11,273 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

    UMSL Bulletin 2023-2024

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    The 2023-2024 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1088/thumbnail.jp

    Machine Learning Approaches for the Prioritisation of Cardiovascular Disease Genes Following Genome- wide Association Study

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    Genome-wide association studies (GWAS) have revealed thousands of genetic loci, establishing itself as a valuable method for unravelling the complex biology of many diseases. As GWAS has grown in size and improved in study design to detect effects, identifying real causal signals, disentangling from other highly correlated markers associated by linkage disequilibrium (LD) remains challenging. This has severely limited GWAS findings and brought the method’s value into question. Although thousands of disease susceptibility loci have been reported, causal variants and genes at these loci remain elusive. Post-GWAS analysis aims to dissect the heterogeneity of variant and gene signals. In recent years, machine learning (ML) models have been developed for post-GWAS prioritisation. ML models have ranged from using logistic regression to more complex ensemble models such as random forests and gradient boosting, as well as deep learning models (i.e., neural networks). When combined with functional validation, these methods have shown important translational insights, providing a strong evidence-based approach to direct post-GWAS research. However, ML approaches are in their infancy across biological applications, and as they continue to evolve an evaluation of their robustness for GWAS prioritisation is needed. Here, I investigate the landscape of ML across: selected models, input features, bias risk, and output model performance, with a focus on building a prioritisation framework that is applied to blood pressure GWAS results and tested on re-application to blood lipid traits

    Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer

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    Colorectal cancer (CRC) is one of the most common cancers in the UK and medulloblastoma is a common cancer found in children. While there has been a progressive improvement in treatment outcomes, success has been marred by drug resistance and severe side effects. Therefore, this project focused on two aspects of chemotherapeutic drug resistance, the first using the antimitotic agent vincristine in combination with inhibitors of the anti-apoptotic Bcl-2 family proteins, while the second investigated the role of the long non-coding RNA (lncRNA), HCP5 in the resistance of cells to genotoxic agents. In the first part, three medulloblastoma cell lines (DAOY, MB03, ONS76) were analysed for the expression of Bcl-xL and ONS76 cells found to have the highest level of this anti-apoptotic protein. Subsequent results indicated that Bcl-xL encourages mitotic slippage and stemness and that knockdown of Bcl-xL in the high expressing ONS76 cells, reduces these and sensitizes the cells to the anti-mitotic agent vincristine. Thus, pharmacological inhibition of Bcl-xL should sensitize medulloblastoma cells to low doses of vincristine. Regarding the lncRNA HCP5, results showed that HCP5 was generally more highly expressed in a panel of CRC cell lines than the three medulloblastoma cell lines, corroborating data from an in-silico analysis for the corresponding tumours. One function of HCP5 is to translocate the multifunctional YB-1 protein from the cytoplasm to the nucleus where it carries out many of its functions. Knockdown of HCP5 followed by immunofluorescence indicated a reduction in the amount of YB-1 in the nucleus, confirming this function. Subsequently, HCP5 silencing sensitized all cell lines tested to the DNA damaging agents, cisplatin, oxaliplatin and tert-butyl hydroperoxide and also resulted in an increase in double-strand breaks as determined by H2AX formation. Finally, fluorescence activated cell sorting using Annexin V and propidium iodide confirmed a decrease in cell viability in HCP5 knockdown cells following treatment with genotoxic agents and that this was mirrored by an increased apoptotic fraction. Together, these studies indicate the possibilities of using novel therapeutics to increase the functionality of existing treatments to combat acquired drug resistance in cancer patients

    Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank

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    Objective Acute knee injury is associated with post-traumatic OA (PTOA). Very little is known about the genome-wide associations of PTOA when compared with idiopathic OA (iOA). Our objective was to describe the development of knee OA after knee injury and its genetic associations in UK Biobank (UKB). Design Clinically significant structural knee injuries in those <=50 years were identified from electronic health record and self-reported data in 502,409 UKB participants. Time-to-first knee OA code was compared in injured cases and age-/sex-matched non-injured controls using Cox Proportional Hazards models. A time-to-OA genome-wide association study (GWAS) sought evidence for PTOA risk variants 6 months-20 years following injury. Evidence for associations of two iOA polygenic risk scores (PRS) was sought. Results Of 4233 knee injury cases, 1896 (44.8%) were female (mean age at injury 34.1 years [SD10.4]). Over a median of 30.2 (IQR19.5-45.4) years, 1096 (25.9%) of injured cases developed knee OA. The overall hazards ratio (HR) for knee OA after injury was 1.81[1.70,1.93],P=8.9x10-74. Female sex and increasing age at injury were associated with knee OA following injury (HR1.15[1.02,1.30];1.07[1,07,1.07] respectively). OA risk was highest in the first 5 years after injury (HR3.26[2.67,3.98]), persisting for 40 years. In 3074 knee injury cases included in the time-to-OA GWAS, no variants reached genome-wide significance. iOA PRS was not associated with time-to-OA (HR 0.43[0.02,8.41]). Conclusions Increasing age at injury and female sex appear to be associated with future development of PTOA in UKB, the risk of which was greatest in the 5 years after injury. Further international efforts towards a better-powered meta-analysis will definitively elucidate genetic similarities and differences of PTOA and iOA

    The evolution of non-small cell lung cancer metastases in TRACERx

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    Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

    Development of Smart Polymeric Nanocontainers for the Therapy of Head and Brain Malignancies

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    Head and brain tumours account for 2% to 4% of all cancers globally. Despite progress made in diagnosis and adjuvant therapies, they remain a global burden with unsatisfactory survival rates, reduced treatment outcome, poor prognosis and high risks of recurrence. First line chemotherapy drugs used in current regimens lack specificity, which ensues long term and unpleasant side effects for the patient. Encapsulating the chemotherapy drugs within nanocontainers (NCs) is one approach to improving their efficacy and therapeutic outcome as well as reducing side effects. Due to their nano-size and suitable modified surface, polymeric NCs can reach critical areas in the head and brain without causing any damage to the healthy tissue. The aim was to synthesize polymeric NCs capable of carrying and delivering chemotherapy drugs in tumour cells to increase their efficacy and reduce their side effects. Hollow P(MAA-co-MBA-co-NIPAM-co-EGDMA) NCs with dual sensitivity were synthesised and characterized structurally and morphologically throughout the synthesis steps. Daunorubicin, cisplatin, and temozolomide loaded NCs, and free NCs were assessed by haemolysis assay, MTT assay, fluorescence microscopy, western blot, and flow cytometry in rhabdomyosarcoma TE671 cell line and glioblastoma U87 MG cell line. The free NCs showed high biocompatibility and non-toxicity trait with good cellular uptake. Also, the loading capacities were between 27% and 63%, and the release studies showed a sustained release profile for up to 72h. Treatment of rhabdomyosarcoma and glioblastoma cells with different drugs loaded in NCs showed high cancer cell cytotoxicity, variation in induced DNA damage levels, induced apoptosis and cell cycles arrest for 24h and 72h. Overall, smart polymeric NCs showed reliability in carrying and delivering chemotherapy drugs in rhabdomyosarcoma and glioblastoma cells with efficiency in tackling the tumour cells. Our polymeric NCs exhibited excellent potential as a novel therapeutic approach for targeted drug delivery in head and brain tumours. This could be verified in the preclinical models to assess their improved efficacy and reducing side effects of first line cancer therapies. It could further pave the way for clinical trials of head and brain cancers in human patients

    Predicting alcohol-related memory problems in older adults: A machine learning study with multi-domain features

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    Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50-81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive uplift life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life
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