229 research outputs found

    Implementing screening and brief Interventions for excessive alcohol consumption in primary health care

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    O consumo de bebidas alcoólicas é um dos principais fatores de risco da morbilidade e mortalidade prematura a nível mundial. As pessoas que consomem este género de bebidas têm um risco aumentado de vir a desenvolver mais de 200 problemas de saúde diferentes. A maioria do impacto do consumo de álcool na saúde humana é determinado por duas dimensões: o volume total de álcool consumido e o padrão de consumo. Existem várias medidas com comprovada eficácia que podem ser empregues para reduzir o risco associado ao consumo de álcool, entre as quais se encontra a deteção precoce e intervenção breve ao nível dos Cuidados de Saúde Primários. A maioria dos profissionais de saúde neste nível de cuidados considera o consumo de álcool como um importante problema de saúde e manifesta o seu apoio a medidas que visem reduzir o seu impacto. No entanto, poucos são os profissionais dos Cuidados de Saúde Primários que de forma sistemática identificam e aconselham os seus doentes relativamente aos seus hábitos etílicos. Como tal, o objetivo geral desta tese foi investigar como implementar a deteção precoce e intervenção breve no consumo excessivo de álcool nos Cuidados de Saúde Primários. Foi realizada uma revisão sistemática das barreiras e facilitadores à implementação da deteção precoce e intervenção breve no consumo excessivo de álcool nos Cuidados de Saúde Primários. As barreiras e facilitadores identificados nesta revisão foram analisados à luz da teoria de modificação comportamental para compreender a ligação destes fatores aos determinantes da mudança de comportamento, e para identificar as estratégias conceptualmente mais eficazes para abordar as barreiras e facilitadores à mudança de comportamento dos profissionais dos Cuidados de Saúde Primários no sentido de aumentar as taxas de deteção precoce e intervenção breve no consumo excessivo de álcool. Esta metodologia foi utilizada para desenhar um programa de implementação com base em pressupostos teóricos que foi testado num estudo experimental randomizado e controlado em clusters. Esta tese identificou diversas barreiras à implementação, ligadas a todos os domínios teóricos da mudança comportamental. As barreiras mais frequentemente mencionadas pelos profissionais foram: preocupação sobre as suas competências e eficácia para realizar a deteção precoce e intervenção breve; falta de conhecimento específico sobre o consumo de álcool; falta de tempo; falta de materiais; falta de apoio; e atitudes para com o doente com consumos excessivos de álcool. Esta tese mostrou também a existência de dois grupos distintos de médicos de família com base nas suas atitudes para com estes doentes, um com atitudes mais positivas, o outro com atitudes mais negativas. Esta tese mostrou ainda que um programa de implementação da deteção precoce e intervenção breve, desenhado com base em pressupostos teóricos de modificação comportamental, adaptado às barreiras e facilitadores da implementação, aumenta de forma significativa as taxas de identificação precoce dos consumos de álcool. Esta tese contribui para aumentar o conhecimento atual no sentido em que põe à disposição dos investigadores evidência prática sobre como abordar os fatores com influência na implementação da identificação precoce e intervenção breve para o consumo de álcool ao nível dos Cuidados de Saúde Primários. Esta tese contribui também para um melhor entendimento dos mecanismos subjacentes à resistência e à mudança de comportamento dos profissionais dos Cuidados de Saúde Primários no que respeita à implementação da deteção precoce e intervenção breve do consumo de álcool. Os resultados desta tese poderão ser usados por investigadores e decisores políticos para desenhar novos programas de implementação tendo como objetivo modificar esta prática clínica ao nível dos Cuidados de Saúde Primários.Alcohol use is among the leading risk factors for the global burden of disease and premature death. People who drink alcoholic beverages are at risk of developing more than 200 diseases and injury conditions. Most of the impact of alcohol consumption on human health and well-being is determined by two dimensions of drinking: the total volume of alcohol consumed and the pattern of drinking. Several effective strategies exist to reduce the harmful use of alcohol, which includes screening and brief interventions for excessive alcohol use in primary health care. The majority of primary health care providers agree that the excessive consumption of alcohol is an important health issue and express their support to policies for reducing the impact of alcohol on the health of their patients. Notwithstanding, implementation of screening and brief interventions is low at the primary health care level. Therefore, the overall aim of this thesis is to investigate how to implement screening and brief interventions for excessive alcohol consumption in primary health care. This thesis reviewed the barriers of, and facilitators for, the implementation of alcohol screening and brief interventions in primary health care. Behaviour change theory was used to understand how these factors linked to the determinants of behaviour change and how they could be addressed in order to change primary health care providers’ behaviour, i.e. to increase the delivery of alcohol screening and brief interventions. A comprehensive theory-based implementation programme was designed and tested in a cluster randomized controlled trial. This thesis identified several barriers to implementation which were mapped to all the theoretical domains of behaviour change. Primary health care providers concerns about their ability to deliver alcohol screening and brief interventions and to help patients to cut down, lack of alcohol-related knowledge, lack of time, lack of materials and support, and providers’ attitudes towards at-risk drinkers were among the most commonly cited barriers. This thesis found evidence that the attitudes of family physicians could be used to divide practitioners into two distinct groups, one with more positive and the other with more negative attitudes towards at-risk drinkers. This thesis also found that a behaviour change theory-based programme, tailored to the barriers for, and facilitators of, the implementation of screening and brief intervention in primary health care is effective in increasing alcohol screening rates. This thesis contributed to the evidence base by providing researchers with practical evidence on how to address the factors influencing the implementation of screening and brief interventions in primary health care. This thesis also provides researchers with insight into the behavioural mechanisms mediating primary health care providers’ decision to deliver alcohol screening and brief interventions. The results of this thesis could be used by researchers and policymakers to inform the design of novel theory-oriented interventions to support the implementation of alcohol screening and brief interventions in primary health care

    The 26th Annual Boston University Undergraduate Research (UROP) Abstracts

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    The file is available to be viewed by anyone in the BU community. To view the file, click on "Login" or the Person icon top-right with your BU Kerberos password. You will then be able to see an option to View.Abstracts for the 2023 UROP Symposium, held at Boston University on October 20, 2023 at GSU Metcalf Ballroom. Cover and logo design by Morgan Danna. Booklet compiled by Molly Power

    Sleep in Childhood Attention Deficit Hyperactivity Disorder

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    Background Sleep impairments frequently co-occur in children with Attention Deficit Hyperactivity Disorder (ADHD), and the nature of their relationship is bidirectional. Sleep problems in this population manifest as difficulties falling asleep, maintaining sleep and in poorer sleep quality, greater daytime sleepiness, altered sleep duration and increased limb movement in sleep. These concerns affect the quality of life, academic performance, cognitive functions, behavioural and family health of the child, negatively impacting their functional outcomes. Early identification and management of sleep problems in this population therefore has deep-rooted clinical utility. In this thesis we aimed to comprehensively delineate the nature of sleep problems in children with ADHD, explore the possible ADHD related cognitive/behavioural facets and environmental factors that might be influencing the child’s sleep and translate our understanding to the design of ADHD-specific sleep assessment tool for clinical utility. Methods and Results Chapter 2 reports the systematic review of studies investigating sleep in children between the age of 5-13 years who are diagnosed with ADHD. 148 empirical studies published between 2009-2019 were reviewed and a narrative synthesis was presented categorising studies into five sections. These included studies exploring the nature of these difficulties (subjective reports, sleep macrostructure and microstructure); studies exploring circadian rhythm patterns in this population, consequences of sleep problems, non-pharmacological interventions affecting sleep and ADHD symptoms, and pharmacological interventions affecting sleep in this population. We found that sleep disturbances may worsen behavioral outcomes; moreover, sleep interventions may improve ADHD symptoms, and pharmacotherapy for ADHD may impact sleep. Gaps in research focussed on the need for using mixed methodologies utilizing objective and subjective reports of sleep, designing well powered studies that define the role of sleep in ADHD clinical picture and facilitate assessment and management of sleep problems. Chapter 3 qualitatively investigated the nature of sleep problems and sleep related behaviours in children with ADHD. 26 parents of children diagnosed with ADHD aged between 6-12 years were interviewed about their child’s sleep. Thematic analysis of the interviews generated three broad themes which revolved around facets of children’s sleep difficulties as perceived by parents, the perceived impacts of these difficulties, and steps taken by parents to improve their child’s sleep. Parents expressed that sleep problems can be a significant disruptor for their children’s functioning and the wider household. Parents reported using need-based individualised behavioural and sleep hygiene approaches to counter their child’s sleep problems. Chapter 4 examined the associations of parent-rated sleep problems and sleep timings of pre-adolescent ADHD children with parental insomnia symptoms, ADHD (screener based) features and dysfunctional attitudes and beliefs about sleep (in 120 parent-child pairs). 82% of children exceeded the threshold for a paediatric sleep disorder, and parental insomnia, ADHD symptoms and dysfunctional beliefs about sleep were associated with childrens’s sleep problem scores, and with the subfactors of sleep anxiety and parasomnias. Sleep was poorer for children whose parents were both insomnia probable and had ADHD consistent features, thereby underlying the significant double impact of both on the child. In Chapter 5, a thirty-five-item parent rated sleep problems questionnaire for children with ADHD was developed. This questionnaire, called Childhood ADHD Sleep Scale (CASS), included 5 domains: Bedtime, Behaviours in Sleep, Sleep Quality, Daytime Functions and Impacts on Family, where the respondent has to choose one out of five options for a sleep problem statement (‘strongly agree’, ‘somewhat agree’, ‘neither agree or disagree’, ‘somewhat disagree’, and ‘strongly disagree’). CASS showed acceptable test-retest reliability and good internal consistency. Exploratory factor analysis of the CASS generated the 4-factor reduced CASS including sleep problems and impacts, executive and sensory regulation, daytime functions, and parasomnias. The reduced CASS demonstrated good test-retest reliability and internal consistency. Both unreduced CASS and reduced CASS were compared with scores from Child Sleep Habits Questionnaire (CSHQ) and Brown Executive Functions and Attention Scales (Brown -EFA). Differences in the trends of associations were discussed, to understand the utility of an ADHD specific sleep assessment questionnaire. In Chapter 6, we used an emotional Stroop test to assess the presence of sleep related attentional bias in 155 young adults and examined whether their Stroop test performance and sleep bias scores would associate with their ADHD screener-based symptom scores. Sleep quality scores, insomnia probability scores and social jetlag and chronotype. ADHD consistency scores, and insomnia probability scores were not found to be associated with sleep attentional bias scores. Sleep attentional bias also did not associate with chronotype or social jetlag, but it was found that habitual use of alarm clocks on workfree days did associate with greater sleep attentional bias, indicating that curtailed sleep due to functional demands on these days might increase attention towards sleep related stimulus. Conclusion This thesis highlighted how sleep functioning manifests in the clinical picture of childhood ADHD. The bidirectional relationship between the two entities were explored through varied methodological approaches to draw associations between the child’s environment, their own neurodevelopmental diversity and the accompanying sleep features that define their ADHD specific sleep functioning. We aimed at creating a framework within which sleep problems in ADHD can be understood and utilized for clinical utility, both in terms of assessment and management of these concerns. We also found that social demands can enhance cognitive processing of sleep related stimulus in older cohorts with or without ADHD features

    Benchmarking of univariate pleiotropy detection methods, with an application to epilepsy phenotypes

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    Over the past decades, various methods have been used to scan the human genome to identify genetic variations associated with diseases, in particular with common, complex disorders. One of such approaches is the genome-wide association study (GWAS), which compares genetic variation between affected and healthy individuals to find genomic variants in the DNA sequence associated with a trait. GWAS are usually conducted separately for individual traits, and the same single nucleotide polymorphisms (SNP)/loci are associated with different traits in independent studies 7-10. These findings buttress the knowledge that most complex traits are correlated and have shared genetic architecture, therefore, sharing the same heritable risk factors11. Knowledge of the genetic risk factors can directly or indirectly contribute to improvements in risk assessment, drug target development, and ultimately in providing effective therapies to the affected individuals. Pleiotropy is the phenomenon of a hereditary unit affecting more than one trait, and the earliest reported evidence was provided by Mendel when he noted that some set of features were always observed together in a plant. Although this example could have been purely due to linkage and could be regarded as spurious pleiotropy in recent times, it opened up more discussion and research into pleiotropy, which has since been an active area of research12. In this work, I focused on complex epilepsies and the overlap in the genetic factors impacting their phenotypes. Epilepsy is a brain disorder comprising monogenic and common/complex forms characterized by recurrent partial or generalized seizures. However, the extent to which genetic variants contribute to the disorder and how much of the genetic contribution is shared between the different phenotypes is not yet fully understood. This motivated this project, where I benchmarked available pleiotropy detection approaches to select the best performing method in terms of power and false-positive rate to detect true pleiotropy. Then, I applied the selected method to summary statistics of focal epilepsy (FE) and genetic generalized epilepsy (GGE), provided by the International League Against Epilepsy Consortium (ILAE) on complex epilepsies and the EPI25 collaborative, to identify shared genetic factors in both phenotypes of epilepsy. Identifying pleiotropic SNPs or genes is an active area of research with multiple proposed approaches, broadly categorized into univariate and multivariate methods. Multivariate approaches have the limitation that they require all phenotypes to be measured in the same individual and their corresponding genotype data provided, which is often not the case since GWAS are usually performed per specific trait. However, various consortia studying complex traits readily share the summary statistics (effect sizes and p-values) from genome-wide association studies, making it easier to apply univariate pleiotropy detection approaches that combine these statistics to identify SNPs or loci with a concordant or discordant direction of effects. Therefore, in this project, I first compared the relative power and false-positive rate (FPR) performance of five univariate pleiotropy detection approaches, classic meta-analysis, cFDR, PLACO, ASSET, and CPBayes (see section 6.1), through simulation studies. After that, I applied the best-performing method to the analysis of phenotypes of epilepsy using actual data. The data simulation procedure was performed in 3 steps. First, a population of 1 million individuals of European ancestry was simulated via resampling using the HAPGEN2 software13 and haplotypes of central Europeans from the 1000 genomes project14. In the second phase of the simulation, disease SNPs were randomly selected and used for the additive liability threshold model (ALTM)15 to simulate multifactorial disease phenotypes from the simulated genetic data. As expected, the performance of the methods varied in terms of power and false positive rate (FPR). The variability between the methods is higher for FPR, while most methods are comparable in terms of power, especially for larger sample sizes and RR. Although the classical meta-analysis is very powerful, it is also riddled with a very high false-positive rate, making it less suitable for identifying pleiotropic loci. While all the methods performed well in terms of power, the ASSET method gave a better trade-off between power and FPR for the different simulation approaches. Applying ASSET to the two phenotypes of epilepsy, GGE and FE, resulted in identifying a new putative locus 17q21.32 while replicating locus 2q24.3, previously reported by the ILAE consortium 16. Further, applying the ASSET method to summary statistics of larger samples of epilepsy phenotypes resulted in the identification of loci 2q24.3 and 9q21.13. These findings corroborate the result obtained by the ILAE consortium through mega and meta-analysis. Classical meta-analysis (MA) is not recommended for pleiotropy detection, based on the simulation study results. Though MA demonstrated good power to detect pleiotropy, it also recorded high FPR across all simulation scenarios. However, the ASSET method is highly recommended as it kept the FPR low while demonstrating good power to detect pleiotropy. This study also contributed three new pleiotropic loci (2q24.3, 17q21.32, and 9q21.13) to understanding the relationship of genetic variation with epilepsy phenotypes and the inter-relationship between these phenotypes. Although the locus 17q21.32 could not be replicated in the larger sample set, it is not necessarily a false positive discovery. The locus was genome-wide significant for GGE but marginally significant for FE, which confirmed the trend observed in the FE cases in the EPI25 collaborative dataset, where no genome-wide significance result was found. Therefore, replication in an independent sample is desirable. One limitation of using the univariate pleiotropy detection approaches as seen with the classical MA is that one trait with a very low P-value could drive the observed pleiotropic association. Also, methods like cFDR and PLACO could only accommodate two traits, though this was not a challenge in this project. Despite these limitations, the presented work established a benchmark of the relative performance of the assessed methods and could also guide researchers in related fields in their future work. This study also contributed to understanding the shared genetic factors between GGE and FE with the expectation that larger sample sizes will lead to more discoveries

    The Parent Perspective Of Parental Involvement, Academic Achievement, And Latino Fathers In An Urban School

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    In the past 50 years, a significant body of literature has confirmed the importance of parental involvement in children’s education (Gugiu et al., 2018). However, despite its significance, parental involvement is not robust in many school communities (Lawson et al., 2018). According to traditional definitions of parental involvement, parents of color tend to be less involved in their child’s school (Joseph et al., 2016). Although the literature on parental involvement and communities of color has increased, most research involves mothers. What is often overlooked is the role that fathers have in supporting their children. The population for this study consisted of Latino fathers with more than one child in school and who had at least one child attending the school for at least two years. A purposeful sampling strategy was used to select the participants. Using Epstein’s (2016) framework of parental involvement, the guiding research question was: How do Latino fathers of elementary aged students understand and make meaning of their parental involvement? Additional questions were: (a) How do Latino fathers of elementary aged students make meaning of their culture in relation to parental involvement? (b) How does Epstein’s (1981) model of parental involvement illuminate the role of Latino fathers in their child’s academic career? The findings revealed three themes: Importance of Education, Value of Hard Work, and Latino Fathers and the School System. The data suggests that Latino fathers are involved in the education of their children in ways not captured by traditional definitions. Keywords: parental involvement, Latino fathers and parental involvement, Latino families and parental involvemen

    Examining cerebrovascular burden using neuroimaging techniques in ageing brains

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    Cerebral vasculature plays an important role in maintaining brain function and homeostasis. In ageing, a number of genetic and environmental risk factors can compromise brain vascular health and contribute to multiple neurological disorders. White matter (WM) is more vulnerable in cerebrovascular ageing compared with grey matter. With the development of automated and reproducible neuroimaging techniques, there is an opportunity to detect many ageing-related or diseases-related WM changes at an early stage with greater sensitivity. The overall objective of this PhD project is, therefore, to develop reliable neuroimaging biomarkers for characterising WM integrity and examine their relationships with cerebrovascular burden. Four separate studies were carried out to investigate this topic in depth. In the first study, a new diffusion-weighted imaging (DWI) measure, Difference in Distribution Functions (DDF), was developed to overcome the limitations of existing DWI measures in characterising the white matter (WM) microstructural integrity. DDF showed a stronger correlation with age and cognition than other DWI measures investigated. The second study extended the first study by employing longitudinal datasets to examine the effects of various risk factors on WM microstructural integrity over time. Results showed that older age is the primary risk factor for decline in WM integrity in a healthy general population sample. In the third study, a new imaging metric, WM brain age, was introduced to comprehensively assess the health of WM and cerebrovascular disease burdens for each individual. WM brain age was calculated by using a three-dimensional convolutional neural network (3D-CNN) deep learning model. Findings showed that WM brain age is sensitive to most vascular risk factors and cognitive domains related to vascular dysfunction. In the fourth study, the impacts of high blood pressure on grey matter (GM) and WM, respectively, were examined using 3D-CNN to construct GM and WM ages. Findings revealed that hypertension is associated with both GM and WM impairment, and that WM integrity is more vulnerable to hypertension. In conclusion, by developing novel neuroimaging biomarkers for the changes in cerebrovascular ageing, this thesis provides novel contributions to the existing literature. These findings have the potential to better quantify the vascular burden in future research work and in clinical practice

    Evaluation of strategies for reducing the burden of COPD in the UK using Bayesian methods

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    Chronic obstructive pulmonary disease (COPD) is responsible for 5.3% of all deaths and 1.7% of all hospital admissions in the UK. This thesis focuses on strategies to reduce COPD burden by targeting three aspects across the public healthcare system: prevention, emergency treatment, and long-term management. Analyses were performed in a Bayesian framework to exploit its flexibility in modelling uncertainty and the incorporation of prior knowledge. First, I assessed whether communication of personalised disease risk in primary care is an effective smoking cessation intervention, using cost-effectiveness and value of information analyses based on various data sources across the literature. The odds ratio for the effectiveness of communication of personalised disease risk was 1.48 (95%CrI:0.91-2.26). While I found a probability of cost-effectiveness of about 90%, further research up to a maximum of £27 million is justified to reduce the uncertainty around this estimate. Secondly, I assessed whether case ascertainment affects the detection of poorly performing hospital trusts in the treatment of acute exacerbation of COPD (AECOPD) in secondary care, using data from the National Asthma and COPD Audit Programme. Case ascertainment was associated with 30-day mortality (OR:1.74; 1.25-2.41) and adjusting for it impacted the findings, with 5 trusts becoming outliers and 2 trusts no longer classified as outliers. Finally, using general practice data from Clinical Practice Research Datalink, I assessed whether new guidelines suggesting triple therapy (long-acting beta-2 agonists, LABA + long-acting muscarinic antagonists, LAMA + inhaled corticosteroids, ICS) for the treatment of those with poorly-controlled COPD on LABA+LAMA dual therapy improves disease outcomes. Triple therapy was not associated with severe AECOPD (IRR:1.00; 0.93-1.07) or mortality (IRR:0.95; 0.86-1.06), but was associated with increased risk of pneumonia (IRR:1.19; 1.05-1.35). This thesis applied sophisticated Bayesian methods to increase understanding of how COPD burden could be reduced in different areas of the public healthcare system.Open Acces

    The interplay between metabolome, epigenome and metabolic syndrome in severe obesity: the influence of sex and age

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    Antecedentes: la obesidad en adultos se define como una acumulación anormal o excesiva de grasa que representa un importante factor de riesgo para la salud, contribuyendo a aumentar la morbilidad y la mortalidad. Aunque las condiciones de salud subyacentes y la genética podrían ser en algunos casos las principales causas de la obesidad, en la mayoría de los casos es el resultado de estilos de vida poco saludables a largo plazo. En su forma más severa clínicamente (obesidad de Clase III), el tejido adiposo se convierte en el órgano endocrino metabólico más grande que interactúa fuertemente con el sistema endocrino y contribuye al desarrollo del síndrome metabólico (MetS). El MetS es considerado el problema de salud metabólico más comunemente relacionado con la obesidad en la actualidad y presenta signos (obesidad central, colesterol unido a lipoproteínas de alta densidad (HDL) bajo, hipertrigliceridemia, hipertensión, hiperglucemia) que podrían estar relacionados con la presencia de un metabolismo anormal y alteraciones del metaboloma. El metaboloma está directamente influenciado por la dieta y es el resultado de la interacción genes-ambiente, de la que las regulaciones epigenéticas representan su nexo de unión. Por tanto, es lógico pensar que exista una posible interconexión entre la metabolómica y la epigenética, que repercuta en la edad epigenética, el estado funcional de todo el organismo y su esperanza de vida. Aunque MetS afecte tanto a hombres como a mujeres indistintamente, la prevalencia de cada factor de riesgo de MetS aparece depender del sexo y la edad y se ve afectada por procesos hormonales y endocrinos. En particular, MetS es un problema de salud importante en mujeres posmenopáusicas. Esto podría estar relacionado con los niveles de hormonas sexuales y la disposición, metabolismo y acción endocrina del tejido adiposo que provocan complicaciones cardiovasculares y el envejecimiento acelerado de múltiples órganos y su mal funcionamiento, especialmente en los ancianos. Objetivos: 1) investigar la influencia del sexo y la edad en el perfil metabólico de sujetos con obesidad clínicamente severa y estado metabólicamente saludable (MHO) y pacientes con MetS a través del estudio de las diferencias en su metaboloma y epigenoma bajo la influencia hormonal y endocrina en relación con el sexo y años; 2) investigar la interacción metaboloma-epigenoma-MetS, sus efectos y el papel potencial del metabolismo del tejido adiposo en la patología; 3) analizar específicamente el perfil metabólico de las mujeres en edad fértil y posmenopáusicas y su comparación con los hombres de los mismos grupos de edad, centrándose en el MetS extremo (MetS.5); 4) investigar las interacciones entre metaboloma y epigenoma en sujetos mayores de 54 años con MHO o MetS.5 para obtener una caracterización fisiopatológica de los pacientes de mayor riesgo; 5) utilizar un modelo experimental de rata con dieta alta en grasas (HFD) como fuente de adipocitos para la validación in vitro de las hipótesis derivadas de los estudios en la cohorte humana y la investigación dirigida al efecto de la dieta en el metaboloma del tejido adiposo y adipocitos en MetS en obesidad severa; 6) evaluar mediante experimentos in vitro el papel potencial de la modificación metabolómica y epigenética inducida por los metabolitos más significativamente modificados en sujetos con MetS. Diseño y métodos: se realizó un estudio caso-control con 1350 sujetos de la cohorte de Piancavallo (mujeres 65 %, hombres 35 %; edad 19-85) con obesidad extrema (índice de masa corporal (IMC) ≥ 40 kg/m2 entre 35,0 y 39,9 kg/m² con una o más condiciones comórbidas relacionadas con la obesidad) fueron ampliamente caracterizados por perfiles clínicos y antropométricos. A continuación, los sujetos se dividieron en un total de cuatro grandes subgrupos por edad y sexo (mujeres 54 años, hombres 54 años) y clasificados en controles MHO y casos MetS. Los casos se clasificaron además en subgrupos de MetS (MetS.3, MetS.4 y MetS.5) de acuerdo con los Criterios de la Federación Internacional de Diabetes (IDF) (2005). Los perfiles metabolómicos globales séricos se midieron mediante resonancia magnética nuclear (RMN). Se seleccionaron 96 sujetos (48 casos MetS.5, 48 controles MHO; con edades comprendidas entre 55 y 85 años para ambos grupos) para el análisis epigenético y los niveles de metilación global se midieron en suero utilizando el kit Infinium MethylationEPIC BeadChip. Los acúmulos de grasa perigonadal se obtuvieron de ratas Wistar machos y hembras alimentadas con una dieta modificada enriquecida en grasas HFD (45 % de grasa) o alimentadas con una dieta de control (4 % de grasa) y sacrificadas después de 20 semanas de tratamiento. Se realizaron cultivos de adipocitos y tejidos adiposos para recoger los medios de cultivo metabolizados. Los perfiles metabolómicos globales de los medios de cultivo se midieron mediante RMN. Se desarrollaron análisis estadísticos específicos. Resultados: en línea con la caracterización antropométrica y clínica, el perfil metabólico global de MetS resultó uniformemente diferente de MHO en toda la cohorte, con un cambio visible, constante y progresivo de los niveles de metabolitos de acuerdo con el empeoramiento de la gravedad de MetS. MetS.5 mostró la diferencia más significativa en el perfil metabólico y rutas metabólicas alteradas. Además, los diagramas de dispersión tipo PLS-DA a partir de los espectros de RMN revelaron cambios metabólicos específicos en grupos de control y MetS.5 de hombres y mujeres relacionados con el sexo y la edad. Los perfiles diferenciales diferían en la variedad y el número de metabolitos significativos, especialmente entre la edad fértil y la posmenopáusica. La acetona fue el metabolito preeminente en el grupo de mujeres MetS.5 en edad fértil. En cambio, las mujeres posmenopáusicas mostraron un aumento en las señales de carbonilos en ácidos grasos 2 (FACO2) y de colesterol de lipoproteínas de baja densidad 2 (LDL2), que fueron los metabolitos más significativamente relacionados con MetS.5. Por el contrario, en los hombres, la leucina y los compuestos que contienen colina (CCC) mostraron una mayor repercusión en el MetS.5 hasta los 45 y después de los 55 años, respectivamente. Por lo tanto, aunque la enfermedad tenga una base común independientemente del sexo, las vías metabólicas involucradas en MetS y MetS.5 fueron diferentes entre hombres y mujeres de diferentes edades. El análisis epigenético mostró niveles globales de metilación fueron comparables entre casos y controles. Sin embargo, el análisis de metilación diferencial identificó dos sondas estadísticamente significativas pertenecientes a los genes TXNIP (proteína que interactúa con tiorredoxina) y MYLIP (proteína que interactúa con la cadena ligera reguladora de miosina) relacionados con la hiperglucemia y la hipercolesterolemia. La deriva epigenética reveló en MetS.5 la disminución, en el número promedio de mutaciones epigenéticas estocásticas (SEMs), que apareció más pronunciada en la cohorte de hombres. La edad biológica, reflejada por el predictor de esperanza de vida (DNAm GrimAge), resultó significativamente mayor en la cohorte MetS.5. El GrimAge también pareció ser mayor, en promedio, en hombres que mujeres de edad cronológica similar, independientemente del estado patológico, aunque el diagnóstico de MetS se relacionó con un peor escenario epigenético. Finalmente, el análisis metabolómico del medio de crecimiento de adipocitos extraídos de los acúmulos de grasa perigonadal de ratas control y HFD también mostró diferencias significativas relacionadas con la dieta y el sexo de los animales. Sin embargo, las causas y los factores que contribuyen al síndrome metabólico no fueron idénticos entre nuestra cohorte humana y el modelo de estudio en rata. La metionina/isoleucina, combinadas, constituyeron los metabolitos principalmente asociados con HFD en cultivos celulares de adipocitos y los metabolitos más significativos en ratas HFD hembras. Por el contrario, el 3metil2oxovalerato fue el metabolito más significativo en los machos. La glutamina mostró el VIP score más alto en cultivos de tejido adiposo, probablemente por la presencia de macrófagos que juegan un papel fundamental en el inicio, mantenimiento y resolución de la inflamación causada por la hipertrofia de los adipocitos. Conclusiones: el estudio de la obesidad clínicamente severa tanto a nivel clínico y antropométrico como sobre todo a nivel metabolómico-epigenético representa una ayuda para el descubrimiento de biomarcadores de riesgo para el desarrollo del estado de obesidad metabólicamente no saludable (MUHO) y el MetS. Combinados con los datos epigenéticos, los resultados metabolómicos pueden proporcionar nuevos conocimientos sobre los mecanismos fisiopatológicos en la obesidad grave saludable o no saludable y MetS, con un enfoque particular en la relación recíproca entre el epigenoma y el metaboloma bajo la influencia del sexo, la edad y la función endocrina del tejido adiposo. Las mujeres y los hombres de MUHO tienen diferentes factores de riesgo relacionados con la edad que se destacan y reflejan entre los perfiles metabólicos y epigenéticos, puestos de manifiesto por la diferencia entre la edad cronológica y la edad biológica (epigenética) entre hombres y mujeres. Estas últimas pueden tener cierta protección proporcionada por los estrógenos hasta la menopausia, lo que les permite permanecer "metabólica y fisiológicamente más jóvenes" incluso cuando la influencia de los estrógenos disminuye. El estudio de estos biomarcadores implicados en el desarrollo y caracterización de la enfermedad en diferentes etapas de la vida y el sexo podría ayudar a proporcionar nuevas dianas para estrategias y terapias preventivas y terapéuticas. Además, los modelos celulares podrían utilizarse para proporcionar más pruebas in vitro sobre los resultados de los estudios en muestras humanas. En función de las características biológicas y clínicas específicas de los pacientes, esta evidencia podría proporcionar nuevos conocimientos para las estrategias farmacológicas, conductuales y nutricionales sobre el cometabolismo huésped/microbiota y las vías metabólicas, y el progreso hacia la medicina personalizada.Background: obesity in adults is defined as an abnormal or excessive fat accumulation that presents a significant risk factor for health and contributes to increased morbidity and mortality. Although underlying health conditions and genetics could be in some cases the principal causes of obesity, it is predominantly the result of long-term unhealthy lifestyles. In its clinically most severe form (or Class III obesity) adipose tissue becomes the largest metabolic endocrine organ that strongly interacts with the endocrine system and contributes to the development of metabolic syndrome (MetS). MetS is considered the most common metabolic health problem related to obesity nowadays and it involves signs (central obesity, low high-density lipoprotein cholesterol (HDL), hypertriglyceridemia, hypertension, hyperglycemia) that could be related to the presence of abnormal metabolism and metabolome alterations. The metabolome is directly influenced by the diet and is the output of genes-environment interaction, of which epigenetics regulations represent their linker. So, a possible interconnection between metabolomics and epigenetics is reasonable, with repercussions on the epigenetic age, the functional state of the whole organism and its lifespan. Although MetS affects both men and women indistinctly, the prevalence of each MetS risk factor is reported to be sex- and age-dependent and it is affected by hormonal and endocrine processes. In particular, MetS is a significant health problem in postmenopausal women. This could be related to sex hormone levels and adipose tissue's disposition, metabolism and endocrine action that cause cardiovascular complications and accelerated ageing of multiple organs and their malfunction, especially in the elderly. Aims: 1) to investigate the influence of sex and age on the metabolic profile of subject with clinically severe obesity and metabolically healthy status (MHO) and patients with MetS through the study of differences in their metabolome and epigenome under the hormonal and endocrine influence in conjunction to sex and age; 2) to investigate the metabolome-epigenome-MetS interaction, its effects and the potential role of adipose tissue metabolism in the pathology; 3) to analyse specifically the metabolic profile of women of fertile age and postmenopausal and their comparison with men of the same age groups, focusing on extreme MetS (MetS.5); 4) to investigate the interactions between metabolome and epigenome in subjects over 54 years with MHO or MetS.5 to obtain a pathophysiological characterization patients at greater risk; 5) to use a high-fat diet (HFD) rat experimental model as a source of adipocytes for the in vitro validation of the hypotheses derived from the studies on the human cohort and to investigate the effect of a HFD diet on the metabolome of adipose tissue and adipocytes in MetS in severe obesity; 6) to evaluate by in vitro experiments the potential role of metabolomic and epigenetic modification induced by metabolites most significantly changed in subjects with MetS. Design and methods: a case-control study was conducted with 1350 subjects of the Piancavallo cohort (women 65 %, men 35 %; age 19-85 with extreme obesity (body mass index (BMI) ≥ 40 kg/m2 or between 35.0 and 39.9 kg/m² with one or more obesity-related comorbid conditions) was extensively characterized for clinical and anthropometrical profiles. The subjects were then divided into a total of four big subgroups for age and sex (women 54 years, men 54 years) and classified into controls MHO and cases MetS. Cases were further classified into MetS subgroups (MetS.3, MetS.4 and MetS.5) according to the International Diabetes Federation (IDF) Criteria (2005). Serum global metabolomic profiles were measured using nuclear magnetic resonance (NMR). Ninety-six subjects (48 cases MetS.5, 48 controls MHO; aged between 55-85 years for both groups) were selected for the epigenetic analysis and global methylation levels were measured in serum using the Infinium MethylationEPIC BeadChip kit. Perigonadal fat pads were obtained from male and female Wistar rats fed with a modified HFD (45 % of fat) or fed with a control diet (4% fat) and sacrificed after 20 weeks of treatment. Cultures of adipocytes and adipose tissues were performed to collect metabolized culture media. Global metabolomic profiles of culture media were measured using NMR. Specific statistical analyses were developed. Results: according to the anthropometric and clinical characterization, the global metabolic profile of MetS resulted uniformly different from MHO in the entire cohort, with a visible, constant and progressive change of the metabolites' levels according to the worsening of MetS gravity. MetS.5 showed the most significant difference in the metabolic profile and altered metabolic pathways. Moreover, PLS-DA scores plots revealed specific metabolic changes in control and MetS.5 groups of men and women related to sex and age. The differential profiles differed in the variety and the number of significant metabolites, especially between fertile and postmenopausal ages. Acetone was the preeminent metabolite in MetS.5 women’s group of fertile age. Instead, postmenopausal women showed a raise in carbonyls in fatty acid 2 (FACO2) and low-density lipoprotein 2 (LDL2) cholesterol signals, which were the metabolites most significantly related to MetS.5. On the contrary, in men, leucine and choline-containing compounds (CCC) showed the main involvement in MetS.5 until 45 and after 55 years, respectively. Therefore, the metabolic pathways involved in MetS and MetS.5 were different between men and women of different ages, even though the disease had a common basis regardless of sex. At the epigenetic level, the global methylation levels were comparable between cases and controls. However, differential methylation analysis identified two statistically significant probes belonging to TXNIP (thioredoxin interacting protein) and MYLIP (myosin regulatory light chain interacting protein) genes related to hyperglycemia and hypercholesterolemia. The epigenetic drift revealed in MetS.5 the decrease in the average number of stochastic epigenetic mutations (SEMs), which appeared more pronounced in the cohort of males. The biological age, reflected by the predictor of lifespan (DNAm GrimAge), resulted significantly higher in MetS.5 cohort. The GrimAge also appeared to be higher, on average, in men than in women of similar chronological age, regardless of disease status, although the diagnosis of MetS was related to a worse epigenetic scenario. Finally, the metabolomic analysis of the adipocytes' growth medium extracted from the perigonadal fat pads of control and HFD rats also showed significant differences related to the diet and sex of the animals. Nevertheless, the causes and contributors were non-identical between our human cohort and the rat model under study. Methionine/isoleucine, jointly, constituted the metabolites primarily associated with HFD in adipocyte cell cultures and the most significant metabolites in female HFD rats. Differently, 3methyl2oxovalerate was the most significant metabolite in males. Glutamine showed the highest VIP score value in adipose tissue organ cultures probably because of the presence of macrophages that play a critical role in initiating, maintaining, and resolving inflammation caused by the hypertrophy of adipocytes. Conclusions: the study of clinically severe obesity both at the clinical, anthropometric and above all at the metabolomic-epigenetic level represents an aid to the discovery of risk biomarkers for the development of metabolically unhealthy obese status (MUHO) and MetS. Combined with the epigenetics data, the metabolomic results may provide new insights into the pathophysiological mechanisms in severe healthy or unhealthy obesity and MetS, with a particular focus on the reciprocal relationship between the epigenome and the metabolome under the influence of sex, age and endocrine function of adipose tissue. MUHO women and men have a different age-related risk factor that is highlighted and reflected between metabolic and epigenetic profiles, manifested by the difference between chronological and biological (epigenetic) age between men and women. The latter may have some protection provided by estrogens until menopause which allows them to remain "metabolically and physiologically younger" even when the influence of estrogens decreases. Studying these biomarkers involved in the development and characterization of the disease in different stages of life and sex could help to provide new targets for preventive and therapeutic strategies and therapies. Moreover, cell models could be used to provide further evidence in vitro on the results of the studies on human samples. Based on patients' specific biological and clinical characteristics, this evidence could provide new insight for pharmacological, behavioural and nutritional strategies on host/microbiota co-metabolism and metabolic pathways, and progress towards personalized medicine

    Twin Research for Everyone. From Biology to Health, Epigenetics, and Psychology

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