633 research outputs found
Risk prediction models for cardiovascular disease and overall mortality
Prediction or prognostication is at the core of modern evidence-based medicine.
Prediction of overall mortality and cardiovascular disease can be improved by a
systematic evaluation of measurements from large-scale epidemiological studies or by
using nested sampling designs to discover new markers from omics technologies.
In study I, we investigated if prediction measures such as calibration, discrimination
and reclassification could be calculated within traditional sampling designs and which
of these designs were the most efficient. We found that is possible to calculate
prediction measures by using a proper weighting system and that a stratified casecohort
design is a reasonable choice both in terms of efficiency and simplicity.
In study II, we investigated the clinical utility of several genetic scores for incident
coronary heart disease. We found that genetic information could be of clinical value
in improving the allocation of patients to correct risk strata and that the assessment of
a genetic risk score among intermediate risk subjects could help to prevent about one
coronary heart disease event every 318 people screened.
In study III, we explored the association between circulating metabolites and incident
coronary heart disease. We found four new metabolites associated with coronary heart
disease independently of established cardiovascular risk factors and with evidence of
clinical utility. By using genetic information we determined a potential causal effect
on coronary heart disease of one of these novel metabolites.
In study IV, we compared a large number of demographics, health and lifestyle
measurements for association with all-cause and cause-specific mortality. By ranking
measurements in terms of their predictive abilities we could provide new insights
about their relative importance, as well as reveal some unexpected associations.
Moreover we developed and validated a prediction score for five-year mortality with
good discrimination ability and calibrated it for the entire UK population.
In conclusion, we applied a translational approach spanning from the discovery of
novel biomarkers to their evaluation in terms of clinical utility. We combined this
effort with methodological improvements aimed to expand prediction measures in
settings that were not previously explored. We identified promising novel
metabolomics markers for cardiovascular disease and supported the potential clinical
utility of a genetic score in primary prevention. Our results might fuel future studies
aimed to implement these findings in clinical practice
Characterizing personalized effects of family information on disease risk using graph representation learning
Family history is considered a risk factor for many diseases because it
implicitly captures shared genetic, environmental and lifestyle factors. A
nationwide electronic health record (EHR) system spanning multiple generations
presents new opportunities for studying a connected network of medical
histories for entire families. In this work we present a graph-based deep
learning approach for learning explainable, supervised representations of how
each family member's longitudinal medical history influences a patient's
disease risk. We demonstrate that this approach is beneficial for predicting
10-year disease onset for 5 complex disease phenotypes, compared to
clinically-inspired and deep learning baselines for a nationwide EHR system
comprising 7 million individuals with up to third-degree relatives. Through the
use of graph explainability techniques, we illustrate that a graph-based
approach enables more personalized modeling of family information and disease
risk by identifying important relatives and features for prediction
Mapping the human genetic architecture of COVID-19 by worldwide meta-analysis
The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. We further identified smoking and body mass index as causal risk factors for severe COVID-19. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. This working model of international collaboration provides a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease
Participation of TRPV1 in the activity of the GnRH system in male rats
GnRH neuron activity is under the influence of multiple stimuli, including those coming from the endocannabinoid and the immune systems. Since it has been previously suggested that some of the main elements controlling the GnRH pulse generator possess the TRPV1 receptor, the aim of the present study was to evaluate the participation of the hypothalamic TRPV1, through its pharmacological blockade, in the activity of the hypothalamic-pituitary-testicular axis in male rats under basal or acute inflammatory conditions. Our hypothesis was based on the idea that the hypothalamic TRPV1 participates in the synthesis of the main neuromodulatory signals controlling GnRH, and therefore the reproductive axis. Our results showed that the hypothalamic TRPV1 blockade induced pro-inflammatory effects by increasing Tnfα and Il-1β mRNA Hypothalamic levels, and inhibited the reproductive axis by affecting Gnrh, Kiss1 and Rfrp3 mRNA levels and decreasing plasma levels of luteinizing hormone and testosterone under basal conditions, without significant additive effects in rats exposed to systemic LPS. Altogether, these results suggest that the hypothalamic TRPV1 receptor participates in the regulation of the GnRH system, probably by modulating immune-dependent mechanisms.Fil: Surkin, Pablo Nicolas. Universidad de Buenos Aires. Facultad de OdontologĂa. Cátedra de FisiologĂa; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Dmytrenko, Ganna. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Centro de Estudios FarmacolĂłgicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios FarmacolĂłgicos y Botánicos; ArgentinaFil: Di Giorgio, Noelia Paula. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; ArgentinaFil: Bizzozzero, Marianne. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; ArgentinaFil: de Laurentiis, Andrea. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Centro de Estudios FarmacolĂłgicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios FarmacolĂłgicos y Botánicos; ArgentinaFil: Fernández Solari, JosĂ© Javier. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Universidad de Buenos Aires. Facultad de OdontologĂa. Cátedra de FisiologĂa; Argentin
Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome
Background: Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. Methods: We explored the association between 405 clinical conditions diagnosed before baseline and 9080 incident cases of ACS in 387 832 individuals from the UK Biobank. Results were replicated in 6430 incident cases of ACS in 177 876 individuals from FinnGen. Results: We identified 80 conventional (eg, stable angina pectoris and type 2 diabetes) and unconventional (eg, diaphragmatic hernia and inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of stable angina pectoris yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction P=2.87x10(-8)) risk for ACS in individuals with stable angina pectoris (hazard ratio, 1.163 [95% CI, 1.082-1.251]) compared with individuals without stable angina pectoris (hazard ratio, 1.531 [95% CI, 1.497-1.565]). These findings were replicated in FinnGen (interaction P=1.38x10(-6)). Conclusions: In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable coronary heart disease. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for coronary heart disease.Peer reviewe
Quantifying the causal impact of biological risk factors on healthcare costs
Understanding the causal impact that clinical risk factors have on healthcare-related costs is critical to evaluate healthcare interventions. Here, we used a genetically-informed design, Mendelian Randomization (MR), to infer the causal impact of 15 risk factors on annual total healthcare costs. We calculated healthcare costs for 373,160 participants from the FinnGen Study and replicated our results in 323,774 individuals from the United Kingdom and Netherlands. Robust causal effects were observed for waist circumference (WC), adult body mass index, and systolic blood pressure, in which a standard deviation increase corresponded to 22.78% [95% CI: 18.75-26.95], 13.64% [10.26-17.12], and 13.08% [8.84-17.48] increased healthcare costs, respectively. A lack of causal effects was observed for certain clinically relevant biomarkers, such as albumin, C-reactive protein, and vitamin D. Our results indicated that increased WC is a major contributor to annual total healthcare costs and more attention may be given to WC screening, surveillance, and mitigation
Protective effect of Opuntia ficus-indica L. cladodes against UVA-induced oxidative stress in normal human keratinocytes
Opuntia ficus-indica L. is known for its beneficial effects on human health, but still little is known on
cladodes as a potent source of antioxidants. Here, a direct, economic and safe method was set up to obtain
water extracts from Opuntia ficus-indica cladodes rich in antioxidant compounds. When human keratinocytes
were pre-treated with the extract before being exposed to UVA radiations, a clear protective
effect against UVA-induced stress was evidenced, as indicated by the inhibition of stress-induced processes,
such as free radicals production, lipid peroxidation and GSH depletion. Moreover, a clear protective
effect against apoptosis in pre-treated irradiated cells was evidenced. We found that eucomic and
piscidic acids were responsible for the anti-oxidative stress action of cladode extract. In conclusion, a
bioactive, safe, low-cost and high value-added extract from Opuntia cladodes was obtained to be used
for skin health/protection
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