Klára Bíró

Relationship between Statin Utilization and Socioeconomic Deprivation in Hungary

The risk of premature mortality caused by cardiovascular diseases (CVDs) is approximately three times higher in the Central Eastern European region than in high income European countries, which suggests a lack and/or ineffectiveness of preventive interventions against CVDs. The aim of the present study was to provide data on the relationship between premature CVD mortality, statin utilization as a preventive medication and socioeconomic deprivation at the district level in Hungary. As a conceptually new approach, the prescription of statins, the prescription redemption and the ratio between redemption and prescription rates were also investigated. The number of prescriptions for statins and the number of redeemed statin prescriptions were obtained from the National Health Insurance Fund Administration of Hungary for each primary healthcare practice for the entire year of 2012. The data were aggregated at the district level. To define the frequency of prescription and of redemption, the denominator was the number of the 40+-year-old population adjusted by the rates of 60+-year-old population of the district. The standardized mortality rates, frequency of statin prescriptions, redeemed statin prescriptions, and ratios for compliance in relation to the national average were mapped using the “disease mapping” option, and their association with deprivation (tertile of deprivation index as a district-based categorical covariate) was defined using the risk analysis capabilities within the Rapid Inquiry Facility. The risk analysis showed a significant positive association between deprivation and the relative risk of premature cardiovascular mortality, and a reverse J-shaped association between the relative frequency of statin prescriptions and deprivation. Districts with the highest deprivation showed a low relative frequency of statin prescriptions; however, significantly higher primary compliance (redemption) was observed in districts with the highest deprivation. Our data clearly indicate that insufficient statin utilization is strongly linked to the so-called physician-factor, i.e., a statin prescription. Consequently, statin treatment is poor and represents a significant barrier to reducing mortality, particularly among people living in highly deprived areas of the country.

The "proactive" model of learning: Integrative framework for model-free and model-based reinforcement learning utilizing the associative learning-based proactive brain concept.

Reinforcement learning (RL) is a powerful concept underlying forms of associative learning governed by the use of a scalar reward signal, with learning taking place if expectations are violated. RL may be assessed using model-based and model-free approaches. Model-based reinforcement learning involves the amygdala, the hippocampus, and the orbitofrontal cortex (OFC). The model-free system involves the pedunculopontine-tegmental nucleus (PPTgN), the ventral tegmental area (VTA) and the ventral striatum (VS). Based on the functional connectivity of VS, model-free and model based RL systems center on the VS that by integrating model-free signals (received as reward prediction error) and model-based reward related input computes value. Using the concept of reinforcement learning agent we propose that the VS serves as the value function component of the RL agent. Regarding the model utilized for model-based computations we turned to the proactive brain concept, which offers an ubiquitous function for the default network based on its great functional overlap with contextual associative areas. Hence, by means of the default network the brain continuously organizes its environment into context frames enabling the formulation of analogy-based association that are turned into predictions of what to expect. The OFC integrates reward-related information into context frames upon computing reward expectation by compiling stimulus-reward and context-reward information offered by the amygdala and hippocampus, respectively. Furthermore we suggest that the integration of model-based expectations regarding reward into the value signal is further supported by the efferent of the OFC that reach structures canonical for model-free learning (e.g., the PPTgN, VTA, and VS).

‘Proactive’ use of cue-context congruence for building reinforcement learning’s reward function

BackgroundReinforcement learning is a fundamental form of learning that may be formalized using the Bellman equation. Accordingly an agent determines the state value as the sum of immediate reward and of the discounted value of future states. Thus the value of state is determined by agent related attributes (action set, policy, discount factor) and the agent’s knowledge of the environment embodied by the reward function and hidden environmental factors given by the transition probability. The central objective of reinforcement learning is to solve these two functions outside the agent’s control either using, or not using a model.ResultsIn the present paper, using the proactive model of reinforcement learning we offer insight on how the brain creates simplified representations of the environment, and how these representations are organized to support the identification of relevant stimuli and action. Furthermore, we identify neurobiological correlates of our model by suggesting that the reward and policy functions, attributes of the Bellman equitation, are built by the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), respectively.ConclusionsBased on this we propose that the OFC assesses cue-context congruence to activate the most context frame. Furthermore given the bidirectional neuroanatomical link between the OFC and model-free structures, we suggest that model-based input is incorporated into the reward prediction error (RPE) signal, and conversely RPE signal may be used to update the reward-related information of context frames and the policy underlying action selection in the OFC and ACC, respectively. Furthermore clinical implications for cognitive behavioral interventions are discussed.

Inhibition of TRPC6 by protein kinase C isoforms in cultured human podocytes

Transient receptor potential canonical‐6 (TRPC6) ion channels, expressed at high levels in podocytes of the filtration barrier, are recently implicated in the pathogenesis of various forms of proteinuric kidney diseases. Indeed, inherited or acquired up‐regulation of TRPC6 activities are suggested to play a role in podocytopathies. Yet, we possess limited information about the regulation of TRPC6 in human podocytes. Therefore, in this study, we aimed at defining how the protein kinase C (PKC) system, one of the key intracellular signalling pathways, regulates TRPC6 function and expression. On human differentiated podocytes, we identified the molecular expressions of both TRPC6 and several PKC isoforms. We also showed that TRPC6 channels are functional since the TRPC6 activator 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) induced Ca2+‐influx to the cells. By assessing the regulatory roles of the PKCs, we found that inhibitors of the endogenous activities of classical and novel PKC isoforms markedly augmented TRPC6 activities. In contrast, activation of the PKC system by phorbol 12‐myristate 13‐acetate (PMA) exerted inhibitory actions on TRPC6 and suppressed its expression. Importantly, PMA treatment markedly down‐regulated the expression levels of PKCα, PKCβ, and PKCη reflecting their activation. Taken together, these results indicate that the PKC system exhibits a ‘tonic’ inhibition on TRPC6 activity in human podocytes suggesting that pathological conditions altering the expression and/or activation patterns of podocyte‐expressed PKCs may influence TRPC6 activity and hence podocyte functions. Therefore, it is proposed that targeted manipulation of certain PKC isoforms might be beneficial in certain proteinuric kidney diseases with altered TRPC6 functions.

Creating a common language: defining individualized, personalized and precision prevention in public health

Background Because of the limited success of population-based prevention methods and due to developments in genomic screening, public health professionals and health policy makers are increasingly interested in more individualized prevention strategies. However, the terminology applied in this field is still ambiguous and thus has the potential to create misunderstandings. Methods A narrative literature review was conducted to identify how individualized, personalized and precision prevention are used in research papers and documents. Based on the findings a set of definitions were created that distinguish between these activities in a meaningful way. Results Definitions were found only for precision prevention, not for individualized or personalized prevention. The definitions of individualized, personalized and precision medicine were therefore used to create the definitions for their prevention counterparts. By these definitions, individualized prevention consists of all types of prevention that are individual-based; personalized prevention also consists of at least one form of -omic screening; and precision prevention further includes psychological, behavioral and socioeconomic data for each patient. Conclusions By defining these three key terms for different types of individual-based prevention both researchers and health policy makers can differentiate and use them in their proper context.

High Inequalities Associated With Socioeconomic Deprivation in Cardiovascular Disease Burden and Antihypertensive Medication in Hungary

The wide life expectancy gap between the old and new member states of the European Union is most strongly related to the high rate of premature mortality caused by cardiovascular diseases (CVDs). To learn more about the background of this gap, the relationship of socioeconomic status (SES) with CVD mortality, morbidity and the utilization of antihypertensive drugs was studied in Hungary, a Central-Eastern European country with an extremely high relative risk of premature CVD mortality. Risk analysis capabilities were used to estimate the relationships between SES, which was characterized by tertiles of a multidimensional composite indicator (the deprivation index) and CVD burden (mortality and morbidity) as well as the antihypertensive medications at the district level in Hungary. The excess risks caused by premature mortality from CVDs showed a strong correlation with deprivation using the Rapid Inquiry Facility. The distribution of prevalence values related to these diseases was found to be similar, but in the areas of highest deprivation, where the prevalence of chronic ischaemic heart diseases and cerebrovascular diseases was found to be higher than the national average by 30 and 20%, the prevalence of hypertension exceeded the national average by only 4%. A linear association between the relative frequency of prescriptions/redemptions and deprivation for most antihypertensive drugs, except angiotensinogen receptor blockers, was shown. More intense screening for hypertension is proposed to improve the control of CVDs in countries affected by high disease burden.