Academic literature on the topic 'Tošev'

Let N denote a sufficiently large integer satisfying N ≡ 4 (mod 24), and Pr denote an almost-prime with at most r prime factors, counted according to multiplicity. In this paper, we proved that the equation [Formula: see text] is solvable in one prime and three P42, or in four P13. These results constitute improvements upon that of Heath-Brown and Tolev.

We consider and studyBlaschke inductive limit algebrasA(b), defined as inductive limits of disc algebrasA(D)linked by a sequenceb={Bk}k=1∞of finite Blaschke products. It is well known that bigG-disc algebrasAGover compact abelian groupsGwith ordered dualsΓ=Gˆ⊂ℚcan be expressed as Blaschke inductive limit algebras. Any Blaschke inductive limit algebraA(b)is a maximal and Dirichlet uniform algebra. Its Shilov boundary∂A(b)is a compact abelian group with dual group that is a subgroup ofℚ. It is shown that a bigG-disc algebraAGover a groupGwith ordered dualGˆ⊂ℝis a Blaschke inductive limit algebra if and only ifGˆ⊂ℚ. The local structure of the maximal ideal space and the set of one-point Gleason parts of a Blaschke inductive limit algebra differ drastically from the ones of a bigG-disc algebra. These differences are utilized to construct examples of Blaschke inductive limit algebras that are not bigG-disc algebras. A necessary and sufficient condition for a Blaschke inductive limit algebra to be isometrically isomorphic to a bigG-disc algebra is found. We consider also inductive limitsH∞(I)of algebrasH∞, linked by a sequenceI={Ik}k=1∞of inner functions, and prove a version of the corona theorem with estimates for it. The algebraH∞(I)generalizes the algebra of bounded hyper-analytic functions on an open bigG-disc, introduced previously by Tonev.

ABSTRACTExtracellular vesicles (EVs) produced by a sulfur-reducing, hyperthermophilic archaeon, “Thermococcus onnurineus” NA1T, were purified and characterized. A maximum of four EV bands, showing buoyant densities between 1.1899 and 1.2828 g cm−3, were observed after CsCl ultracentrifugation. The two major EV bands, B (buoyant density at 25°C [ρ25] = 1.2434 g cm−3) and C (ρ25= 1.2648 g cm−3), were separately purified and counted using a qNano particle analyzer. These EVs, showing different buoyant densities, were identically spherical in shape, and their sizes varied from 80 to 210 nm in diameter, with 120- and 190-nm sizes predominant. The average size of DNA packaged into EVs was about 14 kb. The DNA of the EVs in band C was sequenced and assembled. Mapping of theT. onnurineusNA1TEV (ToEV) DNA sequences onto the reference genome of the parent archaeon revealed that most genes ofT. onnurineusNA1Twere packaged into EVs, except for an ∼9.4-kb region from TON_0536 to TON_0544. The absence of this specific region of the genome in the EVs was confirmed from band B of the same culture and from bands B and C purified from a different batch culture. The presence of the 3′-terminal sequence and the absence of the 5′-terminal sequence of TON_0536 were repeatedly confirmed. On the basis of these results, we hypothesize that the unpackaged part of theT. onnurineusNA1Tgenome might be related to the process that delivers DNA into ToEVs and/or the mechanism generating the ToEVs themselves.

Abstract Background: Nilotinib and dasatinib are common second-line therapy for patients with Ph+ CML-CP who are resistant or intolerant to imatinib. Since their approval, several CEAs comparing second-line nilotinib vs dasatinib have been published (Rogers et al., Health Technol Assess 2012; 16(22); Loveman et al., Health Technol Assess 2012; 16(23)). However, these models were developed in the absence of any comparative effectiveness evidence between the two drugs. Another major limitation of these models as recognized by a leading health technology assessment (HTA) agency was the use of surrogate markers to impute survival endpoints (e.g., progression-free survival [PFS] and overall survival [OS]). As direct comparative evidence of the two drugs based on real-world data become available, this study was conducted to address these limitations and re-evaluate the cost-effectiveness of second-line nilotinib vs dasatinib for Ph+ CML-CP using real-world comparative PFS and OS data from a third-party payer perspective in the U.S. Methods: A lifetime partitioned survival model was developed to compare healthcare costs, life years (LYs) and quality-adjusted life years (QALYs) associated with second-line therapy with nilotinib vs dasatinib in patients with Ph+ CML-CP who were resistant or intolerant to first-line imatinib. The model included four health states: CP on second-line treatment (CP on treatment), CP post-discontinuation of second-line treatment (CP post-discontinuation), accelerated phase or blast crisis (progressive disease), and death. Patients can only transition into a subsequent health state but not in the other direction; patients in the first three health states can all transition to death. Time on treatment (TOT), PFS, and OS for second-line nilotinib and dasatinib were estimated using data from a real-world comparative effectiveness study (Griffin et al., Curr Med Res Opin 2013; 29(6):623-31). Parametric survival models were used to extrapolate outcomes beyond the study period. Drug treatment costs, medical costs, and adverse event (AE) costs were obtained from literature and publicly available databases. Utilities for health states were derived from literature. Costs, LYs, and QALYs were discounted at 3% per annum. Incremental cost-effectiveness ratios (ICERs), including incremental cost per LY gained and incremental cost per QALY gained, were estimated comparing nilotinib vs dasatinib. Deterministic sensitivity analyses (DSAs) were performed by varying starting age, sex-ratio, adherence level of second-line therapies, drug treatment costs for post-second-line states, medical costs for all health states, AE costs, and utility for CP post-discontinuation. Results: Over life time, initiating second-line treatment with nilotinib was associated with 11.69 LYs, 9.13 QALYs, and total costs of $1,406,265; initiating second-line with dasatinib was associated with 9.51 LYs, 7.30 QALYs, and total costs of $1,418,235. Second-line nilotinib was associated with better health outcomes (difference in LY = 2.18 years, difference in QALY = 1.84 years) and lower costs (difference in total cost = $11,970) relative to dasatinib. DSA results similarly showed better outcomes and lower costs for nilotinib vs dasatinib based on variations of sex-ratio, progressive disease treatment costs, medical costs for all health states, AE costs, and utility for CP post-discontinuation; DSA results also showed better outcomes but higher costs for nilotinib vs dasatinib based on variations of starting age, adherence to second-line therapies, and CP post-discontinuation treatment cost with ICERs of $10,738/QALY, $2,648/QALY, and $2,318/QALY, respectively.Table 1.Base Case ResultsNilotinibDasatinibNilotinib vs DasatinibCosts (2015 USD)Treatment costs$1,235,535$1,253,081-$17,546Medical costs$162,326$156,762$5,564AE costs$8,404$8,392$11Total costs$1,406,265$1,418,235-$11,970EffectivenessTotal LYs11.699.512.18Total QALYs9.137.301.84ICERIncremental cost per LY gainedBetter LY with lower costsIncremental cost per QALY gainedBetter QALY with lower costs Conclusions: The CEA based on real-world comparative evidence suggests that second-line nilotinib is associated with better life expectancy, quality of life, and lower cost when compared with dasatinib, among patients with Ph+ CML-CP who are resistant or intolerant to imatinib. Disclosures Li: Novartis Pharmaceuticals Corporation: Consultancy, Other: Nanxin Li is an employee of Analysis Group Inc, which has received consultancy fees from Novartis Pharmaceuticals Corporation; AbbVie Inc., Astellas Pharma US Inc., Bayer Healthcare Pharmaceuticals LLC, Bristol-Myers Squibb Company, Celgene Corporation, Forest Laboratories Inc., Sanofi: Consultancy, Other: Nanxin Li is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Yang:Astellas Pharma US, Inc.: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Astellas Pharma US, Inc.; Bristol-Myers Squibb Company: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Bristol-Myers Squibb Company; Forest Laboratories, Inc.: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Forest Laboratories, Inc.; Sanofi: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Sanofi; AbbVie Inc.: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Abbvie Inc.; Shire Pharmaceuticals Inc.: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Shire Pharmaceuticals Inc.; GE Healthcare: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from GE Healthcare; Millennium Pharmaceuticals, Inc.: Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation: Consultancy, Other: Chelsey Yang is an employee of Analysis Group Inc, which has received consultancy fees from Novartis Pharmaceuticals Corporation. Fan:Novartis Pharmaceuticals Corporation: Consultancy, Other: Liangyi Fan is an employee of Analysis Group Inc, which has received consultancy fees from Novartis Pharmaceuticals Corporation; AbbVie Inc, Astellas Pharma US Inc, Bristol-Myers Squibb Co, Ethicon Inc, Forest Labs Inc, GE Healthcare, Genentech Inc, MedImmune LLC, Millennium Pharmaceuticals Inc, Sanofi, Shire Pharmaceuticals Inc, Takeda Pharmaceuticals Inc, Teva Specialty Brands: Consultancy, Other: Liangyi Fan is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Totev:Novartis Pharmaceuticals Corporation: Consultancy, Other: Todor Totev is an employee of Analysis Group Inc, which has received consultancy fees from Novartis Pharmaceuticals Corporation; AbbVie Inc., Astellas Pharma US Inc., Bayer Healthcare Pharmaceuticals LLC, Biogen Idec Inc., Boehringer Ingelheim, Bristol-Myers Squibb Company, Cleveland HeartLab Inc., Eli Lilly & Company, Forest Laboratories Inc., Gilead Sciences Inc., GlaxoSmithKline: Consultancy, Other: Todor Totev is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Janssen Scientific Affairs LLC, Sanofi, Shire Pharmaceuticals Inc, UCB Inc, Vertex Pharmaceuticals Inc: Consultancy, Other: Todor Totev is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Guerin:Pfizer Canada, Inc.,RX&D, Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc.,Takeda Global Research & Development Center, Inc., Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; GlaxoSmithKline, Janssen Scientific Affairs, Janssen-Ortho, Inc., Merck & Co., Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ogilvy Renault, Ortho-Clinical Diagnostics, Inc., Otsuka America Pharmaceutical, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; AbbVie Inc., Alcon Laboratories, Bayer Healthcare Pharmaceuticals, LLC, Celgene Corporation, Cempra Inc., Centocor Ortho Biotech, Cooley LLP, Cyberonics, Inc., DLA Piper, Eli Lilly & Company, Forest Laboratories, Inc., Genentech, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Chen:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership, Other: Lei Chen is an employee of and owns stocks/options of Novartis Pharmaceuticals Corporation, the sponsor of this study.

Abstract Background: Aplastic anemia (AA) is a rare disease, with an incidence of 1-2 new cases per million per year in Europe and North America. Primary therapies for AA for patients who do not have a sibling or matched unrelated donor or are unfit for allogeneic hematopoietic stem cell transplantation (HSCT) include immunosuppressive therapy (IST) with the combination of antithymocyte globulin (ATG) and calcineurin inhibitors. Therapeutic options beyond IST are limited and include eltrombopag, which was approved by the US FDA for use in patients with severe AA who fail to respond adequately to IST. The health economic burden of this rare and debilitating condition is poorly understood, especially for refractory cases. Objective: To examine health resource utilization associated with severe AA among patients with insufficient response to IST in real-world practice settings in a recent time period. Methods: We conducted a retrospective, longitudinal chart review of patients with severe AA treated at clinical centers in the US (Dana-Farber Cancer Institute [DFCI]) and France (Service d'Hématologie Greffe, Hôpital Saint-Louis [AGRAH]). Severe AA in this study was identified as having bone marrow cellularity <25%, or 25-50% with <30% residual hematopoietic cells; and at least two of the following laboratory findings: neutrophil count <500 cell/µL, platelets <20,000/µL, reticulocyte count <20,000/µL. Eligible patients were ≥18 years old, first diagnosed with severe AA between January 1, 2006 and January 31, 2016, had insufficient response to at least one course of IST following severe AA diagnosis, and had ≥12 months of medical data after first diagnosis with severe AA. Patients with congenital disorders of hematopoiesis were excluded. Kaplan-Meier method was used to analyze time from first IST to time of HSCT. Cumulative incidence and incidence rates were used to summarize frequency of blood transfusions and AA-related health care resource utilization. The study was approved by local IRB. Results: The study included 34 refractory severe AA patients (NDFCI=20; NAGRAH =14). Mean age at severe AA diagnosis was 43.3 (standard deviation [SD]: 16.8) years and 52.9% (18/34) of patients were women. Median follow-up time after severe AA diagnosis was 56.1 (range: 12.0-118.7) months. Thirty-three (97.1%) patients received ATG in combination with calcineurin inhibitor (cyclosporine or tacrolimus) with or without corticosteroid as primary therapy. Among patients treated with ATG, 51.5% (17/33) patients received only one course of ATG and 48.5% (16/33) patients received ≥2 courses of ATG. The most common secondary AA therapy included eltrombopag (17.6%, N=6) and androgens (8.8%, N=3). The median treatment duration for eltrombopag was 6.4 (range: 5.6-53.4) months. The average frequency of transfusions per patient per month was 2.8 (SD: 2.8) red blood cell (RBC) and 3.3 (SD: 3.5) platelet transfusions. The mean AA-related health care utilization rates per patient per year were 0.8 (95% confidence interval [CI]: 0.6, 1.0) for inpatient visits, 0.5 (95% CI: 0.4, 0.8) for emergency room visits, and 19.1 (95% CI: 17.9, 20.5) for office visits prior to undergoing HSCT. Among the subgroup of patients treated with eltrombopag, the mean number of RBC transfusions per patient per month was reduced from 2.4 (SD: 2.0) before to 0.9 (SD: 0.8) after eltrombopag treatment, and from 3.0 (SD: 2.3) to 1.3 (SD: 1.6) for platelet transfusions. Similarly, AA-related health care utilization rates were lower after eltrombopag initiation (∆inpatient visits: -0.3 (95% CI: -1.1, 0.5); ∆emergency room visits: -0.6 (95% CI: -1.5, 0.4); ∆office visits: -11.7 (95% CI: -16.2, -7.1) per patient per year). Thirty (88.2%) patients received HSCT with a median time of 12.9 (95% CI: 7.9, 17.3) months after first IST initiation. During the follow-up period, 29.4% (10/34) patients died; nine patients died after HSCT. Two (5.9%) patients transformed to myelodysplastic syndrome and/or acute myeloid leukemia. Conclusion: This is one of the first studies to quantify the transfusion and health resource burden of refractory severe AA. In a small subgroup of patients receiving eltrombopag, there was a trend toward reduction in blood transfusion frequency, AA-related hospitalization rate, and outpatient office and emergency room visits after eltrombopag initiation. Disclosures Peffault De Latour: Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Huynh: Novartis Pharmaceuticals Corporation: Research Funding. Ivanova: Novartis, GSK, Teva, Lilly: Research Funding. Totev: Novartis Pharmaceuticals Corporation, Shire Pharmaceuticals Inc.: Research Funding. Bilginsoy: Novartis Pharmaceuticals Corporation: Research Funding. Roy: Novartis: Employment, Equity Ownership. Duh: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Abstract We study some counting questions concerning products of positive integers $u_1, \ldots , u_n$, which form a nonzero perfect square, or more generally, a perfect $k$-th power. We obtain an asymptotic formula for the number of such integers of bounded size and in particular improve and generalize a result of D. I. Tolev (2011). We also use similar ideas to count the discriminants of number fields that are multiquadratic extensions of ${\mathbb{Q}}$ and improve and generalize a result of N. Rome (2017).