Strategy for Launching Product "A" in the Czech and Slovak Marketplaces

Cílem této práce je vypracovat strategii vstupu produktu "A" farmaceutické společnosti "F" na český a slovenský trh. V této práci je tato strategie analyzována a hodnocena pomocí metody NPV (Net Present Value) a dalších metod. Na základě tohoto hodnocení je strategie vybrána. První kapitola zahrnuje teoretická východiska jednotlivých metod použitých pro účely této práce. Je zde zejména osvětlena metoda NPV a metody vhodné pro analýzu relevantních trhů, společnosti "F" produktu "A". Ve druhé kapitole je provedena analýza trhu České a Slovenské republiky a také analýza společnosti "F" a produktu "A". Tyto analýzy zahrnují jak vnitřní tak vnější potenciál společnosti i produktu. V závěrečné kapitole je vypracována navrhovaná strategie vstupu pro produkt 'A', jež je poté ekonomicky hodnoceny pomocí modelu NPV a dalších modelů.The purpose of this dissertation is to elaborate a specific market entry strategy of a product "A" manufactured by company "F". This market entry strategy is then analysed and evaluated by NPV (Net Present Value) method and others. Based on this evaluation the strategy is then selected. The first chapter covers theoretical and methodological background of methods used for the purpose of this paper. Mostly the NPV method is introduced followed by methods suitable for relevant markets, company "F" and its product "A" analysis. In the second chapter the Czech and Slovak market analyses are elaborated accompanied by the analysis of company "F" and its product "A". These cover both the internal and external potential of the company and its product. The last chapter analyses the elaborated market entry strategy of a product "A" accompanied by the economic evaluation using the NPV method and other methods.

Cardiac papillary fibroelastomas: A 10-year single-center surgical experience and long-term echocardiographic follow-up study

Aims. Limited contemporary data are available on the clinical and echocardiographic outcomes after surgery for cardiac papillary fibroelastoma (CPF). The aim of this study was to review the clinical manifestations, pathological characteristics, surgical management, and prognoses of patients with histologically verified CPF, who underwent surgery at our cardiac surgery center from 2008 to 2018. Methods and Results. Twelve patients of median age 62 years (28 to 77 years) were treated. Embolic stroke or transient ischemic attack (five patients, 42%) were the only CPF clinical manifestations. Eleven (92%) tumors were localized on the valves, with the aortic valve being the most common tumor site (seven patients; 58%). Multiple factor analysis revealed no independent predictor of CPF-related embolization. Simple shave tumor excision was sufficient in most patients (10 patients, 83%). No operative or tumor-related late mortality during the median follow-up period of 4.7 years (1.1 to 10.2 years) was recorded. Asymptomatic metachronous valve tumor recurrence (in a location different from that of the original tumor) was revealed in two patients (17%) by transesophageal echocardiography (TEE), not detected by transthoracic echocardiography (TTE). One of these two patients underwent repeated surgery for CPF but later suffered a recurrent embolic stroke, due to another tumor recurrence. Conclusion. CPF can be safely and effectively treated surgically. TEE is superior to the TTE option in CPF post-operative recurrence detection. There is a clear need for a prospective study to determine criteria for embolization risk stratification and optimum management in patients with CPF.Web of Science1641918

In vitro pharmacoregulation of CC chemokine ligand 5 and its receptor CCR5 in diffuse lung diseases.

BACKGROUND: CC chemokine ligand (CCL)5 and its receptor CCR5 contribute to leukocyte migration into lungs of patients with diffuse lung diseases (DLD). Pharmacological regulation of CCL5 and CCR5 expression was therefore explored in bronchoalveolar cells obtained from patients with DLD. METHODS: Cells from 21 patients were co-cultivated in vitro with tumour necrosis factor-alpha and dexamethasone, cyclosporin A (CyA) or pentoxifylline. Chemokine mRNA expression and protein production was assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Dexamethasone altered CCL5 mRNA expression and suppressed its protein levels. CyA inhibited chemokine mRNA expression but not protein production. Pentoxifylline did not affected chemokine expression. Both dexamethasone and CyA suppressed CCR5 mRNA transcripts. CONCLUSION: In conclusion, while dexamethasone downregulates the CCL5 functional form, CyA and pentoxifylline have no effects on CCL5 protein. These data provide in vitro correlation for clinical applications of immunomodulators in therapy of DLD

PSMB2 and RPL32 are suitable denominators to normalize gene expression profiles in bronchoalveolar cells

<p>Abstract</p> <p>Background</p> <p>For accuracy of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), normalisation with suitable reference genes is required. To date, no reference genes have been validated for expression studies of bronchoalveolar (BAL) cells. The aims of this study were to identify gene(s) with stable mRNA expression in BAL cells irrespective of gender, smoking, BAL cellular composition, lung pathology, treatment; and to assess the influence of reference genes on target gene expression data.</p> <p>Results</p> <p>The mRNA expression of ten housekeeping genes (ACTB, ARF1, CANX, G6PD, GAPDH, GPS1, GNB2L1, PSMB2, PSMD2, RPL32) was investigated by qRT-PCR in BAL cells from 71 subjects across a spectrum of lung diseases. The analyses were validated in an independent BAL cohort from 63 sarcoidosis patients and 17 control subjects. A second derivative method was used to calculate expression values (CTt); an equivalence test, applets BestKeeper, geNorm and NormFinder were applied to investigate gene expression stability. Of the investigated genes, PSMB2 (CTt ± SD, 23.66 ± 0.86) and RPL32 (18.65 ± 0.92) were the most stable; both were constantly expressed in BAL samples from parallel investigated cohorts irrespective of evaluated variables. Finally, to demonstrate effect of traditional (ACTB/GAPDH) and novel (PSMB2/RPL32) reference genes as denominators, expression of two cytokines known associated with sarcoidosis was investigated in sarcoid BAL cells. While normalization with PSMB2/RPL32 resulted in elevated IFNG mRNA expression (<it>p </it>= 0.004); no change was observed using GAPDH/ACTB (<it>p </it>> 0.05). CCL2 mRNA up-regulation was observed only when PSMB2/RPL32 were used as denominators (<it>p </it>< 0.03).</p> <p>Conclusion</p> <p>PSMB2 and RPL32 are, therefore, suitable reference genes to normalize qRT-PCR in BAL cells in sarcoidosis, and other interstitial lung disease.</p

Side by Side Battery Technologies with Lithium‐Ion Based Batteries

In recent years, the electrochemical power sources community has launched massive research programs, conferences, and workshops on the “post Li battery era.” However, in this report it is shown that the quest for post Li‐ion and Li battery technologies is incorrect in its essence. This is the outcome of a three day discussion on the future technologies that could provide an answer to a question that many ask these days: Which are the technologies that can be regarded as alternative to Li‐ion batteries? The answer to this question is a rather surprising one: Li‐ion battery technology will be here for many years to come, and therefore the use of “post Li‐ion” battery technologies would be misleading. However, there are applications with needs for which Li‐ion batteries will not be able to provide complete technological solutions, as well as lower cost and sustainability. In these specific cases, other battery technologies will play a key role. Here, the term “side‐by‐side technologies” is coined alongside a discussion of its meaning. The progress report does not cover the topic of Li‐metal battery technologies, but covers the technologies of sodium‐ion, multivalent, metal–air, and flow batteries

Effect of Spatial Charge Inhomogeneity on 1/f Noise Behavior in Graphene

Scattering mechanisms in graphene are critical to understanding the limits of signal-to-noise-ratios of unsuspended graphene devices. Here we present the four-probe low frequency noise (1/f) characteristics in back-gated single layer graphene (SLG) and bilayer graphene (BLG) samples. Contrary to the expected noise increase with the resistance, the noise for SLG decreases near the Dirac point, possibly due to the effects of the spatial charge inhomogeneity. For BLG, a similar noise reduction near the Dirac point is observed, but with a different gate dependence of its noise behavior. Some possible reasons for the different noise behavior between SLG and BLG are discussed.Comment: 28 pages, 3 figures + 3 supplement figure

SNP Variants in Major Histocompatibility Complex Are Associate with Sarcoidosis Susceptibility - A Joint Analysis in Four European Populations

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Lofgren's syndrome. In a joint analysis, seven SNPs were associated with non-Lofgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E-07, OR = 1.9) and eight with Lofgren's syndrome [ Lofgren syndrome (LS); the strongest association with rs3129843, P = 3.44E-12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P <0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.Peer reviewe

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from &lt;1x10-3 to &lt;1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

ARIA 2016 : Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.Peer reviewe