Characterization of TRIB2 mediated drug resistance and its validation as a novel diagnostic marker

Intrinsic and acquired resistance to conventional and targeted chemotherapeutics is the fundamental reason for treatment failure in many cancer patients. Identifying molecular mechanisms involved in drug resistance or sensitization to targeted therapy is of enormous clinical importance. Critical transcription factors such as forkhead box O (FOXO) proteins and p53 have been shown to mediate the action of multiple anti-cancer drugs. Our lab discovered a novel mechanism of drug resistance facilitated by TRIB2 by activating AKT and, consequently, the inactivation of both FOXO and p53. Furthermore, this lab has established TRIB2 as a potential biomarker for melanoma, and its expression correlated with disease stage (I-IV). As TRIB2 may potentially be used as a biomarker and confers resistance to several standard front-line therapeutics to treat melanoma, these results are extremely relevant for the clinical management of melanoma. While accounting for less than 5% of all skin cancer patients, melanoma is the deadliest form of skin cancer, responsible for over 90% of all skin cancer deaths. Furthermore, metastatic melanoma incidence has increased over the past three decades, with a mortality rate that continues to rise faster than almost all other cancers. Genetic analyses of melanoma have uncovered several key pathways in disease onset and progression, most prominently are the Ras/Raf/MEK/ERK and the PI3K/AKT/FOXO signalling pathways. In the decades 70 and 80, the established treatment for metastatic melanoma included high-dose interleukin-2 or dacarbazine (DTIC) administration associated with response rates of between 10-20% with severe side effects during treatment. The limited success prompted investigators to further characterize and understand the disease, leading to the development of immunotherapy, namely immune checkpoint inhibitors (pembrolizumab, nivolumab and ipilimumab), and targeted therapy, namely the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib, which are approved to treat melanoma patients with mutated BRAF (about 50% of patients). Simultaneously, several PI3K, AKT, mTOR, and MEK inhibitors have been tested in clinical trials but, intrinsic or acquired resistance limits the efficacy of all these treatments. Our lab has previously shown that the tumour suppressor FOXO is the central downstream transcriptional mediator of the PI3K/AKT pathway after PI3K inhibition, which is in accordance with other studies that also show that FOXOs are crucial for the anti-cancer action of several drugs, in particular, PI3K pathway inhibitors. Therefore, proteins capable of inactivating FOXO factors are good candidates for mediating tumour formation, progression and resistance to these agents. Strikingly, our lab previously established TRIB2 as an oncogenic protein that suppresses FOXO factors in melanoma and induces resistance to the dual PI3K/mTOR inhibitor BEZ235 (dactolisib). We hypothesize that TRIB2 mediates therapy resistance by altering the gene expression profile of the cells, and we can pharmacologically reverse these effects of TRIB2. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. The natural alkaloids harmine and piperlongumine produced inverse gene expression profiles and synergistically increased BEZ235-induced cell toxicity. Notably, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might help overcome TRIB2-mediated therapy resistance in cancer patients.Os pacientes oncológicos sujeitos a quimioterapia convencional e dirigida, nem sempre obtêm um resultado clínico positivo. Uma das principais razões é a resistência ao tratamento intrínseca e adquirida. Como tal, é de extrema importância clínica identificar e caracterizar os mecanismos moleculares envolvidos na resistência ao tratamento oncológico e promover a resensitização do paciente à terapêutica dirigida. Diversos factores de transcrição, dos quais as proteínas forkhead box O (FOXO) e p53 são as mais conhecidas, têm sido identificados como principais responsáveis pela modulação da eficácia de diversos fármacos anti-cancro. O nosso laboratório identificou previamente um novo mecanismo de resistência à terapêutica oncológica originada pela proteína TRIB2. O TRIB2 activa a proteína AKT, o que leva à inibição dos factores de transcrição FOXO e p53. Adicionalmente, o nosso laboratório demonstrou que o TRIB2 mostra potencial como biomarcador em melanoma, em que a expressão de TRIB2 correlaciona-se com o avançar do estadio da doença (I-IV). Tendo em conta que o TRIB2 poderá ser um biomarcador e também confere resistência a diversas estratégias terapêuticas no tratamento do melanoma, estes resultados são extremamente relevantes para o futuro da terapêutica em melanoma (a incidência de novos casos de melanoma nos Estados Unidos da America é de 73870). Embora só 5% dos pacientes com cancro de pele sejam diagnosticados com melanoma, esta doença é no entanto a mais fatal de todos os cancros de pele, responsável por mais de 90% de falecimentos de pacientes com cancro de pele. Além do mais, a incidência de melanoma metastático tem aumentado nas últimas três décadas, caracterizada por uma taxa de mortalidade superior a todos os restantes cancros. Análises genéticas ao melanoma permitiram a identificação de diversas vias de sinalização envolvidas na origem e na progressão da doença, principalmente as vias de sinalização Ras/Raf/MEK/ERK e PI3K/AKT/FOXO. Nas décadas de 70 e 80, a terapêutica standard para o melanoma metastático incluía administração de doses elevadas de interleucina 2 or dacarbazina (DTIC), usualmente com taxas de resposta clínica positiva de 10 a 20%, mas como efeitos secundários severos durante o tratamento. A sua eficácia limitada impulsionou o estudo e a caracterização da doença, o que levou ao surgimento de immunoterapia, nomeadamente inibidores de immune checkpoints (pembrolizumab, nivolumab e ipilimumab), e terapia dirigida, nomeadamente os inibidores de BRAF, como o vemurafenib e dabrafenib, e os inibidores de MEK como o trametinib, que se encontram-se aprovados para o tratamento de melanoma em pacientes com mutações em BRAF, que ocorrem em cerca de 50% dos pacientes diagnosticados com melanoma. Adicionalmente, também estão a ser estudados em ensaios clínicos, diversos inibidores the PI3K, AKT, mTOR e MEK, no entanto, a eficácia destas terapêuticas é de momento limitada devido à presença de resistência ao tratamento intrínsica e adquirida em diversos pacientes. Como tal, é necessário o desenvolvimento de novas estratégias terapêuticas, que visam reverter esta resistência. O nosso laboratório demonstrou previamente que o suppressor de tumor FOXO é o principal mediador de transcrição regulado pela via sinalização PI3K/AKT, após a inibição de PI3K. Estes resultados encontram-se de acordo com a literatura que demonstra que os factores de transcrição FOXO são os principais moduladores da eficácia de fármacos, nomeadamente os inibidores da via de sinalização PI3K. Portanto, proteínas que sejam capazes de inactivar FOXO, são potenciais candidatos como responsáveis pela formação e progressão de tumores, e de aparecimento de resistência ao tratamento destas patologias. Notavelmente, o nosso laboratório estabeleceu previamente TRIB2 como uma proteína oncogénica que inibe os factores de transcrição FOXO em melanoma, e outros estudos demonstraram que TRIB2 também se comporta como um oncogene em diversos tumores sólidos, como os cancros do pulmão, colorectal e fígado. Tanto o nosso laboratório como outros estudos, demonstrou-se que TRIB2 confere resistência a diversos fármacos para o tratamento de cancro, incluindo inibidores de PI3K/mTOR , gemcitabina, dacarbazina e temozolomida. A resistência mediada por TRIB2 é causada por activação de AKT por TRIB2. Mecanisticamente, TRIB2 tem preferência em se ligar directamente a AKT1 cataliticamente inactivo (resíduo treonina 308 não fosforilado), o que induz a fosforilação de AKT no resíduo serina 473 em células humanas, indicando o aumento da actividade catalítica de AKT. A activação de AKT via TRIB2, resulta na inibição de FOXO, o que por sua vez altera a expressão de genes alvo de FOXO, incluindo a redução da expressão de genes envolvidos na regulação da apoptose. Consequentemente, a apoptose resultante da terapêutica oncológica, é diminuida na presença de elevados níveis de TRIB2. Um exemplo de um fármaco cuja eficácia é diminuida na presença de TRIB2, é o derivado de imidazoquinolina, conhecido como BEZ235. Este composto é um inibidor de PI3K e mTOR, que consiste numa molécula de baixo peso molecular que compete com o ATP pelo sítio cataliticamente activo nestas cinases. A eficácia de BEZ235 tem sido avaliada em vários ensaios clínicos, e muitos outros inibidores de PI3K e mTOR têm sido aprovados para uso clínico para vários tipos de cancro. Interferir com a actividade de TRIB2 poderá ser uma potencial estratégia terapêutica para o tratamento de vários tipos de cancro, especialmente no contexto de superar a resistência ao tratamento. Neste estudo, pretendemos caracterizar os efeitos de TRIB2 a nível molecular e identificar estratégias farmacológicas que possam interferir com a sua actividade. Para avaliar a contribuição dos efeitos de TRIB2 em células humanas, procedemos à criação de linhas celulares humanas de osteosarcoma (U2OS) isogénicas, com níveis de expressão de TRIB2 elevada e baixa, respectivamente. Estas linhas celulares também foram tratadas com BEZ235 para avaliar os efeitos de TRIB2 na resistência ao tratamento. Seguidamente, procedemos à sequenciação de RNA para analisar o perfil de expressão génica induzido por TRIB2, nas células não tratadas e tratadas com BEZ235. A sobreexpressão de TRIB2 resultou na alteração da expressão de genes envolvidos na proliferação, apoptose e migração celulares, incluindo genes alvo de FOXO e p53. Na tentativa de identificar potenciais fármacos ou compostos que possam interferir na actividade de TRIB2, utilizámos o perfil de expressão génica induzido por TRIB2 para identificar compostos que induzissem um perfil de expressão génica oposto ao do TRIB2, utilizando uma ferramenta denominada de connectivity Map. Entre os compostos identificados, procedemos à validação dos compostos naturais alcalóides, harmina e piperlongumina, que não só apresentam um perfil de expressão génica oposta ao TRIB2, como também demonstraram um efeito sinérgico com o tratamento BEZ235, induzindo toxicidade cellular na presença de TRIB2, comparando com o tratamento BEZ235 sozinho. Notavelmente, harmina e a piperlongumina promoveram a translocação nuclear de FOXO, sem interferir com os mecanismos de exportação nuclear, e que foi consistente com FOXO sendo transcripcionalmente activo, resultando na indução da transcrição de genes alvo de FOXO. Os nossos resultados indicam o potencial desta estratégia terapêutica, recorrendo ao reaproveitamento de fármacos, e sugere que harmina, piperlongumina e outros compostos similares possam vir a ser úteis na clínica para superar a resistência induzida por TRIB2 no tratamento oncológico em pacientes

Photobiomodulation reduces the cytokine storm syndrome associated with Covid-19 in the zebrafish model

Although the exact mechanism of the pathogenesis of COVID-19 is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red PBM as an attractive therapy to downregulate the cytokine storm caused by COVID-19 from a zebrafish model. RT-PCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that rSpike was responsible for generating systemic inflammatory processes with significantly increased pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a, coa1) mRNA markers, with a pattern like those observed in COVID-19 cases in humans. On the other hand, PBM treatment decreased the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most impacted metabolic pathways between PBM and the rSpike-treated groups were related to steroid metabolism, immune system, and lipids metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19, and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials.publishedVersio

Observation of Higgs boson production in association with a top quark pair at the LHC with the ATLAS detector

The observation of Higgs boson production in association with a top quark pair ( tt¯H ), based on the analysis of proton–proton collision data at a centre-of-mass energy of 13 TeV recorded with the ATLAS detector at the Large Hadron Collider, is presented. Using data corresponding to integrated luminosities of up to 79.8 fb −1 , and considering Higgs boson decays into bb¯ , WW⁎ , τ+τ− , γγ , and ZZ⁎ , the observed significance is 5.8 standard deviations, compared to an expectation of 4.9 standard deviations. Combined with the tt¯H searches using a dataset corresponding to integrated luminosities of 4.5 fb −1 at 7 TeV and 20.3 fb −1 at 8 TeV, the observed (expected) significance is 6.3 (5.1) standard deviations. Assuming Standard Model branching fractions, the total tt¯H production cross section at 13 TeV is measured to be 670 ± 90 (stat.) −100+110 (syst.) fb, in agreement with the Standard Model prediction.Peer Reviewe

Measurement of photon–jet transverse momentum correlations in 5.02 TeV Pb + Pb and pppp collisions with ATLAS

Jets created in association with a photon can be used as a calibrated probe to study energy loss in the medium created in nuclear collisions. Measurements of the transverse momentum balance between isolated photons and inclusive jets are presented using integrated luminosities of 0.49 nb$^{-1}$ of Pb+Pb collision data at $\sqrt{s_\mathrm{NN}}=5.02$ TeV and 25 pb$^{-1}$ of $pp$ collision data at $\sqrt{s}=5.02$ TeV recorded with the ATLAS detector at the LHC. Photons with transverse momentum $63.1 31.6$ GeV and pseudorapidity $\left|\eta^\mathrm{jet}\right| 7\pi/8$. Distributions of the per-photon jet yield as a function of $x_\mathrm{J\gamma}$, $(1/N_\gamma)(\mathrm{d}N/\mathrm{d}x_\mathrm{J\gamma})$, are corrected for detector effects via a two-dimensional unfolding procedure and reported at the particle level. In $pp$ collisions, the distributions are well described by Monte Carlo event generators. In Pb+Pb collisions, the $x_\mathrm{J\gamma}$ distribution is modified from that observed in $pp$ collisions with increasing centrality, consistent with the picture of parton energy loss in the hot nuclear medium. The data are compared with a suite of energy-loss models and calculations.Peer Reviewe

SARS-CoV-2 introductions and early dynamics of the epidemic in Portugal

Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARSCoV-2 introductions and early dissemination in Portugal. Results We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions Here we conclude that the earlier implementation of measures could have minimized the number of introductions and subsequent virus expansion in Portugal. This study lays the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlights the need for systematic and geographically-representative genomic surveillance.We gratefully acknowledge to Sara Hill and Nuno Faria (University of Oxford) and Joshua Quick and Nick Loman (University of Birmingham) for kindly providing us with the initial sets of Artic Network primers for NGS; Rafael Mamede (MRamirez team, IMM, Lisbon) for developing and sharing a bioinformatics script for sequence curation (https://github.com/rfm-targa/BioinfUtils); Philippe Lemey (KU Leuven) for providing guidance on the implementation of the phylodynamic models; Joshua L. Cherry (National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health) for providing guidance with the subsampling strategies; and all authors, originating and submitting laboratories who have contributed genome data on GISAID (https://www.gisaid.org/) on which part of this research is based. The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. This study is co-funded by Fundação para a Ciência e Tecnologia and Agência de Investigação Clínica e Inovação Biomédica (234_596874175) on behalf of the Research 4 COVID-19 call. Some infrastructural resources used in this study come from the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).info:eu-repo/semantics/publishedVersio

Diretriz Brasileira sobre a Saúde Cardiovascular no Climatério e na Menopausa – 2024

Women, who represent approximately half of the global population according to estimates as of January 2024, may experience signs and symptoms of menopause for at least one-third of their lives, during which they have a higher risk of cardiovascular morbidity and mortality. The effects of menopausal hormone therapy (MHT) on the progression of atherosclerosis and cardiovascular disease (CVD) events vary depending on the age at which MHT is initiated and the time since menopause until its initiation. Beneficial effects on CVD outcomes and all-cause mortality have been observed when MHT was initiated before the age of 60 or within 10 years after menopause. The decision regarding the initiation, dose, regimen, and duration of MHT should be made individually after discussing the benefits and risks with each patient. For primary prevention of postmenopausal chronic conditions, the combined use of estrogen and progestogen is not recommended in asymptomatic women, nor is the use of estrogen alone in hysterectomized women. Hormone-dependent neoplasms contraindicate MHT. For the treatment of genitourinary syndrome of menopause, vaginal estrogen therapy may be used in patients with known cardiovascular risk factors or established CVD. For women with contraindications to MHT or who refuse it, non-hormonal therapies with proven efficacy (antidepressants, gabapentin, and fezolinetant) may improve vasomotor symptoms. Compounded hormonal implants, or "bioidentical" and "compounded" hormones, and "hormone modulation" are not recommended due to lack of scientific evidence of their effectiveness and safety.Mujeres, que representan aproximadamente la mitad de la población mundial según estimaciones de enero de 2024, pueden experimentar signos y síntomas de la menopausia durante al menos un tercio de sus vidas, durante los cuales tienen un mayor riesgo de morbilidad y mortalidad cardiovascular. Los efectos de la terapia hormonal de la menopausia (THM) en la progresión de la aterosclerosis y los eventos de enfermedad cardiovascular (ECV) varían según la edad en que se inicia la THM y el tiempo transcurrido desde la menopausia hasta su inicio. Se han observado efectos beneficiosos en los resultados de ECV y la mortalidad por todas las causas cuando la THM se inició antes de los 60 años o dentro de los 10 años posteriores a la menopausia. La decisión sobre la iniciación, dosis, régimen y duración de la THM debe tomarse individualmente después de discutir los beneficios y riesgos con cada paciente. Para la prevención primaria de condiciones crónicas en la posmenopausia, no se recomienda el uso combinado de estrógeno y progestágeno en mujeres asintomáticas, ni el uso de estrógeno solo en mujeres histerectomizadas. Las neoplasias dependientes de hormonas contraindican la THM. Para el tratamiento del síndrome genitourinario de la menopausia, se puede usar terapia estrogénica vaginal en pacientes con factores de riesgo cardiovascular conocidos o ECV establecida. Para mujeres con contraindicaciones a la THM o que la rechazan, las terapias no hormonales con eficacia demostrada (antidepresivos, gabapentina y fezolinetant) pueden mejorar los síntomas vasomotores. Los implantes hormonales compuestos, o hormonas "bioidénticas" y "compuestas", y la "modulación hormonal" no se recomiendan debido a la falta de evidencia científica sobre su efectividad y seguridad.As mulheres, que representam cerca de metade da população mundial segundo estimativas de janeiro de 2024, podem sofrer com sinais e sintomas da menopausa durante pelo menos um terço de suas vidas, quando apresentam maiores risco e morbimortalidade cardiovasculares. Os efeitos da terapia hormonal da menopausa (THM) na progressão de eventos de aterosclerose e doença cardiovascular (DCV) variam de acordo com a idade em que a THM é iniciada e o tempo desde a menopausa até esse início. Efeitos benéficos nos resultados de DCV e na mortalidade por todas as causas ocorreram quando a THM foi iniciada antes dos 60 anos de idade ou nos 10 anos que se seguiram à menopausa. A decisão sobre o início, a dose, o regime e a duração da THM deve ser tomada individualmente após discussão sobre benefícios e riscos com cada paciente. Para a prevenção primária de condições crônicas na pós-menopausa, não se recomendam o uso combinado de estrogênio e progestagênio em mulheres assintomáticas nem o uso de estrogênio sozinho em mulheres histerectomizadas. Neoplasias hormônio-dependentes contraindicam a THM. Para tratamento da síndrome geniturinária da menopausa, pode-se utilizar terapia estrogênica por via vaginal em pacientes com fatores de risco cardiovascular conhecidos ou DCV estabelecida. Para mulheres com contraindicação à THM ou que a recusam, terapias não hormonais com eficácia comprovada (antidepressivos, gabapentina e fezolinetante) podem melhorar os sintomas vasomotores. Os implantes hormonais manipulados, ou hormônios “bioidênticos” “manipulados”, e a ‘modulação hormonal’ não são recomendados pela falta de evidência científica de sua eficácia e segurança

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups