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Moniba Nazeef,1,2 John P Sheehan1,2 1Department of Medicine, Division of Hematology/Oncology, 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the emerging FIX products possessing extended half-lives, and novel “rebalancing” approaches to hemophilia therapy. Keywords: hemophilia B, factor IX, bleeding disorders, plasma half-life, therapy

A convenient and metal-free synthesis of vinyloxyimidazopyridine derivatives has been attained via BF 3 .OEt 2 promoted one-pot multicomponent approach. This procedure involves a facile coupling of 2-aminopyridine derivatives with arylglyoxal and alkyne derivatives. BF 3 .OEt 2 complexation has successfully catalyzed the reaction at room temperature. Utilization of transition metal-free catalyst, mild reaction conditions, easy handling and operational simplicity are key features of developed process., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A new metal-free approach to construct medicinally valuable 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles under visible light irradiation in aqueous ethanol medium at room temperature has been developed. The present process was performed with 1,2-phenylenediamines, aromatic aldehydes and 2-mercaptoacetic acid utilizing a simple household 22 W compact fluorescent lamp to generate C-S, C-N bonds through radical intermediates. This visible-light-promoted synthesis provides lower cost, operation simplicity and high functional groups tolerating ability with short reaction time and high yield under mild reaction conditions., (© 2020. Springer Nature Switzerland AG.)

Objectives: Microvascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis., Design: Retrospective observational cohort study., Setting: Single-center academic medical center., Patients: Ten patients with polymerase chain reaction-confirmed coronavirus disease 2019 disease complicated by acute respiratory distress syndrome., Interventions: Measurement of thromboelastography ( n = 10) and thrombolysis with alteplase ( n = 4)., Measurements and Main Results: Hypercoagulability and decreased or absent fibrinolysis were demonstrated by thromboelastography. Thrombocytopenia and hypofibrinogenemia were not observed, while seven of 10 patients had elevated d-dimer values. For patients who received thrombolytic therapy, repeat thromboelastography demonstrated improvements in coagulation index and lysis at 30 minutes reflecting reduced hypercoagulability and increased fibrinolysis. One major bleeding complication was detected following thrombolysis. Eight of 10 patients survived and were successfully extubated, and six of 10 have since been discharged., Conclusions: In coronavirus disease 2019 patients with acute respiratory distress syndrome in whom thromboelastography was performed, hypercoagulability and impaired fibrinolysis were observed. In the context of autopsy studies demonstrating pulmonary microvascular thromboses in coronavirus disease 2019 patients, noninvasive detection of hypercoagulability and deficient fibrinolysis in coronavirus disease 2019 acute respiratory distress syndrome using thromboelastography could improve understanding and management of coronavirus disease 2019., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Opinion Statement: Mantle cell lymphoma is a distinct subtype of non-Hodgkin's lymphoma, which has historically been associated with a poor prognosis. It is now recognized as a heterogeneous disease with variable biologic and clinical behavior. Treatment paradigms have evolved along two lines. Younger, fit mantle cell lymphoma (MCL) patients are generally treated with intensive strategies and older less fit patients with non-intensive strategies. Most of the published literature has focused on intensive strategies, which appear to result in more durable remissions, but with an unclear impact on overall survival. The literature is more sparse for the roughly 50% of patients who are not candidates for intensive strategies, and no "standard" approach has been established for this patient population. However, clues are emerging. Randomized clinical trials have (a) established that bendamustine-rituximab (BR) is more efficacious and less toxic than rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); (b) established that bortezomib should replace vincristine if using an R-CHOP backbone; and (c) established that maintenance rituximab (MR) is beneficial after an R-CHOP induction. In our opinion, it is reasonable to extrapolate the data supporting MR after R-CHOP and apply MR after a BR induction. In our practice, we recommend BR followed by MR for 2 years to MCL patients not eligible for intensive therapy. An ongoing US intergroup trial is testing the addition of bortezomib to the BR backbone and the addition of lenalidomide to MR. This trial may establish a standard of care in the older MCL population. In addition, exciting options for relapsed MCL have emerged in the last few years, with the introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the development of the lenalidomide-rituximab combination. In this article, we will discuss the current available options for these older MCL patients and the evidence supporting those options.