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1.
PLoS Comput Biol ; 20(7): e1011946, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39018334

RESUMO

Dynamical system models typically involve numerous input parameters whose "effects" and orthogonality need to be quantified through sensitivity analysis, to identify inputs contributing the greatest uncertainty. Whilst prior art has compared total-order estimators' role in recovering "true" effects, assessing their ability to recover robust parameter orthogonality for use in identifiability metrics has not been investigated. In this paper, we perform: (i) an assessment using a different class of numerical models representing the cardiovascular system, (ii) a wider evaluation of sampling methodologies and their interactions with estimators, (iii) an investigation of the consequences of permuting estimators and sampling methodologies on input parameter orthogonality, (iv) a study of sample convergence through resampling, and (v) an assessment of whether positive outcomes are sustained when model input dimensionality increases. Our results indicate that Jansen or Janon estimators display efficient convergence with minimum uncertainty when coupled with Sobol and the lattice rule sampling methods, making them prime choices for calculating parameter orthogonality and influence. This study reveals that global sensitivity analysis is convergence driven. Unconverged indices are subject to error and therefore the true influence or orthogonality of the input parameters are not recovered. This investigation importantly clarifies the interactions of the estimator and the sampling methodology by reducing the associated ambiguities, defining novel practices for modelling in the life sciences.


Assuntos
Simulação por Computador , Humanos , Biologia Computacional/métodos , Modelos Cardiovasculares , Modelos Estatísticos , Algoritmos , Modelos Biológicos , Incerteza
2.
J Med Genet ; 59(2): 133-140, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568438

RESUMO

BACKGROUND: Women testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers. METHODS: Women were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk. RESULTS: In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01-24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%. CONCLUSION: Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.


Assuntos
Neoplasias da Mama/prevenção & controle , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos Profiláticos , Salpingo-Ooforectomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Feminino , Seguimentos , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Mastectomia Profilática , Estudos Prospectivos , Medição de Risco , Adulto Jovem
3.
Chaos ; 33(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37307158

RESUMO

Atrial and ventricular fibrillation (AF/VF) are characterized by the repetitive regeneration of topological defects known as phase singularities (PSs). The effect of PS interactions has not been previously studied in human AF and VF. We hypothesized that PS population size would influence the rate of PS formation and destruction in human AF and VF, due to increased inter-defect interaction. PS population statistics were studied in computational simulations (Aliev-Panfilov), human AF and human VF. The influence of inter-PS interactions was evaluated by comparison between directly modeled discrete-time Markov chain (DTMC) transition matrices of the PS population changes, and M/M/∞ birth-death transition matrices of PS dynamics, which assumes that PS formations and destructions are effectively statistically independent events. Across all systems examined, PS population changes differed from those expected with M/M/∞. In human AF and VF, the formation rates decreased slightly with PS population when modeled with the DTMC, compared with the static formation rate expected through M/M/∞, suggesting new formations were being inhibited. In human AF and VF, the destruction rates increased with PS population for both models, with the DTMC rate increase exceeding the M/M/∞ estimates, indicating that PS were being destroyed faster as the PS population grew. In human AF and VF, the change in PS formation and destruction rates as the population increased differed between the two models. This indicates that the presence of additional PS influenced the likelihood of new PS formation and destruction, consistent with the notion of self-inhibitory inter-PS interactions.


Assuntos
Fibrilação Atrial , Fibrilação Ventricular , Humanos , Átrios do Coração , Cadeias de Markov , Probabilidade
4.
Int J Cancer ; 148(5): 1155-1163, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152107

RESUMO

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is highly effective for the prevention of high-grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow-up before 35/45 years was "risk free" and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow-up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow-up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty-one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013-0.14), with combined Kaplan-Meier analysis HR = 0.029 (95% CI = 0.009-0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001-0.13) compared to non-specialist centres (HR = 0.11; 95% CI = 0.02-0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95-1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias Ovarianas/prevenção & controle , Neoplasias Peritoneais/prevenção & controle , Salpingo-Ooforectomia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Especialização
5.
Philos Trans A Math Phys Eng Sci ; 378(2173): 20190335, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32448070

RESUMO

Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.


Assuntos
Fenômenos Eletrofisiológicos , Coração/fisiologia , Modelos Cardiovasculares , Incerteza , Coração/fisiopatologia , Humanos , Miocárdio/citologia , Miocárdio/patologia
6.
Philos Trans A Math Phys Eng Sci ; 378(2173): 20190345, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32448072

RESUMO

In patients with atrial fibrillation, local activation time (LAT) maps are routinely used for characterizing patient pathophysiology. The gradient of LAT maps can be used to calculate conduction velocity (CV), which directly relates to material conductivity and may provide an important measure of atrial substrate properties. Including uncertainty in CV calculations would help with interpreting the reliability of these measurements. Here, we build upon a recent insight into reduced-rank Gaussian processes (GPs) to perform probabilistic interpolation of uncertain LAT directly on human atrial manifolds. Our Gaussian process manifold interpolation (GPMI) method accounts for the topology of the atrium, and allows for calculation of statistics for predicted CV. We demonstrate our method on two clinical cases, and perform validation against a simulated ground truth. CV uncertainty depends on data density, wave propagation direction and CV magnitude. GPMI is suitable for probabilistic interpolation of other uncertain quantities on non-Euclidean manifolds. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.


Assuntos
Função Atrial , Sistema de Condução Cardíaco/fisiologia , Modelos Cardiovasculares , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Distribuição Normal , Probabilidade
7.
Health Educ Res ; 33(4): 261-270, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982394

RESUMO

Risk of experiencing alcohol and medication interactions (AMI) is significant among older adults due to the substantial prevalence of alcohol and medication use in this segment of the population. Given the lack of community-level AMI prevention interventions for older adults, this study aimed to examine the immediate effects of a brief, pharmacy-based intervention to prevent AMI among older adults, as well as assess differential effects by past-month drinking status. A convenience sample of 134 adults aged 59 and older was recruited from four pharmacies in rural Virginia. Participants were assessed on their AMI awareness, intentions and importance prior to and immediately after exposure to intervention materials. Findings support immediate, positive intervention effects on AMI awareness, intentions and perceived importance of AMI messaging. Changes from pre to post-test did not differ by drinking status, but participants who consumed alcohol were less likely than non-drinkers to recognize the potential consequential severity of alcohol and medication interactions at both time points. Recommendations and future research to prevent AMI are discussed.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Serviços Comunitários de Farmácia/organização & administração , Interações Medicamentosas , Conhecimentos, Atitudes e Prática em Saúde , Educação de Pacientes como Assunto/organização & administração , Idoso , Idoso de 80 Anos ou mais , Conscientização , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Fatores Socioeconômicos , Virginia
8.
J Mol Cell Cardiol ; 96: 49-62, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26611884

RESUMO

Cardiac electrophysiology models have been developed for over 50years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, with quantities such as ion channel kinetics or expression levels being difficult to measure or variable between samples. Until recently, the original approach of describing model parameters using single values has been retained, and consequently the majority of mathematical models in use today provide point predictions, with no associated uncertainty. In recent years, statistical techniques have been developed and applied in many scientific areas to capture uncertainties in the quantities that determine model behaviour, and to provide a distribution of predictions which accounts for this uncertainty. In this paper we discuss this concept, which is termed uncertainty quantification, and consider how it might be applied to cardiac electrophysiology models. We present two case studies in which probability distributions, instead of individual numbers, are inferred from data to describe quantities such as maximal current densities. Then we show how these probabilistic representations of model parameters enable probabilities to be placed on predicted behaviours. We demonstrate how changes in these probability distributions across data sets offer insight into which currents cause beat-to-beat variability in canine APs. We conclude with a discussion of the challenges that this approach entails, and how it provides opportunities to improve our understanding of electrophysiology.


Assuntos
Potenciais de Ação , Coração/fisiologia , Modelos Biológicos , Miocárdio/metabolismo , Algoritmos , Animais , Cães , Fenômenos Eletrofisiológicos , Canais Iônicos/metabolismo , Potenciais da Membrana
9.
J Physiol ; 594(23): 6833-6847, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-26990229

RESUMO

KEY POINTS: Mathematical and computational models of cardiac physiology have been an integral component of cardiac electrophysiology since its inception, and are collectively known as the Cardiac Physiome. We identify and classify the numerous sources of variability and uncertainty in model formulation, parameters and other inputs that arise from both natural variation in experimental data and lack of knowledge. The impact of uncertainty on the outputs of Cardiac Physiome models is not well understood, and this limits their utility as clinical tools. We argue that incorporating variability and uncertainty should be a high priority for the future of the Cardiac Physiome. We suggest investigating the adoption of approaches developed in other areas of science and engineering while recognising unique challenges for the Cardiac Physiome; it is likely that novel methods will be necessary that require engagement with the mathematics and statistics community. ABSTRACT: The Cardiac Physiome effort is one of the most mature and successful applications of mathematical and computational modelling for describing and advancing the understanding of physiology. After five decades of development, physiological cardiac models are poised to realise the promise of translational research via clinical applications such as drug development and patient-specific approaches as well as ablation, cardiac resynchronisation and contractility modulation therapies. For models to be included as a vital component of the decision process in safety-critical applications, rigorous assessment of model credibility will be required. This White Paper describes one aspect of this process by identifying and classifying sources of variability and uncertainty in models as well as their implications for the application and development of cardiac models. We stress the need to understand and quantify the sources of variability and uncertainty in model inputs, and the impact of model structure and complexity and their consequences for predictive model outputs. We propose that the future of the Cardiac Physiome should include a probabilistic approach to quantify the relationship of variability and uncertainty of model inputs and outputs.


Assuntos
Coração/fisiologia , Modelos Cardiovasculares , Humanos , Incerteza
10.
Pituitary ; 19(3): 251-61, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26724807

RESUMO

PURPOSE: Acromegaly has traditionally been associated with significant mortality and cardiovascular morbidity. The aim of this study was to assess the overall mortality and improvement in mortality and morbidity in acromegaly and correlate these with cumulative growth hormone exposure. METHODS: All patients treated for acromegaly at our centre until 2012 were analysed in this retrospective observational study. Baseline demographic details such as age at diagnoses, radiological features and pituitary status were obtained on these 167 patients. Cumulative GH levels (GHy) were calculated as a sum of average of GH readings in consecutive years. Mortality rates and development of new diabetes, hypertension and cardiovascular events (stroke, congestive cardiac failure and ischaemic heart disease) were assessed. RESULTS: The SMR for overall cohort was 1.6. There has been a significant improvement in SMR over the past two decades (SMR until 1992 2.5; SMR since 1992 1.0). Cumulative GH exposure was significantly high in patients who died (35.2 vs 24.1, p < 0.01) and in those with incident metabolic or vascular events during follow up (51.6 vs 24.4, p = 0.0001). The cardiovascular event rate of the 'new' cohort was significantly better than the 'old' cohort (8.0 vs. 29.1 %, p < 0.001). CONCLUSION: There has been significant improvement in mortality and morbidity associated with acromegaly, in the setting of routine care in a specialized endocrine unit. Early and effective treatment to 'control' acromegaly could reduce GH exposure and hence vascular comorbidities.


Assuntos
Adenoma/epidemiologia , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Hormônio do Crescimento Humano/metabolismo , Adenoma/metabolismo , Adenoma/terapia , Adulto , Idoso , Causas de Morte , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Insuficiência Cardíaca/epidemiologia , Humanos , Hipertensão/epidemiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Adulto Jovem
11.
Am J Drug Alcohol Abuse ; 42(4): 422-30, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27184414

RESUMO

BACKGROUND: Alcohol and medication interactions are projected to increase due to the growth of older adults that are unsafely consuming alcohol and medications. Plus, aging adults who reside in rural areas are at the highest risk of experiencing medication interactions. OBJECTIVE: Estimate concurrent alcohol and medication (alcohol/medication) hospitalizations in adults 50+ years, comparing age groups and rural/urban regions. METHODS: Kentucky nonfederal, acute care inpatient hospital discharge electronic records for individuals aged 50+ years from 2001 to 2012 were examined. Rate differences were estimated across age and regional strata. Differences in the underlying principal diagnosis, intent, and medications were also examined. RESULTS: There were 2168 concurrent alcohol/medication hospitalizations among 50+ year olds identified. There was a 187% increase in alcohol/medication hospitalizations from 2001 (n = 104) to 2012 (n = 299). The per capita alcohol/medication hospitalization rate increased from 8.91 (per 100,000) in 2001 to 19.98 (per 100,000) in 2012, a 124% increase. The characteristics of the hospitalizations included 75% principal diagnosis as medication poisoning, self-harm as the primary intent (55%) in 50-64-year olds, and unintentional intent (41%) in 65+ adults. Benzodiazepines were most often involved in the poisonings (36.5%). CONCLUSIONS: Concurrent alcohol/medication hospitalizations in Kentucky are increasing among aging adults. Greater increases in rural areas and the 65+ aged adults were seen, although there were also higher alcohol/medication hospitalizations in urban and 50-64 aged adults. These findings indicate the need for public-health prevention and clinical intervention to better educate and manage alcohol consuming older adults on safe medication and alcohol practices.


Assuntos
Etanol/intoxicação , Hospitalização/estatística & dados numéricos , Medicamentos sob Prescrição/intoxicação , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Idoso , Envelhecimento/efeitos dos fármacos , Interações Medicamentosas , Feminino , Hospitalização/tendências , Humanos , Kentucky , Masculino , Pessoa de Meia-Idade
12.
J Am Pharm Assoc (2003) ; 56(5): 544-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27594107

RESUMO

OBJECTIVES: To examine rural and urban pharmacy staff perceptions on messaging, barriers, and motivators for preventing alcohol and medication interactions (AMI) in older adults (≥65 years of age). METHODS: A survey was distributed through the local pharmacist association and statewide pharmacy registry in Kentucky. A total of 255 responses were received from pharmacists, pharmacy technicians, and pharmacy students. RESULTS: Across rural and urban regions alike, among the AMI prevention messages provided, participants identified the most important messages to be: AMI can be potentially dangerous and life threatening; emergency rooms should be used when experiencing an AMI; and doctors and pharmacists should be consulted about AMI. The most common AMI prevention barriers indicated were stigma, costs, and low perceived risks. The most common AMI prevention motivators indicated were physical health improvement, promoting a healthy lifestyle, convenient setting, and financial incentives. CONCLUSION: Regardless of geography, participants similarly rated the presented AMI prevention messages, barriers, and motivators. With the use of these findings, the development of an AMI prevention program is suggested to use messaging about AMI threat, behavioral management, and behavioral prevention.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Atitude do Pessoal de Saúde , Serviços Comunitários de Farmácia/organização & administração , Farmacêuticos/organização & administração , Adulto , Idoso , Interações Medicamentosas , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Farmacêuticos/estatística & dados numéricos , Técnicos em Farmácia/organização & administração , Técnicos em Farmácia/estatística & dados numéricos , Desenvolvimento de Programas , Serviços de Saúde Rural , Estudantes de Farmácia/estatística & dados numéricos , Serviços Urbanos de Saúde , Adulto Jovem
13.
PLoS Comput Biol ; 10(11): e1003891, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25375999

RESUMO

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.


Assuntos
Coração/fisiopatologia , Modelos Cardiovasculares , Isquemia Miocárdica/fisiopatologia , Miocárdio/patologia , Fibrilação Ventricular/fisiopatologia , Simulação por Computador , Humanos , Hiperpotassemia , Hipóxia , Imageamento Tridimensional , Isquemia Miocárdica/patologia , Fibrilação Ventricular/patologia
15.
Pituitary ; 18(5): 674-84, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25557289

RESUMO

INTRODUCTION: Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression. RESULTS: In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA-targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression. CONCLUSIONS: These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Proteínas HMGA/metabolismo , Inibidores de Histona Desacetilases/farmacologia , MicroRNAs/metabolismo , Hipófise/efeitos dos fármacos , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Linhagem Celular , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Ilhas de CpG , Citidina/análogos & derivados , Citidina/farmacologia , Metilação de DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteínas HMGA/genética , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , MicroRNAs/genética , Hipófise/metabolismo , Hipófise/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima
16.
Soc Psychiatry Psychiatr Epidemiol ; 50(6): 983-94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25652591

RESUMO

PURPOSE: The heterogeneity of serious emotional disturbance has been thoroughly documented among adolescents with nationally representative data derived from structured interviews, although use of these interviews may not be feasible within the context of brief and self-administered school surveys. This study seeks to identify distinct subtypes of serious emotional disturbance in a large school-based sample. METHODS: A total of 108,736 students fully completed the K6 scale that was included on the 2012 Kentucky Incentives for Prevention Survey. Latent class analysis was used to derive subtypes of serious emotional disturbance among students receiving a positive screen (n = 15,147). To determine significant predictors of class membership, adjusted rate ratios and 95 % confidence intervals were calculated using multinomial logistic regression. RESULTS: A four-class model was the most parsimonious, with four distinct subtypes emerging that varied by both symptom type and severity: comorbid moderate severity, comorbid high severity, anxious moderate severity, and depressed high severity. Age, gender, race/ethnicity, family structure, substance use, antisocial behavior, role impairments, and peer victimization were significant predictors of class membership, although the magnitude of these effects was stronger for the two high severity groups. CONCLUSIONS: Our results suggest heterogeneity of serious emotional disturbance by both symptom type and severity. Prevention programs may benefit by shifting focus from specific disorders to the core features of serious emotional disturbance, including psychological distress, high comorbidity, and role impairments.


Assuntos
Sintomas Afetivos/diagnóstico , Bullying , Grupo Associado , Estudantes/psicologia , Adolescente , Sintomas Afetivos/complicações , Sintomas Afetivos/psicologia , Transtorno da Personalidade Antissocial/complicações , Transtorno da Personalidade Antissocial/diagnóstico , Transtorno da Personalidade Antissocial/psicologia , Criança , Comorbidade , Família , Feminino , Humanos , Masculino , Instituições Acadêmicas , Índice de Gravidade de Doença , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Inquéritos e Questionários
17.
J Ment Health ; 24(5): 283-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26191610

RESUMO

BACKGROUND/AIMS: The transition to adulthood represents a critical period which influences mental health problems, but access to and utilisation of mental health services by young people is poor. Jigsaw is a response to the challenge of transforming how young people access mental health support and attain positive outcomes. This article presents an overview of the characteristics of young people engaging with this service. METHOD: Data about young people who engage with Jigsaw are captured through an online system designed to record salient clinical, case management, service delivery, and outcome information. Participant characteristics are summarised to portray the young people who engaged with the service for the first time during 2013 (N = 2420). RESULTS: The majority of young people engaging with Jigsaw were female, aged 15-17 years, and were referred by their parents. Over half were in full-time education, although many 21-25-year-olds were unemployed. Young people presented with a range of difficulties which varied by age and gender. They reported high levels of distress, with age and gender having a significant impact on their well-being. CONCLUSIONS: This study provides emerging evidence to support the need for an early intervention component within the system of mental health care.


Assuntos
Intervenção Educacional Precoce/estatística & dados numéricos , Transtornos Mentais/prevenção & controle , Serviços de Saúde Mental/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Irlanda , Masculino , Encaminhamento e Consulta , Adulto Jovem
18.
Front Physiol ; 15: 1403545, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39005500

RESUMO

Introduction: Fibrotic scar in the heart is known to act as a substrate for arrhythmias. Regions of fibrotic scar are associated with slowed or blocked conduction of the action potential, but the detailed mechanisms of arrhythmia formation are not well characterised and this can limit the effective diagnosis and treatment of scar in patients. The aim of this computational study was to evaluate different representations of fibrotic scar in models of 2D 10 × 10 cm ventricular tissue, where the region of scar was defined by sampling a Gaussian random field with an adjustable length scale of between 1.25 and 10.0 mm. Methods: Cellular electrophysiology was represented by the Ten Tusscher 2006 model for human ventricular cells. Fibrotic scar was represented as a spatially varying diffusion, with different models of the boundary between normal and fibrotic tissue. Dispersion of activation time and action potential duration (APD) dispersion was assessed in each sample by pacing at an S1 cycle length of 400 ms followed by a premature S2 beat with a coupling interval of 323 ms. Vulnerability to reentry was assessed with an aggressive pacing protocol. In all models, simulated fibrosis acted to delay activation, to increase the dispersion of APD, and to generate re-entry. Results: A higher incidence of re-entry was observed in models with simulated fibrotic scar at shorter length scale, but the type of model used to represent fibrotic scar had a much bigger influence on the incidence of reentry. Discussion: This study shows that in computational models of fibrotic scar the effects that lead to either block or propagation of the action potential are strongly influenced by the way that fibrotic scar is represented in the model, and so the results of computational studies involving fibrotic scar should be interpreted carefully.

19.
Sci Rep ; 14(1): 4493, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38396245

RESUMO

In healthy hearts myocytes are typically coupled to nearest neighbours through gap junctions. Under pathological conditions such as fibrosis, or in scar tissue, or across ablation lines myocytes can uncouple from their neighbours. Electrical conduction may still occur via fibroblasts that not only couple proximal myocytes but can also couple otherwise unconnected regions. We hypothesise that such coupling can alter conduction between myocytes via introduction of delays or by initiation of premature stimuli that can potentially result in reentry or conduction blocks. To test this hypothesis we have developed several 2-cell motifs and investigated the effect of fibroblast mediated electrical coupling between uncoupled myocytes. We have identified various regimes of myocyte behaviour that depend on the strength of gap-junctional conductance, connection topology, and parameters of the myocyte and fibroblast models. These motifs are useful in developing a mechanistic understanding of long-distance coupling on myocyte dynamics and enable the characterisation of interaction between different features such as myocyte and fibroblast properties, coupling strengths and pacing period. They are computationally inexpensive and allow for incorporation of spatial effects such as conduction velocity. They provide a framework for constructing scar tissue boundaries and enable linking of cellular level interactions with scar induced arrhythmia.


Assuntos
Cicatriz , Miócitos Cardíacos , Humanos , Cicatriz/metabolismo , Junções Comunicantes/metabolismo , Comunicação Celular , Fibroblastos/metabolismo
20.
Microbiol Resour Announc ; 13(6): e0116823, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38651916

RESUMO

We sequenced the genome of a hirame novirhabdovirus isolate recovered from a white bass (Morone chrysops). Hirame novirhabdoviruses are in the genus Novirhabdovirus, along with infectious hematopoietic necrosis virus and viral hemorrhagic septicemia virus. This detection highlights that the full host range of rhabdoviruses in fish is not fully understood.

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