7,420 research outputs found

    Oxysterols as drivers of inflammatory diseases

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    Nutrient Intake and Physical Exercise as Modulators of Healthy Women

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    Cumulative evidence demonstrates that healthy nutrient intake and regular physical exercise are both powerful lifestyle strategies that modulate lifelong health through their ability to improve body composition, musculoskeletal health, sex steroid hormones, sleep quality, and physical and cognitive performance, as well as to prevent chronic diseases across the lifespan, especially in women. While the benefits of nutrition and physical exercise are commonly studied separately, the integration of nutrition and physical exercise has the potential to produce greater benefits in women than strategies focusing only on one or the other. Studying the specificities of women in response to interventions is of the utmost importance for providing optimal healthcare and aids the design of guidelines that are better suited for women. A better knowledge regarding nutrient intake and physical exercise and their interaction in women is therefore needed. This Special Issue entitled “nutrient intake and physical exercise as modulators of healthy women” will comprise manuscripts that highlight this integrational approach as a potential modulator of lifelong outcomes in women

    Management of valvular heart disease in patients with cancer: Multidisciplinary team, cancer-therapy related cardiotoxicity, diagnosis, transcatheter intervention, and cardiac surgery. Expert opinion of the Association on Valvular Heart Disease, Association of Cardiovascular Interventions, and Working Group on Cardiac Surgery of the Polish Cardiac Society

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    The Association on Valvular Heart Disease, Association of Cardiovascular Interventions, and the Working Group on CardiacSurgery of the Polish Cardiac Society have released a position statement on risk factors, diagnosis, and management of patients with cancer and valvular heart disease (VHD). VHD can occur in patients with cancer in several ways, for example, it can exist or be diagnosed before cancer treatment, after cancer treatment, be an incidental finding during imaging tests, endocarditis related to immunosuppression, prolonged intravenous catheter use, or combination treatment, and nonbacterial thrombotic endocarditis. It is recommended to employ close cardiac surveillance for patients at high risk of complications during and after cancer treatment and for cancer treatments that may be cardiotoxic to be discussed by a multidisciplinary team. Patients with cancer and pre-existing severe VHD should be managed according to the 2021 European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines for VHD management, taking into consideration cancer prognosis and patient preferences

    Computertomographie-basierte Bestimmung von Aortenklappenkalk und seine Assoziation mit Komplikationen nach interventioneller Aortenklappenimplantation (TAVI)

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    Background: Severe aortic valve calcification (AVC) has generally been recognized as a key factor in the occurrence of adverse events after transcatheter aortic valve implantation (TAVI). To date, however, a consensus on a standardized calcium detection threshold for aortic valve calcium quantification in contrast-enhanced computed tomography angiography (CTA) is still lacking. The present thesis aimed at comparing two different approaches for quantifying AVC in CTA scans based on their predictive power for adverse events and survival after a TAVI procedure.   Methods: The extensive dataset of this study included 198 characteristics for each of the 965 prospectively included patients who had undergone TAVI between November 2012 and December 2019 at the German Heart Center Berlin (DHZB). AVC quantification in CTA scans was performed at a fixed Hounsfield Unit (HU) threshold of 850 HU (HU 850 approach) and at a patient-specific threshold, where the HU threshold was set by multiplying the mean luminal attenuation of the ascending aorta by 2 (+100 % HUAorta approach). The primary endpoint of this study consisted of a combination of post-TAVI outcomes (paravalvular leak ≥ mild, implant-related conduction disturbances, 30-day mortality, post-procedural stroke, annulus rupture, and device migration). The Akaike information criterion was used to select variables for the multivariable regression model. Multivariable analysis was carried out to determine the predictive power of the investigated approaches.   Results: Multivariable analyses showed that a fixed threshold of 850 HU (calcium volume cut-off 146 mm3) was unable to predict the composite clinical endpoint post-TAVI (OR=1.13, 95 % CI 0.87 to 1.48, p=0.35). In contrast, the +100 % HUAorta approach (calcium volume cut-off 1421 mm3) enabled independent prediction of the composite clinical endpoint post-TAVI (OR=2, 95 % CI 1.52 to 2.64, p=9.2x10-7). No significant difference in the Kaplan-Meier survival analysis was observed for either of the approaches.   Conclusions: The patient-specific calcium detection threshold +100 % HUAorta is more predictive of post-TAVI adverse events included in the combined clinical endpoint than the fixed HU 850 approach. For the +100 % HUAorta approach, a calcium volume cut-off of 1421 mm3 of the aortic valve had the highest predictive value.Hintergrund: Ein wichtiger Auslöser von Komplikationen nach einer Transkatheter-Aortenklappen-Implantation (TAVI) sind ausgeprägte Kalkablagerung an der Aortenklappe. Dennoch erfolgte bisher keine Einigung auf ein standardisiertes Messverfahren zur Quantifizierung der Kalklast der Aortenklappe in einer kontrastverstärkten dynamischen computertomographischen Angiographie (CTA). Die vorliegende Dissertation untersucht, inwieweit die Wahl des Analyseverfahrens zur Quantifizierung von Kalkablagerungen in der Aortenklappe die Prognose von Komplikationen und der Überlebensdauer nach einer TAVI beeinflusst.   Methodik: Der Untersuchung liegt ein umfangreicher Datensatz von 965 Patienten mit 198 Merkmalen pro Patienten zugrunde, welche sich zwischen 2012 und 2019 am Deutschen Herzzentrum Berlin einer TAVI unterzogen haben. Die Quantifizierung der Kalkablagerung an der Aortenklappe mittels CTA wurde einerseits mit einem starren Grenzwert von 850 Hounsfield Einheiten (HU) (HU 850 Verfahren) und andererseits anhand eines individuellen Grenzwertes bemessen. Letzterer ergibt sich aus der HU-Dämpfung in dem Lumen der Aorta ascendens multipliziert mit 2 (+100 % HUAorta Verfahren). Der primäre klinische Endpunkt dieser Dissertation besteht aus einem aus sechs Variablen zusammengesetzten klinischen Endpunkt, welcher ungewünschte Ereignisse nach einer TAVI abbildet (paravalvuläre Leckage ≥mild, Herzrhythmusstörungen nach einer TAVI, Tod innerhalb von 30 Tagen, post-TAVI Schlaganfall, Ruptur des Annulus und Prothesendislokation). Mögliche Störfaktoren, die auf das Eintreten der Komplikationen nach TAVI Einfluss haben, wurden durch den Einsatz des Akaike Informationskriterium ermittelt. Um die Vorhersagekraft von Komplikationen nach einer TAVI durch beide Verfahren zu ermitteln, wurde eine multivariate Regressionsanalyse durchgeführt.   Ergebnisse: Die multivariaten logistischen Regressionen zeigen, dass die Messung der Kalkablagerungen anhand der HU 850 Messung (Kalklast Grenzwert von 146 mm3) die Komplikationen und die Überlebensdauer nicht vorhersagen konnten (OR=1.13, 95 % CI 0.87 bis 1.48, p=0.35). Die nach dem +100 % HUAorta Verfahren (Kalklast Grenzwert von 1421 mm3) individualisierte Kalkmessung erwies sich hingegen als sehr aussagekräftig, da hiermit Komplikationen nach einer TAVI signifikant vorhergesagt werden konnten (OR=2, 95 % CI 1.52 bis 2.64, p=9.2x10-7). In Hinblick auf die postoperative Kaplan-Meier Überlebenszeitanalyse kann auch mit dem +100 % HUAorta Verfahren keine Vorhersage getroffen werden.   Fazit: Aus der Dissertation ergibt sich die Empfehlung, die Messung von Kalkablagerungen nach dem +100 % HUAorta Verfahren vorzunehmen, da Komplikationen wesentlich besser und zuverlässiger als nach der gängigen HU 850 Messmethode vorhergesagt werden können. Für das +100 % HUAorta Verfahren lag der optimale Kalklast Grenzwert bei 1421 mm3

    Anuário científico da Escola Superior de Tecnologia da Saúde de Lisboa - 2021

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    É com grande prazer que apresentamos a mais recente edição (a 11.ª) do Anuário Científico da Escola Superior de Tecnologia da Saúde de Lisboa. Como instituição de ensino superior, temos o compromisso de promover e incentivar a pesquisa científica em todas as áreas do conhecimento que contemplam a nossa missão. Esta publicação tem como objetivo divulgar toda a produção científica desenvolvida pelos Professores, Investigadores, Estudantes e Pessoal não Docente da ESTeSL durante 2021. Este Anuário é, assim, o reflexo do trabalho árduo e dedicado da nossa comunidade, que se empenhou na produção de conteúdo científico de elevada qualidade e partilhada com a Sociedade na forma de livros, capítulos de livros, artigos publicados em revistas nacionais e internacionais, resumos de comunicações orais e pósteres, bem como resultado dos trabalhos de 1º e 2º ciclo. Com isto, o conteúdo desta publicação abrange uma ampla variedade de tópicos, desde temas mais fundamentais até estudos de aplicação prática em contextos específicos de Saúde, refletindo desta forma a pluralidade e diversidade de áreas que definem, e tornam única, a ESTeSL. Acreditamos que a investigação e pesquisa científica é um eixo fundamental para o desenvolvimento da sociedade e é por isso que incentivamos os nossos estudantes a envolverem-se em atividades de pesquisa e prática baseada na evidência desde o início dos seus estudos na ESTeSL. Esta publicação é um exemplo do sucesso desses esforços, sendo a maior de sempre, o que faz com que estejamos muito orgulhosos em partilhar os resultados e descobertas dos nossos investigadores com a comunidade científica e o público em geral. Esperamos que este Anuário inspire e motive outros estudantes, profissionais de saúde, professores e outros colaboradores a continuarem a explorar novas ideias e contribuir para o avanço da ciência e da tecnologia no corpo de conhecimento próprio das áreas que compõe a ESTeSL. Agradecemos a todos os envolvidos na produção deste anuário e desejamos uma leitura inspiradora e agradável.info:eu-repo/semantics/publishedVersio

    Anticholinergic use in the UK: longitudinal trends and associations with cognitive outcomes

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    Observational studies have shown an association between the use of anticholinergic drugs and various negative health outcomes. However, when studying cognitive outcomes, there is great heterogeneity in previous results. The objectives of the present thesis are threefold. First, to explore the longitudinal patterns of anticholinergic prescribing in the UK. Second, to examine the association between anticholinergic burden and dementia. Third, to probe the relationship between anticholinergic burden, general cognitive ability, and brain structural MRI in relatively healthy participants. Chapter 1 provides an overview of the role of acetylcholine as a neurotransmitter in the human body. It begins with a description of its molecular characteristics and continues with a summary of anatomical and cellular features of cholinergic pathways in the brain. The chapter concludes with a description of the relevance of cholinergic processing in cognition and Alzheimer’s disease. Chapter 2 gives a summary of anticholinergic drugs. It describes the history of anticholinergic compounds and their present use in medicine. It then appraises the tools used to gauge the anticholinergic potency of drugs. I conclude the Chapter by evaluating the available evidence on the effects of anticholinergic drugs on various important health outcomes. Chapter 3 focuses on UK Biobank, the sample used in all analyses presented in this thesis. The chapter briefly describes the conception of the study, the timeline of assessments, and the available variables. I focus in my descriptions on the variables that were used in the present thesis, especially cognitive tests, brain imaging, and linked health data. Chapters 4 to 6 present the empirical work conducted as part of this thesis. Chapter 4 presents an analysis of anticholinergic prescribing trends in UK primary care from the year 1990 to 2015. I first calculate an anticholinergic burden (AChB) according to 13 different anticholinergic scales and an average to derive a “Meta-scale”. I then describe the prevalence of anticholinergic prescribing and its longitudinal trend for all scales. I use different plots of age-, period- and cohort effects on the AChB according to the Meta-scale to evaluate the contributions of these effects to the linear longitudinal trend. The study finds AChB to have increased 9-fold over 25 years and that this effect was attributable to both age- and cohort/period-related changes. In other words, ageing of the sample is not sufficient to explain the increase in anticholinergic prescribing; cohort- or period-effects must have contributed to the observed changes. Chapter 5 explores the relationship between anticholinergic prescribing and dementia. Previous studies on this topic had provided varied results. One of the goals of the present study was to probe potential factors for this heterogeneity. We find that greater AChB according to most of the studied anticholinergic scales (standardised HRs range: 1.027-1.125), as well as the slope of anticholinergic change (HR=1.094; 95% CI: 1.068-1.119), are associated with dementia. However, we find that not all drug classes are associated with dementia. Antidepressants (HR=1.11, 95% CI=1.07-1.17), antiepileptics (HR=1.07, 95% CI=1.04-1.11), and the antidiuretic furosemide (HR=1.06, 95% CI=1.02-1.10) exhibit the strongest effects. Interestingly, when exploring the effects of groups of anticholinergic drugs with different anticholinergic potencies, only the moderate potency group shows significant associations with dementia (HR=1.10, 95% CI=1.05-1.15). Chapter 6 examines the association between AChB, general cognitive ability, and brain structural MRI. It aims both to explore the potential sources of heterogeneity in previous work, as well as to expand on it by studying relatively healthy community-dwelling adults. We study brain structural MRI in a much bigger sample (at least 5x bigger) and use many more outcomes than previous studies. We find weak, but significant associations between AChB and general cognitive ability, and with 7/9 individual cognitive tests (standardised betas (β) range: -0.039, -0.003). Again, AChB in only some drug classes is associated with lower general cognitive ability, especially β-lactam antibiotics (β=-0.035, pFDR. Finally, chapter 7 summarizes the findings presented in chapters 4 to 6. The chapter also provides a critique of the sample and of my approach when conducting the analyses presented in the present thesis. The chapter concludes by discussing suggestions for future work on this topic

    Antiviral modified siRNA swarms for treatment of herpes simplex virus infection

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    Herpes simplex virus type 1 (HSV-1) is a common virus of humans carried by half of the global population. After the primary infection, HSV has the ability to establish life-long latency, wherefrom it can reactivate. The latent state cannot be eliminated with modern pharmaceuticals, nor is there a vaccine available, despite massive efforts. Instead, the treatment focuses on diminishing viral replication. The current treatment, however, is insufficient, as it relies almost solely on acyclovir (ACV), and its derivatives, which share their mechanism of action, making ACV-resistant infections almost untreatable. Unfortunately, such infections are rather common, as severe HSV infections require long-term prophylactic treatment to prevent recurrences, which selects for ACV-resistant variants. The lack of treatment diversity against HSV-1 infections encourages for research on novel therapies. Previously, enzymatically synthetized swarms of small interfering (si)RNA have been established as feasible means to treat HSV infection in vitro and in vivo. They differ from regular siRNA by their enzymatic synthesis and by their substantially longer target sequence. Thus, the emergence of resistance, even during long-term prophylactic treatment, is unlikely. However, as all RNA therapy, siRNA swarms face challenges with RNA stability. Therefore, in this study, the goal was to improve the siRNA swarms by synthesizing novel anti-HSV siRNA swarms with chemical 2′-fluoro-modifications to increase RNA efficacy and stability. The modified siRNA swarms, representing modifications of each nucleotide, were first validated in vitro in cells of the nervous system. The research was continued in a highly translational cell line representing the human cornea, which we first validated for use in antiviral RNAi studies. In both cell types, the modified siRNA swarm(s) proved well tolerated and potent beyond the unmodified counterparts, with only modest effects on the host innate responses, even in the presence of viral challenge. Furthermore, all studied HSV-1 strains, including various clinical isolates, were highly sensitive to both modified and unmodified siRNA swarms, whereas their ACV sensitivity varied, proving the potential of siRNA swarms for future therapeutic use. This study shows that incorporation of modified nucleotides to the anti-HSV siRNA swarms is advantageous, and should therefore be preferred in future studies

    Mathematical models to evaluate the impact of increasing serotype coverage in pneumococcal conjugate vaccines

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    Of over 100 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumo- coccal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. This thesis has four aims. First, to explore the limitations and assumptions of published pneu- mococcal models and the implications for future vaccine formulation and policy. Second, to conduct a trend analysis assembling all the available evidence for serotype replacement in Europe, North America and Australia to characterise invasive pneumococcal disease (IPD) caused by vaccine-type (VT) and non-vaccine-types (NVT) serotypes. The motivation behind this is to assess the patterns of relative abundance in IPD cases pre- and post-vaccination, to examine country-level differences in relation to the vaccines employed over time since introduction, and to assess the growth of the replacement serotypes in comparison with the serotypes targeted by the vaccine. The third aim is to use a Bayesian framework to estimate serotype-specific invasiveness, i.e. the rate of invasive disease given carriage. This is useful for dynamic transmission modelling, as transmission is through carriage but a majority of serotype-specific pneumococcal data lies in active disease surveillance. This is also helpful to address whether serotype replacement reflects serotypes that are more invasive or whether serotypes in a specific location are equally more invasive than in other locations. Finally, the last aim of this thesis is to estimate the epidemiological and economic impact of increas- ing serotype coverage in PCVs using a dynamic transmission model. Together, the results highlight that though there are key parameter uncertainties that merit further exploration, divergence in serotype replacement and inconsistencies in invasiveness on a country-level may make a universal PCV suboptimal.Open Acces

    Targeting Fusion Proteins of HIV-1 and SARS-CoV-2

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    Viruses are disease-causing pathogenic agents that require host cells to replicate. Fusion of host and viral membranes is critical for the lifecycle of enveloped viruses. Studying viral fusion proteins can allow us to better understand how they shape immune responses and inform the design of therapeutics such as drugs, monoclonal antibodies, and vaccines. This thesis discusses two approaches to targeting two fusion proteins: Env from HIV-1 and S from SARS-CoV-2. The first chapter of this thesis is an introduction to viruses with a specific focus on HIV-1 CD4 mimetic drugs and antibodies against SARS-CoV-2. It discusses the architecture of these viruses and fusion proteins and how small molecules, peptides, and antibodies can target these proteins successfully to treat and prevent disease. In addition, a brief overview is included of the techniques involved in structural biology and how it has informed the study of viruses. For the interested reader, chapter 2 contains a review article that serves as a more in-depth introduction for both viruses as well as how the use of structural biology has informed the study of viral surface proteins and neutralizing antibody responses to them. The subsequent chapters provide a body of work divided into two parts. The first part in chapter 3 involves a study on conformational changes induced in the HIV-1 Env protein by CD4-mimemtic drugs using single particle cryo-EM. The second part encompassing chapters 4 and 5 includes two studies on antibodies isolated from convalescent COVID-19 donors. The former involves classification of antibody responses to the SARS-CoV-2 S receptor-binding domain (RBD). The latter discusses an anti-RBD antibody class that binds to a conserved epitope on the RBD and shows cross-binding and cross-neutralization to other coronaviruses in the sarbecovirus subgenus.</p
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