Monte Carlo Optimization Method Based QSAR Modeling of Placental Barrier Permeability.

PURPOSE: In order to ensure that drug administration is safe during pregnancy, it is crucial to have the possibility to predict the placental permeability of drugs in humans. The experimental method which is most widely used for the said purpose is in vitro human placental perfusion, though the approach is highly expensive and time consuming. Quantitative structure-activity relationship (QSAR) modeling represents a powerful tool for the assessment of the drug placental transfer, and can be successfully employed to be an alternative in in vitro experiments. METHODS: The conformation-independent QSAR models covered in the present study were developed through the use of the SMILES notation descriptors and local molecular graph invariants. What is more, the Monte Carlo optimization method, was used in the test sets and the training sets as the model developer with three independent molecular splits. RESULTS: A range of different statistical parameters was used to validate the developed QSAR model, including the standard error of estimation, mean absolute error, root-mean-square error (RMSE), correlation coefficient, cross-validated correlation coefficient, Fisher ratio, MAE-based metrics and the correlation ideality index. Once the mentioned statistical methods were employed, an excellent predictive potential and robustness of the developed QSAR model was demonstrated. In addition, the molecular fragments, which are derived from the SMILES notation descriptors accounting for the decrease or increase in the investigated activity, were revealed. CONCLUSION: The presented QSAR modeling can be an invaluable tool for the high-throughput screening of the placental permeability of drugs.

Mechanochemical Synthesis of TiO2-CeO2 Mixed Oxides Utilized as a Screen-Printed Sensing Material for Oxygen Sensor.

TiO2 and CeO2 are well known as oxygen sensing materials. Despite high sensitivity, the actual utilization of these materials in gas detection remains limited. Research conducted over the last two decades has revealed synergistic effects of TiO2-CeO2 mixed oxides that have the potential to improve some aspects of oxygen monitoring. However, there are no studies on the sensing properties of the TiO2-CeO2 obtained by mechanochemical treatment. We have tested the applicability of the mechanochemically treated TiO2-CeO2 for oxygen detection and presented the results in this study. The sensing layers are prepared as a porous structure by screen printing a thick film on a commercial substrate. The obtained structures were exposed to various O2 concentrations. The results of electrical measurements showed that TiO2-CeO2 films have a significantly lower resistance than pure oxide films. Mixtures of composition TiO2:CeO2 = 0.8:0.2, ground for 100 min, have the lowest electrical resistance among the tested materials. Mixtures of composition TiO2:CeO2 = 0.5:0.5 and ground for 100 min proved to be the most sensitive. The operating temperature can be as low as 320 °C, which places this sensor in the class of semiconductor sensors working at relatively lower temperatures.

Potential role of d-chiro-inositol in reducing oxidative stress in the blood of nonobese women with polycystic ovary syndrome.

d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n = 38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.

Correction: Cost-effectiveness of apixaban compared to other anticoagulants in patients with atrial fibrillation in the real-world and trial settings.

[This corrects the article DOI: 10.1371/journal.pone.0222658.].

Preventive and Therapeutic Potential of Physical Exercise in Neurodegenerative Diseases.

Significance: The prevalence and incidence of age-related neurodegenerative diseases (NDDs) tend to increase along with the enhanced average of the world life expectancy. NDDs are a major cause of morbidity and disability, affecting the health care, social and economic systems with a significant impact. Critical Issues and Recent Advances: Despite the worldwide burden of NDDs and the ongoing research efforts to increase the underlying molecular mechanisms involved in NDD pathophysiologies, pharmacological therapies have been presenting merely narrow benefits. On the contrary, absent of detrimental side effects but growing merits, regular physical exercise (PE) has been considered a prone pleiotropic nonpharmacological alternative able to modulate brain structure and function, thereby stimulating a healthier and "fitness" neurological phenotype. Future Directions: This review summarizes the state of the art of some peripheral and central-related mechanisms that underlie the impact of PE on brain plasticity as well as its relevance for the prevention and/or treatment of NDDs. Nevertheless, further studies are needed to better clarify the molecular signaling pathways associated with muscle contractions-related myokines release and its plausible positive effects in the brain. In addition, particular focus of research should address the role of PE in the modulation of mitochondrial metabolism and oxidative stress in the context of NDDs.

Physical exercise and liver "fitness": Role of mitochondrial function and epigenetics-related mechanisms in non-alcoholic fatty liver disease.

BACKGROUND: Modern lifestyles, especially high-caloric intake and physical inactivity, contribute to the increased prevalence of non-alcoholic fatty liver disease (NAFLD), which becomes a significant health problem worldwide. Lifestyle changes, however, affect not only parental generation, but also their offspring, reinforcing the need for efficient preventive approaches to deal with this disease. This transgenerational influence of phenotypes dependent on parents (particularly maternal) behaviours may open additional research avenues. Despite persistent attempts to design an effective pharmacological therapy against NAFLD, physical activity, as a non-pharmacological approach, emerges as an exciting strategy. SCOPE OF REVIEW: Here we briefly review the effect of physical exercise on liver mitochondria adaptations in NAFLD, highlighting the importance of mitochondrial metabolism and transgenerational and epigenetic mechanisms in liver diseases. MAJOR CONCLUSIONS: A deeper look into cellular mechanisms sheds a light on possible effects of physical activity in the prevention and treatment of NAFLD through modulation of function and structure of particular organelles, namely mitochondria. Additionally, despite of increasing evidence regarding the contribution of epigenetic mechanisms in the pathogenesis of different diseases, the role of microRNAs, DNA methylation, and histone modification in NAFLD pathogenesis still needs to be elucidated.

Semi-rational design of cellobiose dehydrogenase for increased stability in the presence of peroxide.

Cellobiose dehydrogenase (CDH, EC 1.1.99.18) from white rot fungi Phanerochaete chrysosporium can be used for constructing biosensors and biofuel cells, for bleaching cotton in textile industry, and recently, the enzyme has found an important application in biomedicine as an antimicrobial and antibiofilm agent. Stability and activity of the wild-type (wt) CDH and mutants at methionine residues in the presence of hydrogen peroxide were investigated. Saturation mutagenesis libraries were made at the only methionine in heme domain M65 and two methionines M685 and M738 in the flavin domain that were closest to the active site. After screening the libraries, three mutants with increased activity and stability in the presence of peroxide were found, M65F with 70% of residual activity after 6 h of incubation in 0.3 M hydrogen peroxide, M738S with 80% of residual activity and M685Y with over 90% of residual activity compared to wild-type CDH that retained 40% of original activity. Combined mutants showed no activity. The most stable mutant M685Y with 5.8 times increased half-life in the presence of peroxide showed also 2.5 times increased kcat for lactose compared to wtCDH and could be good candidate for applications in biofuel cells and biocatalysis for lactobionic acid production.

Phenotypic and genetic spectrum of patients with limb-girdle muscular dystrophy type 2A from Serbia.

Limb-girdle muscular dystrophy (LGMD) type 2A (calpainopathy) is an autosomal recessive disease caused by mutation in the CAPN3 gene. The aim of this study was to examine genetic and phenotypic features of Serbian patients with calpainopathy. The study comprised 19 patients with genetically confirmed calpainopathy diagnosed at the Neurology Clinic, Clinical Center of Serbia and the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during a ten-year period. Eighteen patients in this cohort had c.550delA mutation, with nine of them being homozygous. In majority of the patients, disease started in childhood or early adulthood. The disease affected shoulder girdle - upper arm and pelvic girdle - thigh muscles with similar frequency, with muscles of lower extremities being more severely impaired. Facial and bulbar muscles were spared. All patients in this cohort, except two, remained ambulant. None of the patients had cardiomyopathy, while 21% showed mild conduction defects. Respiratory function was mildly impaired in 21% of patients. Standard muscle histopathology showed myopathic and dystrophic pattern. In conclusion, the majority of Serbian LGMD2A patients have the same mutation and similar phenotype.

Cost-effectiveness of apixaban compared to other anticoagulants in patients with atrial fibrillation in the real-world and trial settings.

INTRODUCTION: Randomized clinical trials (RCTs) and real-world data (RWD) in patients with atrial fibrillation have shown that-compared to vitamin K antagonists (VKAs)-non-VKA oral anticoagulants (NOACs) are at least as effective in the prevention of ischaemic stroke, while decreasing the risk of bleeding. OBJECTIVE: We aim to evaluate the cost-effectiveness of the NOAC apixaban versus other NOACs (dabigatran, edoxaban and rivaroxaban) and VKA, for stroke prevention in patients with atrial fibrillation by including the available data both from RCT and real-world analyses of all NOACs into one integrative previously published model. METHODS: The model was updated to the current Dutch healthcare situation. The incremental cost-effectiveness ratio was calculated using either efficacy/effectiveness and safety data derived from a network meta-analysis (NMA) synthesizing NOAC RCTs or RWD. We conducted a systematic literature search to identify eligible publication to best inform the RWD-based analysis. Additional sensitivity and scenario analyses were conducted to test the robustness of the outcomes. RESULTS: In the NMA-based analysis, apixaban appeared to be cost-effective compared to VKA (€3,506 per quality adjusted life-year) and dominant (cost-saving and more effective) over dabigatran 110 mg, dabigatran 150 mg, edoxaban and rivaroxaban. In the RWD-based analysis, apixaban was dominant over all other anticoagulants. In the scenario analysis apixaban appeared to be not cost-effective compared to dabigatran 150 mg, when using equal event-unrelated treatment discontinuation rates for each drug. In all other scenarios apixaban is cost-effective or cost-saving compared to VKA and other NOACs. CONCLUSION: Based on RCTs as well as RWD, we conclude that apixaban is generally cost-effective or even cost-saving (less costly and more effective) compared to VKA and other NOACs in the overall population of patients with atrial fibrillation.

Prognostic Impact of Canonical TGF-ß Signaling in Urothelial Bladder Cancer.

Background and objectives: Dysregulation of TGF-ß signaling plays multiple roles in cancer development and progression. In the canonical TGF-ß pathway, TGF-ß regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-ß1, Smad2, and Smad4, the key components of canonical TGFß pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients' outcome. Materials and Methods: Immunohistochemical analysis of TGF-ß1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results: High expression of TGF-ß1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-ß1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage (p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade (p = 0,003, p = 0.048, respectively), and low tumor stage (p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors (p = 0.014). High TGF-ß1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death (p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression (p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival (p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-ß1 manifested as an independent predictor of poor outcome. Conclusions: Unraveling the complex roles and significance of TGF-ß signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-ß pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-ß signaling cascade.

Self-Paced Free-Running Wheel Mimics High-Intensity Interval Training Impact on Rats' Functional, Physiological, Biochemical, and Morphological Features.

Free-running wheel (FRW) is an animal exercise model that relies on high-intensity interval moments interspersed with low-intensity or pauses apparently similar to those performed in high-intensity interval training (HIIT). Therefore, this study, conducted over a 12-weeks period, aimed to compare functional, thermographic, biochemical and morphological skeletal and cardiac muscle adaptations induced by FRW and HIIT. Twenty-four male Wistar rats were assigned into three groups: sedentary rats (SED), rats that voluntarily exercise in free wheels (FRW) and rats submitted to a daily HIIT. Functional tests revealed that compared to SED both FRW and HIIT increased the ability to perform maximal workload tests (MWT-cm/s) (45 ± 1 vs. 55 ± 2 and vs. 65 ± 2). Regarding thermographic assays, FRW and HIIT increased the ability to lose heat through the tail during MWT. Histochemical analyzes performed in tibialis anterior (TA) and soleus (SOL) muscles showed a general adaptation toward a more oxidative phenotype in both FRW and HIIT. Exercise increased the percentage of fast oxidative glycolytic (FOG) in medial fields of TA (29.7 ± 2.3 vs. 44.9 ± 4.4 and vs. 45.2 ± 5.3) and slow oxidative (SO) in SOL (73.4 ± 5.7 vs. 99.5 ± 0.5 and vs. 96.4 ± 1.2). HITT decreased fiber cross-sectional area (FCSA-µm2) of SO (4350 ± 286.9 vs. 4893 ± 325 and vs. 3621 ± 237.3) in SOL. Fast glycolytic fibers were bigger across all the TA muscle in FRW and HIIT groups. The FCSA decrease in FOG fibers was accompanied by a circularity decrease of SO from SOL fibers (0.840 ± 0.005 vs. 0.783 ± 0.016 and vs. 0.788 ± 0.010), and a fiber and global field capillarization increase in both FRW and HIIT protocols. Moreover, FRW and HIIT animals exhibited increased cardiac mitochondrial respiratory control ratio with complex I-driven substrates (3.89 ± 0.14 vs. 5.20 ± 0.25 and vs. 5.42 ± 0.37). Data suggest that FRW induces significant functional, physiological, and biochemical adaptations similar to those obtained under an intermittent forced exercise regimen, such as HIIT.

N3-MEA Probes: Scooping Neuronal Networks.

In the current work, we introduce a brand new line of versatile, flexible, and multifunctional MEA probes, the so-called Nano Neuro Net, or N3-MEAs. Material choice, dimensions, and room for further upgrade, were carefully considered when designing such probes in order to cover the widest application range possible. Proof of the operation principle of these novel probes is shown in the manuscript via the recording of extracellular signals, such as action potentials and local field potentials from cardiac cells and retinal ganglion cells of the heart tissue and eye respectively. Reasonably large signal to noise ratio (SNR) combined with effortless operation of the devices, mechanical and chemical stability, multifunctionality provide, in our opinion, an unprecedented blend. We show successful recordings of (1) action potentials from heart tissue with a SNR up to 13.2; (2) spontaneous activity of retinal ganglion cells with a SNR up to 12.8; and (3) local field potentials with an ERG-like waveform, as well as spiking responses of the retina to light stimulation. The results reveal not only the multi-functionality of these N3-MEAs, but high quality recordings of electrogenic tissues.

T lymphocytes in the third trimester decidua in preeclampsia.

OBJECTIVE: The aim of study was to conduct immunohistochemical quantification of CD3+ and CD8+ decidual lymphocytes in preeclampsia. METHODS: A study group included 30 cases of preeclampsia and a control group included 20 healthy pregnant women, all delivered by Cesarean section. Samples of placental bed were analyzed after immunohistochemical staining of CD45+, CD3+ and CD8+ cells. RESULTS: The group with preeclampsia included a significantly higher number of CD3+ (p < 0.01) and CD8+ (p < 0.05) T lymphocytes. CONCLUSION: It is certain that thebalance dysregulation of T cell of the immune milieu of deciduais of importance in etiopathogenesis and manifestations of preeclampsia.

Ace/actn3 genetic polymorphisms and athletic performance of female soccer players` / Polimorfismos genéticos em ace/actn3 e desempenho atlético de atletas de futebol feminino / Polimorfismos genéticos en ace/actn3 y desempeño atlético de atletas de fútbol femenino

ABSTRACT Objective: Previous studies have shown controversial relationships between ACE and ACTN3 gene polymorphisms and sports performance. Thus, the aim of our study was to assess anaerobic and aerobic performance indicators of young female soccer players with different ACE/ACTN3 gene profiles. Methods: Twenty-seven female soccer players aged 16-18 underwent acceleration, speed, strength, anaerobic power and aerobic endurance tests and had their ACE and ACTN3 polymorphisms determined. Results: Based on genetic analysis, they were divided into the following groups: ACE II (n=2), ACE ID (n=11), ACE DD (n=14), ACTN3 XX (n=5), ACTN3 RR (n=7) and ACTN3 RX (n=15). ACE DD and ACE ID groups differed significantly in terms of results achieved on the 5 m sprint test (1.15±0.05 s vs 1.10±0.05 s, P=0.42). ACTN3 RR and RX achieved better results than the ACTN3 XX group in seven continuous vertical jumps (26.57±1.59 cm vs 25.77±2.51 cm vs 22.86±1.16 cm, respectively; P=0.007 for RR vs XX and P=0.021 for RX vs XX). Conclusion: High prevalence of ACE DD and ACTN3 RX genotypes in our subjects may suggest that faster and more powerful young females tend to perform better in soccer. Nevertheless, the absence of differences in most of the physical test results indicates that different genotypes are compatible with high-level soccer performance, meaning that it is the phenotype-genotype interaction that makes a successful female soccer player. Level of Evidence I, Prognostic studies — Investigating the effect of a patient characteristic on disease outcome.

RESUMO Objetivo: Estudos anteriores mostraram relações controvertidas entre os polimorfismos dos genes ACE e ACTN3 e desempenho esportivo. Assim sendo, o objetivo deste estudo foi avaliar os indicadores de desempenho anaeróbico e aeróbico de jovens futebolistas do sexo feminino com diferentes perfis dos genes ACE/ACTN3. Métodos: Vinte e sete jogadoras com idade entre 16 e 18 anos realizaram testes de aceleração, velocidade, força, potência anaeróbica e resistência aeróbica e os polimorfismos de seus genes ACE e ACTN3 foram determinados. Resultados: Com base na análise genética, elas foram divididas nos seguintes grupos: ACE II (n = 2), ACE ID (n = 11), ACE DD (n = 14), ACTN3 XX (n = 5), ACTN3 RR (n = 7) e ACTN3 RX (n = 15). Os grupos ACE DD e ACE ID diferiram significativamente quanto aos resultados obtidos no sprint test de 5 metros (1,15 ± 0,05 s vs. 1,10 ± 0,05 s, P = 0,42). Os grupos ACTN3 RR e RX atingiram resultados melhores do que o grupo ACTN3 XX em sete saltos verticais contínuos (26,57 ± 1,59 cm vs. 25,77 ± 2,51 cm vs. 22,86 ± 1,16 cm, respectivamente; P = 0,007 para RR vs. XX e P = 0,021 para RX vs. XX). Conclusão: A alta prevalência de genótipos RX em ACE DD e ACTN3 em nossa amostra pode sugerir que as jovens atletas mais rápidas e com maior potência tendem a ter melhor desempenho no futebol. No entanto, a ausência de diferença na maioria dos resultados dos testes físicos indica que genótipos distintos são compatíveis com o desempenho futebolístico de alto nível, o que significa que é a interação fenótipo-genótipo que faz uma jogadora de futebol ser bem-sucedida. Nível de Evidência I, Estudos prognósticos - Investigação do efeito de característica de um paciente sobre o desfecho da doença.

RESUMEN Objetivo: Estudios anteriores mostraron relaciones controvertidas entre los polimorfismos de los genes ACE y ACTN3 y desempeño deportivo. Siendo así, el objetivo de este estudio fue evaluar los indicadores de desempeño anaeróbico y aeróbico de jóvenes futbolistas del sexo femenino con diferentes perfiles de los genes ACE/ACTN3. Métodos: Veintisiete jugadoras con edad entre 16 y 18 años realizaron tests de aceleración, velocidad, fuerza, potencia anaeróbica y resistencia aeróbica y fueron determinados los polimorfismos de sus genes ACE e ACTN3. Resultados: Con base en el análisis genético, ellas fueron divididas en los siguientes grupos: ACE II (n = 2), ACE ID (n = 11), ACE DD (n = 14), ACTN3 XX (n = 5), ACTN3 RR (n = 7) y ACTN3 RX (n = 15). Los grupos ACE DD y ACE ID difirieron significativamente cuanto a los resultados obtenidos en el sprint test de 5 metros (1,15 ± 0,05 s vs. 1,10 ± 0,05 s, P = 0,42). Los grupos ACTN3 RR y RX alcanzaron resultados mejores que el grupo ACTN3 XX en siete saltos verticales continuos (26,57 ± 1,59 cm vs. 25,77 ± 2,51 cm vs. 22,86 ± 1,16 cm, respectivamente; P = 0,007 para RR vs. XX y P = 0,021 para RX vs. XX). Conclusión: La alta prevalencia de genotipos RX en ACE DD y ACTN3 en nuestra muestra puede sugerir que las jóvenes atletas más rápidas y con mayor potencia tienden a tener mejor desempeño en el fútbol. Sin embargo, la ausencia de diferencia en la mayoría de los resultados de los tests físicos indica que genotipos distintos son compatibles con el desempeño futbolístico de alto nivel, lo que significa que es la interacción fenotipo-genotipo que hace que una jugadora de fútbol sea exitosa. Nivel de Evidencia I, Estudios pronósticos - Investigación del efecto de característica de un paciente sobre el desenlace de la enfermedad.

Quality of life in adult patients with limb-girdle muscular dystrophies.

Although limb-girdle muscular dystrophies (LGMD) can cause permanent disability, to date there are no studies that examined quality of life (QoL) in these patients. Our aim was to evaluate QoL in patients with LGMD, and to identify the most significant predictors of QoL. The study comprised 46 patients with diagnosis of limb-girdle muscular weakness. QoL in patients was evaluated using two scales-SF-36 questionnaire and the Individualized Neuromuscular Quality of Life questionnaire (INQoL). Following scales were also applied: Epworth Sleepiness Scale (ESS), Hamilton Scale for Depression (HamD), and Krupp's Fatigue Severity Scale (FSS). Mean SF-36 score was 52.4 ± 23.5, and physical composite score was worse than mental. Total INQoL score was 46.1 ± 20.4, with worst results obtained for weakness, fatigue and independence, while social relationships and emotions showed better results. Significant predictors of worse SF-36 score in LGMD patients were higher fatigue level (ß = - 0.470, p < 0.01) and use of assistive device (ß = - 0.245, p < 0.05). Significant predictors of worse INQoL score were higher fatigue level (ß = 0.514, p < 0.01) and presence of cardiomyopathy (ß = - 0.385, p < 0.01). It is of special interest that some of the identified factors that correlated with worse QoL in LGMD patients were amenable to treatment.

The cost-effectiveness and monetary benefits of dabigatran in the prevention of arterial thromboembolism for patients with non-valvular atrial fibrillation in the Netherlands.

BACKGROUND: Atrial fibrillation (AF) causes a significant health and economic burden to the Dutch society. Dabigatran was proven to have at least similar efficacy and a similar or better safety profile when compared to vitamin K antagonists (VKAs) in preventing arterial thromboembolism in patients with AF. OBJECTIVE: To evaluate the cost-effectiveness and monetary benefit of dabigatran vs VKAs in Dutch patients with non-valvular AF. Value-based pricing considerations and corresponding negotiations on dabigatran will be explicitly considered. METHODS: The base case economic analysis was conducted from the societal perspective. Health effects and costs were analysed using a Markov model. The main model inputs were derived from the RE-LY trial and Dutch observational data. Univariate, probabilistic sensitivity, and various scenario analyses were performed. RESULTS: Dabigatran was cost saving compared to VKAs. A total of 4,552 QALYs were gained, and €13,892,288 was saved in a cohort of 10,000 AF patients. The economic value of dabigatran was strongly related to the costs of VKA control that are averted. Notably, dabigatran was cost saving compared to VKAs if annual costs of VKA control exceeded €159 per person, or dabigatran costs were below €2.81 per day. CONCLUSION: Dabigatran was cost saving compared to VKAs for the prevention of atrial thromboembolism in patients with non-valvular AF in the Netherlands. This result appeared robust in the sensitivity analysis. Furthermore, volume based reduction of the price in the Netherlands will further increase the monetary benefits of dabigatran.

Extended Treatment with Apixaban for Venous Thromboembolism Prevention in the Netherlands: Clinical and Economic Effects.

Background Dutch guidelines advise extended anticoagulant treatment with direct oral anticoagulants or vitamin K antagonists for patients with idiopathic venous thromboembolism (VTE) who do not have high bleeding risk. Objectives The aim of this study was to analyze the economic effects of extended treatment of apixaban in the Netherlands, based on an updated and adapted previously published model. Methods We performed a cost-effectiveness analysis simulating a population of 1,000 VTE patients. The base-case analysis compared extended apixaban treatment to no treatment after the first 6 months. Five additional scenarios were conducted to evaluate the effect of different bleeding risks and health care payers' perspective. The primary outcome of the model is the incremental cost-effectiveness ratio (ICER) in costs (€) per quality-adjusted life-year (QALY), with one QALY defined as 1 year in perfect health. To account for any influence of the uncertainties in the model, probabilistic and univariate sensitivity analyses were conducted. The treatment was considered cost-effective with an ICER less than €20,000/QALY, which is the most commonly used willingness-to-pay (WTP) threshold for preventive drugs in the Netherlands. Results The model showed a reduction in recurrent VTE and no increase in major bleeding events for extended treatment in all scenarios. The base-case analysis showed an ICER of €9,653/QALY. The probability of being cost-effective for apixaban in the base-case was 70.0% and 91.4% at a WTP threshold of €20,000/QALY and €50,000/QALY, respectively. Conclusion Extended treatment with apixaban is cost-effective for the prevention of recurrent VTE in Dutch patients.

Oxidative stress-dependent contribution of HMGB1 to the interplay between apoptosis and autophagy in diabetic rat liver

The progression of oxidative stress, resulting cell damage, and cell death underlies the etiology of liver damage/dysfunction as a complication of diabetes. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and signaling pathways regulating cell death and cell survival. We previously found that in streptozotocin (STZ)-induced diabetic rats, reduction of oxidative stress after melatonin administration lowered necrotic cell death and increased expression of HMGB1 and hepatocellular damage. In the present study, we examined whether alleviation of diabetes-attendant oxidative stress and ensuing change in HMGB1 expression influence the dynamic equilibrium between apoptosis/autophagy and liver damage. We observed that elevated HMGB1 protein levels in diabetic rat liver accompanied increased interactions of HMGB1 with TLR4 and RAGE, and activation of the intrinsic apoptotic pathway and Beclin 1-dependent autophagy. The absence of p62 degradation in diabetic rat liver pointed to defective autophagy which was responsible for lower autophagosome/autophagolyso some formation and an increased apoptosis/autophagy ratio. Compared to diabetic rats, in melatonin-treated diabetic rats, the structure of liver cells was preserved, HMGB1/TLR4 interaction and downstream apoptotic signaling were significantly reduced, HMGB1/Beclin 1 colocalization and interactions were augmented and Beclin 1-mediated autophagy, mithophagy in particular, were increased. We concluded that in mild oxidative stress, HMGB1 is cytoprotective, whereas in intense oxidative stress, HMGB1 actions promote cell death and liver damage. Since reduced HMGB1 binds to RAGE but not to TLR4, redox modification of HMGB1 as a mechanism regulating the cross-talk between apoptosis and autophagy in diabetes is discussed