A location-scale joint model for studying the link between the time-dependent subject-specific variability of blood pressure and competing events

Given the high incidence of cardio and cerebrovascular diseases (CVD), and its association with morbidity and mortality, its prevention is a major public health issue. A high level of blood pressure is a well-known risk factor for these events and an increasing number of studies suggest that blood pressure variability may also be an independent risk factor. However, these studies suffer from significant methodological weaknesses. In this work we propose a new location-scale joint model for the repeated measures of a marker and competing events. This joint model combines a mixed model including a subject-specific and time-dependent residual variance modeled through random effects, and cause-specific proportional intensity models for the competing events. The risk of events may depend simultaneously on the current value of the variance, as well as, the current value and the current slope of the marker trajectory. The model is estimated by maximizing the likelihood function using the Marquardt-Levenberg algorithm. The estimation procedure is implemented in a R-package and is validated through a simulation study. This model is applied to study the association between blood pressure variability and the risk of CVD and death from other causes. Using data from a large clinical trial on the secondary prevention of stroke, we find that the current individual variability of blood pressure is associated with the risk of CVD and death. Moreover, the comparison with a model without heterogeneous variance shows the importance of taking into account this variability in the goodness-of-fit and for dynamic predictions

Основні риси сучасної правової системи України

Правова система, що досліджується в науковій статті, має суттєве значення в процесі створення та функціонування правових інститутів. Проаналізована категорія має важливе значення, оскільки сприяє реалізації визнаних державою завдань та перспектив. Тому, цілком правомірним є дослідження значення правової системи для формування та розвитку громадського суспільства та правової держави. Ключові слова: правова система, правовий інститут, громадянське суспільство, правова держава.В статье анализируются теоретические и практические проблемы развития правовой системы Украины. Обосновывается мысль о необходимости подготовки и принятия концепции развития правового регулирования общественных отношений в Украине и законодательных актов. Проанализировано взгляды ученых относительно научных подходов к исследованию правовой системы. Анализируется соотношение и взаимодействие таких важных категорий, как правовая система и правовое государство. Ключевые слова: правовая система, правовой институт, гражданское общество, правовое государство.Theoretical and practical problems of Ukrainian legal system development are analyzed in the article. The thought about the necessity of preparation and adoption of concept of the development of social relations legal regulation in Ukraine and legislative regulations is grounded. The scientist’s views as for scientific approaches to the legal system study are analyzed. The correlation and interaction of such important categories as legal system and law-governed state are analyzed. Key words: legal system, legal institution, civil society, law-governed stare

Modelling effectiveness of herd level vaccination against Q fever in dairy cattle

Q fever is a worldwide zoonosis caused by the bacterium Coxiella burnetii. The control of this infection in cattle is crucial: infected ruminants can indeed encounter reproductive disorders and represent the most important source of human infection. In the field, vaccination is currently advised in infected herds but the comparative effectiveness of different vaccination protocols has never been explored: the duration of the vaccination programme and the category of animals to be vaccinated have to be determined. Our objective was to compare, by simulation, the effectiveness over 10 years of three different vaccination strategies in a recently infected dairy cattle herd

The Distribution of Bovine Tuberculosis in Cattle Farms Is Linked to Cattle Trade and Badger-Mediated Contact Networks in South-Western France, 2007–2015

Bovine tuberculosis (bTB), mainly caused by Mycobacterium bovis, can affect domestic and wild animals as well as humans. Identifying the major transmission mechanisms in an area is necessary for disease control and management. In this study, we aimed to evaluate the involvement of different types of contact in M. bovis transmission between cattle farms of south-western France between 2007 and 2015. We analyzed an empirical contact network of cattle farms as nodes, with known infection status and molecular types (16 circulated during the study period of which 14 affected only cattle and two both badgers and cattle). Edges were based on cattle trade data (T-edges) and on spatial neighborhood relationships between farms, either direct (P-edges) or badger-mediated, when two farms neighbored the same badger home range (B-edges), or two distinct but neighboring badger home ranges (D-edges). Edge types were aggregated so that the contact network contained only unique edges labeled by one or several edge types. The association between the contact network structure and bTB infection status was assessed using a non-parametric test, each molecular type being considered a marker of an independent epidemic. Using a logistic regression model, we estimated the contribution of each edge type to the probability for an edge originating from an infected farm to end at another infected farm. A total number of 1946 cattle farms were included in the study and were linked by 54,243 edges. Within this contact network, infected farms (whatever the molecular type) always belonged to the same component, suggesting the contact network may have supported bTB spread among those farms. A significant association between the pattern of bTB-infected farms and the structure of the contact network was observed when all the molecular types were simultaneously considered. The logistic regression model showed a significant association between M. bovis infection in direct neighbors of infected farms and the connection by T-, B- and D-edges, with odds-ratios of 7.4, 1.9, and 10.4, respectively. These results indicate a multifactorial M. bovis transmission between cattle farms of the studied area, with varying implication levels of the trade, pasture and badger networks according to the molecular type

Mutational analysis of the HIV-1 auxiliary protein Vif identifies independent domains important for the physical and functional interaction with HIV-1 reverse transcriptase

The HIV-1 accessory protein Vif plays a dual role: it counteracts the natural restriction factors APOBEC3G and 3F and ensures efficient retrotranscription of the HIV-1 RNA genome. We have previously shown that Vif can act as an auxiliary factor for HIV-1 reverse transcriptase (RT), increasing its rate of association to RNA or DNA templates. Here, by using seven different Vif mutants, we provide in vitro evidences that Vif stimulates HIV-1 RT through direct protein–protein interaction, which is mediated by its C-terminal domain. Physical interaction appears to require the proline-rich region comprised between amino acid (aa) 161 and 164 of Vif, whereas the RT stimulatory activity requires, in addition, the extreme C-terminal region (aa 169–192) of the Vif protein. Neither the RNA interaction domain, nor the Zn++-binding domain of Vif are required for its interaction with the viral RT. Pseudotyped HIV-1 lentiviral vectors bearing Vif mutants deleted in the RNA- or RT-binding domains show defects in retrotranscription/integration processes in both permissive and nonpermissive cells. Our results broaden our knowledge on how three important functions of Vif (RNA binding, RT binding and stimulation and Zn++ binding), are coordinated by different domains

Metapopulation Dynamics Enable Persistence of Influenza A, Including A/H5N1, in Poultry

Thanks to K. Sturm-Ramirez, C. Jessup, J. Rosenthal and the staff of EcoHealth Alliance for feedback. Disclaimer: The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.Conceived and designed the experiments: PRH TF RH DZ CSA AG MJM XX TB PD. Performed the experiments: PRH. Analyzed the data: PRH. Contributed reagents/materials/analysis tools: PRH TF RH DZ CSA AG MJM XX TB JHJ PD. Wrote the paper: PRH TF RH DZ CSA AG MJM XX TB JHJ PD.Highly pathogenic influenza A/H5N1 has persistently but sporadically caused human illness and death since 1997. Yet it is still unclear how this pathogen is able to persist globally. While wild birds seem to be a genetic reservoir for influenza A, they do not seem to be the main source of human illness. Here, we highlight the role that domestic poultry may play in maintaining A/H5N1 globally, using theoretical models of spatial population structure in poultry populations. We find that a metapopulation of moderately sized poultry flocks can sustain the pathogen in a finite poultry population for over two years. Our results suggest that it is possible that moderately intensive backyard farms could sustain the pathogen indefinitely in real systems. This fits a pattern that has been observed from many empirical systems. Rather than just employing standard culling procedures to control the disease, our model suggests ways that poultry production systems may be modified.Yeshttp://www.plosone.org/static/editorial#pee