depression; (6) trauma; (7) symptoms of attention-deficit/hyperactivity disorder; and (8) mental health concerns associated with autism spectrum disorder. Substantial evidence was found for the efficacy of behavioral and cognitive behavioral interventions for general mental health concerns, externalizing symptoms (generally, as well as ADHD, conduct, and other behavioral symptoms) and internalizing symptoms (generally, as well as anxiety) aged 4-9 years. Emerging evidence was identified for interventions targeting trauma symptoms, depression symptoms, and social, emotional and behavioral symptoms in autism spectrum disorder in children aged 4-9 years. Currently there is only limited emerging evidence regarding non-behavioral or non-cognitive behavioral interventions for programs targeting children ages 4-9 years where the aim is to deliver an evidence-based program to improve child social, emotional and/or behavioral functioning. Given the recent rises in mental health needs reported in children, targeted behavioral-and/or cognitive behavior therapy-based interventions should be made widely available to children (and their families) who experience elevated symptoms.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Terapia Cognitivo-Comportamental , Criança , Humanos , Pré-Escolar , Saúde Mental , Transtorno do Espectro Autista/terapia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , AnsiedadeRESUMO
As one of the predominant benthic organisms in the Palaeozoic, brachiopod was largely eliminated in the Permian-Triassic boundary mass extinction, and then highly diversified in the Middle Triassic. Since fossil data from the Early Triassic are rarely reported, the recovery patterns of Early Triassic brachiopods remain unclear. This study documents a well-preserved fauna that is the most diverse Olenekian brachiopod fauna so far (age constrained by conodont biostratigraphy) from the Datuguan section of ramp facies in South China. This fauna is composed of 14 species within nine genera, including six genera (Hirsutella, Sulcatinella, Paradoxothyris, Dioristella, Neoretzia and Isocrania) found in the Early Triassic for the first time and three new species, including Paradoxothyris flatus sp. nov., Hirsutella sulcata sp. nov. and Sulcatinella elongata sp. nov. The Datuguan fauna indicates that the diversity of Olenekian brachiopod fauna has been underestimated, which can be caused by a combination of reduced habitats (in geographic size and sedimentary type) compared with the end-Permian, great bed thickness making it difficult to find fossils and most species in the fauna having low abundance. Based on the faunal change in the Datuguan section and environmental changes in South China, it can be inferred that brachiopod recovery in the studied section occurred in the latest Spathian rather than the Smithian when the environment started to ameliorate. Global brachiopod data also indicates that the initial recovery of brachiopods happened in the Spathian, and many genera that widely occurred in the Middle or Late Triassic had originated in the Olenekian.
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PURPOSE: Pre-operative scores based on patient characteristics are commonly used to predict hip fracture outcomes. Mobility, an indicator of pre-operative function, has been neglected as a potential predictor. We assessed the ability of pre-fracture mobility to predict post-operative outcomes following hip fracture. METHODS: We analysed prospectively collected data from hip fracture surgery patients at a large-volume trauma unit. Mobility was classified into four groups. Post-operative outcomes studied were mortality and residence at 30 days, medical complications within 30- or 60-days post-operatively, and prolonged length of stay (LOS, ≥ 28 days). We performed multivariate regression analyses adjusting for age and sex to assess the discriminative ability of the Nottingham Hip Fracture Score (NHFS), with and without mobility, for predicting outcomes using the area under the receiver operating characteristic curve (AUROC). RESULTS: 1919 patients were included, mean age 82.6 (SD 8.2); 1357 (70.7%) were women. Multivariate analysis demonstrated patients with worse mobility had a 1.7-5.5-fold higher 30-day mortality (p ≤ 0.001), and 1.9-3.2-fold higher likelihood of prolonged LOS (p ≤ 0.001). Worse mobility was associated with a 2.3-3.8-fold higher likelihood of living in a care home at 30-days post-operatively (p < 0.001) and a 1.3-2.0-fold higher likelihood of complications within 30 days (p ≤ 0.001). Addition of mobility improved NHFS discrimination for discharge location, AUROC NHFS 0.755 [0.733-0.777] to NHFS + mobility 0.808 [0.789-0.828], and LOS, AUROC NHFS 0.584 [0.557-0.611] to NHFS + mobility 0.616 [0.590-0.643]. CONCLUSION: Incorporating mobility assessment into risk scores may improve casemix adjustment, prognostication following hip fracture, and identify high-risk patient groups requiring enhanced post-operative care at admission.
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Fraturas do Quadril , Humanos , Feminino , Idoso de 80 Anos ou mais , Masculino , Medição de Risco , Fraturas do Quadril/cirurgia , Fatores de Risco , Curva ROC , HospitalizaçãoRESUMO
Recognising the world's lack of preparedness for the COVID-19 pandemic, international organisations like the World Health Organization, World Bank, and International Monetary Fund are calling for extensive additional funding to strengthen pandemic preparedness and response systems in low-income and middle-income countries, including through domestic resource mobilisation. This article examines the prospects of national health budgets increasing in such a context, drawing on new International Monetary Fund projections on public spending around the world. We show that by 2024 public spending will be lower than the 2010s average for almost half of all low-income and middle-income countries. A key driver of this new wave of austerity is the dramatic increase in public spending dedicated to repaying external debt-underpinned by growing debt stocks, US interest rates rises, and commodity price hikes. As in earlier crises, the stage is set for a situation where population health deteriorates-via compound effects of the pandemic and widespread economic hardship-while public health services required to tackle increased need are facing steep cuts. We conclude by considering what can be done to avoid repeating the mistakes of the past.
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COVID-19 , Saúde Global , Estados Unidos , Humanos , Pandemias , Organização Mundial da Saúde , PobrezaRESUMO
The International Monetary Fund (IMF) is (in)famous for its structural adjustment programs, which provide fresh credit for borrowing governments in exchange for market-liberalizing policy reforms. While studies have documented a causal relationship between structural adjustment and political instability, scholarly understanding of the mechanisms underlying this relationship remain perfunctory. The received wisdom is that IMF policy conditions generate material hardship which then drives political instability. We advance an additional pathway-that instability is also prompted by alienation effects related to the foreign imposition of policies. Drawing on a sample of up to 168 countries between 1980 and 2014, we test for the presence of both mechanisms. Our results suggest that there are alienation effects, indicated by a persistent protest-inducing impact of IMF program participation when controlling for market-liberalizing conditions, and especially when programs are concluded by left-wing governments and non-repeat borrowers. We also find evidence of hardship effects, indicated by a positive relationship between the intensity of fiscal austerity required and the number of protests. Our findings have important implications for the relationship between structural adjustment, contentious politics, and the role of international organizations in domestic policy reform.
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Países em Desenvolvimento , Administração Financeira , Humanos , Governo , Política Pública , PolíticaRESUMO
INTRODUCTION: Tobacco companies have used below-the-line marketing in novel ways to promote their brands to youth in low/middle-income countries in Southeast Asia. This study explores how young male smokers in Cambodia experience below-the-line marketing strategies. METHODS: Convenience sampling was used to recruit 147 young male smokers (18-24 years) in Cambodia in early 2020. Local research assistants conducted mixed-methods interviews with participants in Khmer or English. Participants recalled exposure to below-the-line marketing strategies and provided in-depth descriptions about their experiences with individual sales promotions. Quantitative data were analysed using descriptive statistics and qualitative data were analysed using thematic analysis. RESULTS: 54% of participants recalled exposure to at least one below-the-line marketing strategy, including point-of-sale promotions (32.7%), individual sales promotions (27.9%) and online advertising (14.3%). Participants described individual sales promotions in public settings, and recalled that promoters were mostly female, attractive and targeted young males. Tactics used to encourage young people to accept promotional offers included free cigarettes and sample packets, swapping current cigarettes for new brands and collecting consumer details after interviewing. The brands and product features of cigarettes being promoted were readily described by participants. CONCLUSION: This study provides evidence that illegal below-the-line marketing is still occurring in Cambodia, and increased monitoring and enforcement of advertising restrictions is needed.
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Indústria do Tabaco , Produtos do Tabaco , Adolescente , Masculino , Humanos , Feminino , Publicidade , Nicotiana , Fumantes , Camboja , Fumar , Indústria do Tabaco/métodos , Marketing/métodosRESUMO
INTRODUCTION: While most Association of Southeast Asian Nations (ASEAN) countries have adopted the Framework Convention on Tobacco Control (FCTC), implementation and enforcement of measures are lacking in some low- and middle-income countries (LMICs) in the region. This study aimed to describe: 1) how the tobacco industry has undermined tobacco control efforts and adapted its tactics in response to the COVID-19 pandemic and other external factors, 2) the political factors that hinder progress, and 3) the expert recommendations to overcome challenges of tobacco control in the ASEAN region. METHODS: During the COVID-19 pandemic, qualitative interviews were conducted with tobacco control experts to explore their perspectives and recommendations to address the barriers and challenges of tobacco control in ASEAN LMICs. RESULTS: Eleven tobacco control experts participated in interviews. Five themes emerged from the data: 1) a shift to below-the-line marketing and digital technologies to target youth; 2) industry develops new tactics to undermine tobacco control; 3) cigarette packet branding - the last remaining marketing channel; 4) political factors hindering tobacco control; and 5) broader involvement and collaboration in tobacco control. CONCLUSIONS: The tobacco industry continues to undermine tobacco control in ASEAN LMICs, shifting its marketing, corporate social responsibility (CSR) and lobbying tactics in response to changing regulations, digital technologies, and the COVID-19 pandemic. While lack of government leadership also hinders progress, full adoption of the FCTC and increased collaboration in tobacco control are recommended to overcome these issues.
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OBJECTIVES: To explore how cigarette packet branding and colours influence young male smokers' perceptions of tobacco brands in Cambodia. DESIGN: Mixed-methods study. SETTING: Worksites, living accommodations, a university and public locations in Phnom Penh, Cambodia. PARTICIPANTS: 147 male Cambodian smokers (18-24 years). INTERVENTIONS: Participants were shown mock-up pictures of different cigarette packet branding and colour variations and asked to respond to close-ended and short-response questions. OUTCOME MEASURES: Brand recognition, appeal and harm perceptions of cigarette packet branding and colours. RESULTS: When shown three packets with brand names removed, 98.6% of participants recognised packet one as Mevius brand, 21.1% recognised packet two as Marlboro and 38.8% recognised packet three as 555. For the three fully-branded and three matching plain packets, most participants selected a fully-branded packet as the most appealing taste (83.0%) and most appealing to youth (81.7%). Participants described their chosen brand as appealing due to beliefs about its superior taste/quality, reduced harm and symbolic attitudes surrounding tobacco brands and smokers of different brands in a social status hierarchy. When shown six different colours of unbranded packets, participants selected the blue packet (51.0%) as the most appealing for taste, the white packet as the least harmful (25.2%), and the red (15.0%) and black (12.9%) packets as the most harmful to health. They described their associations of packet colours with abstract imagery concerning smoking-related harms and their future well-being. CONCLUSIONS: Findings suggest that packet branding and colours influence young male smokers' recognition, appeal and harm perceptions of tobacco brands in Cambodia and remain an influential marketing tool for tobacco companies where advertising is banned. Consequently, Cambodia and other low and middle-income countries in Southeast Asia should implement plain packaging.
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Fumantes , Produtos do Tabaco , Adolescente , Camboja , Cor , Humanos , Masculino , Embalagem de Produtos/métodos , NicotianaRESUMO
The squamates (lizards, snakes, and relatives) today comprise more than 10,000 species, and yet their sister group, the Rhynchocephalia, is represented by a single species today, the tuatara. The explosion in squamate diversity has been tracked back to the Cretaceous Terrestrial Revolution, 100 million years ago (Ma), the time when flowering plants began their takeover of terrestrial ecosystems, associated with diversification of coevolving insects and insect-eating predators such as lizards, birds, and mammals. Squamates arose much earlier, but their long pre-Cretaceous history of some 150 million years (Myr) is documented by sparse fossils. Here, we provide evidence for an initial radiation of squamate morphology in the Middle and Late Jurassic (174-145 Ma), and show that they established their key ecological roles much earlier than had been assumed, and they have not changed them much since.
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Ecossistema , Lagartos , Animais , Evolução Biológica , Fósseis , Insetos , Lagartos/anatomia & histologia , Mamíferos , FilogeniaRESUMO
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of somatic cell reprogramming, which suggests full reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first "maturation phase transient reprogramming" (MPTR) method, where reprogramming factors are selectively expressed until this rejuvenation point then withdrawn. Applying MPTR to dermal fibroblasts from middle-aged donors, we found that cells temporarily lose and then reacquire their fibroblast identity, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome was rejuvenated to a similar extent, including H3K9me3 levels and the DNA methylation ageing clock. The magnitude of rejuvenation instigated by MPTR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.