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Christopher Hillis,1 Kathryn E Flynn,2 Erinn Hoag Goldman,3 Tracy S Moreira-Lucas,4 Josie Visentini,4 Stephanie Dorman,4 Rachel Ballinger,5 Hilary F Byrnes,6 Andrea De Palma,7 Valentin Barbier,8 Lisa Machado,9 Ehab Atallah2 1Department of Oncology, McMaster University, Hamilton, Canada; 2Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 3US Medical Affairs, Pfizer Inc, New York, NY, USA; 4Medical Affairs, Pfizer Canada Inc., Kirkland, Quebec, Canada; 5Patient Centred Outcomes (PCO), ICON Clinical Research Inc., Reading, UK; 6Patient Centred Outcomes (PCO), ICON Clinical Research Inc., Blue Bell, PA, USA; 7Patient Centred Outcomes (PCO), ICON Clinical Research Inc., Milan, Italy; 8Patient Centred Outcomes (PCO), ICON Clinical Research Inc., Lyon, France; 9The Canadian CML Network, Toronto, Ontario, CanadaCorrespondence: Andrea De Palma, Tel +39 06 45 20 8037, Email Andrea.DePalma@iconplc.comPurpose: With treatment, chronic myeloid leukemia (CML) has a favorable prognosis, however, individuals with CML experience impairment to their quality of life (QoL). The aim of this study was to examine the perspectives and experiences of individuals with CML and to understand their challenges communicating with their CML physician.Patients and Methods: An online survey in adults with CML (n=100) in the US and Canada assessed QoL, patient-provider relationships, treatment satisfaction, and understanding of CML and treatment goals via the MD Anderson Symptom Inventory, the Cancer Therapy Satisfaction Questionnaire and de novo survey questions. Participants were recruited via an external patient recruiter and CML Patient Groups.Results: Many participants reported hardships due to CML and its treatment. The main impacts were on the ability to work (21%), engage in personal activities (e.g., hobbies, 28%), and to enjoy sexual relations (median=2.00, IQR=8.50). A substantial proportion (21– 39%) wished to discuss additional topics with their providers (e.g., management of CML and/or its impacts). While participants reported satisfaction with therapy overall (median=85.71, IQR=17.86), they indicated low to moderate treatment satisfaction with specific components, including concerns regarding side effects (median=43.75, IQR=43.75). Participants generally had a good understanding of CML (97%) and its treatment goals (92%).Conclusion: These findings advance our understanding of issues that need improvement to support QoL for individuals living with CML. Future work is needed to improve patient-provider relationships, address treatment-related side effects, and provide clinical information that is easier for patients to understand.Keywords: chronic myeloid leukemia, quality of life, patient-health care provider relationship, patient experience, survey, North America

Srdan Verstovsek,1 Jason Gotlib,2 Vikas Gupta,3 Ehab Atallah,4 John Mascarenhas,5 Alfonso Quintas-Cardama,1 William Sun,6 Nicholas J Sarlis,6 Victor Sandor,6 Richard S Levy,6 Hagop M Kantarjian,1 Ruben A Mesa71University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Stanford Cancer Institute, Stanford, CA, USA; 3Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; 4Medical College of Wisconsin, Milwaukee, WI, USA; 5Mount Sinai School of Medicine, New York, NY, USA; 6Incyte Corporation, Wilmington, DE, USA; 7Mayo Clinic, Scottsdale, AZ, USAPurpose: Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate- or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with Oral JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.Patients and methods: COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 109/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100–200 × 109/L and >200 × 109/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).Results: The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8–12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.Conclusion: This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.Keywords: COMFORT-I, dose titration, JAK2 inhibitor, myelofibrosis, ruxolitinib, treatment-related cytopenias

This paper introduces a new numerical technique that utilizes the Chebyshev collocation method to solve the nonlinear SIR mathematical model for dengue disease dynamics. The main goal of this study is the development of a highly accurate and efficient numerical approach that allows for the simulation of dengue fever infection and transmission mechanisms. The suggested methodology provides a strong and adaptable tool for studying the intricate dynamics of dengue fever, which is essential for improving our comprehension and control of this significant public health problem. The numerical approach is totally programmable and can be customized to incorporate a user-friendly interface for data input, hence enhancing its accessibility and practicality for researchers and public health practitioners. The conducted numerical simulations provide evidence of the accuracy and computational efficiency of the suggested technique. This unique numerical framework is positioned as a standard for managing and regulating a diverse array of biological problems. The creation of this sophisticated numerical tool signifies significant progress in the realm of dengue fever modeling. It offers a versatile and dependable platform to investigate different epidemiological scenarios and assess the possible effects of intervention efforts. The results of this study have significant consequences for enhancing dengue monitoring, safeguarding, and control initiatives in areas where the disease is prevalent.

This research paper presents a numerical investigation of Troesch’s problem using the collocation method based on the cubic trigonometric B-Spline technique. Troesch’s problem is a well-known BVP that arises in the field of mathematical physics and engineering. The objective of this study is to provide an accurate and efficient numerical solution to Troesch’s problem. Our method utilizes the properties of cubic trigonometric B-splines with collocation technique to approximate the solution of Troesch’s problem. The method is employed to satisfy the boundary conditions, resulting in a system of algebraic equations. A comprehensive error analysis is conducted to assess the accuracy and convergence of the proposed scheme. The obtained numerical results are compared with the exact solution, where available, and with other existing numerical methods to validate the accuracy and efficiency of the proposed technique. The significance and relevance of this work lie in its ability to provide highly accurate solutions to Troesch’s problem. Furthermore, the proposed method exhibits good convergence properties and demonstrates superiority over other numerical techniques in terms of accuracy and efficiency. These findings have practical implications in the field of mathematical physics and engineering, where precise solutions to Troesch’s problem can greatly enhance the understanding and optimization of various systems.

We propose a new method for constructing an approximate solution of the two-dimensional Laplace equation in an arbitrary doubly connected domain with smooth boundaries for Dirichlet boundary conditions. Using the fact that the solution of the Dirichlet problem in a doubly connected domain is represented as the sum of a solution of the Schwarz problem and a logarithmic function, we reduce the solution of the Schwartz problem to the Fredholm integral equation with respect to the boundary value of the conjugate harmonic function. The solution of the integral equation in its turn is reduced to solving a linear system with respect to the Fourier coefficients of the truncated expansion of the boundary value of the conjugate harmonic function. The unknown coefficient of the logarithmic component of the solution of the Dirichlet problem is determined from the following fact. The Cauchy integral over the boundary of the domain with a density that is the boundary value of the analytical in this domain function vanishes at points outside the domain. The resulting solution of the Dirichlet problem is the sum of the real part of the Cauchy integral in the given domain and the logarithmic function. In order to avoid singularities of the Cauchy integral at points near the boundary, the solution at these points is replaced by a linear function. The resulting numerical solution is continuous in the domain up to the boundaries. Three examples of the solution of the Dirichlet problem are given: one example demonstrates the solution with constant boundary conditions in the domain with a complicated boundary; the other examples provide a comparison of the approximate solution with the known exact solution in a noncircular domain.

Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.