Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

Joint bleeds in mild hemophilia: Prevalence and clinical characteristics.

INTRODUCTION: Joint bleeds are a common and frequent complication associated with hemophilia, increasing the risk of hemophilic arthropathy. It is important to define and characterize the presence of joint complications in mild hemophilia to develop strategies to mitigate disease burden. AIMS: To characterize the prevalence, clinical characteristics of joint bleeds, and risk factors that may lead to hemarthrosis in people with mild hemophilia. METHODS: Following Institutional Review Board approval, a retrospective chart review was conducted for patients with mild hemophilia seen at the Yale Hemophilia Treatment Center or Classical Hematology Program. RESULTS: The medical records of 70 patients were reviewed. Eighty one percent were male and 19 percent were female. Twenty individuals with mild hemophilia had a history of joint bleeding, 13 were traumatic bleeds, 7 were spontaneous. The age of first joint bleed ranged from 4 to 58 years old, with an average age of 20.8-years old. Ten patients developed joint bleeds between the ages of 10 and 20 years old. The most common locations of joint bleeding were the knee (n = 11) and ankle (n = 7). Eight of 70 patients had hepatitis C (HCV), 6 experienced joint bleeding. CONCLUSIONS: In this study, almost one third of patients with mild hemophilia experienced joint bleeding, often without history of trauma. Joint range of motion was abnormal in more than a third of the patients with mild hemophilia regardless. These data highlight the need for ongoing evaluation and characterization of joint health in individuals with mild hemophilia. HIGHLIGHTS: Twenty-nine percent of individuals with mild hemophilia had history of joint bleed. PwH and mild diseases with previous or current hepatitis C had higher likelihood of joint bleeding. Approximately 15% of PwH and mild diseases had abnormal joint examinations without a confirmed history of joint bleeding.

Cost-effectiveness of prophylactic emicizumab versus prophylactic recombinant factor VIII in patients with moderate or mild hemophilia A without inhibitors in the United States.

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population.

Association of iron infusion reactions with ABO blood type.

OBJECTIVES: We sought to determine risk factors for iv iron infusion-related reactions (IRR), and identify strategies for iron repletion after IRR. METHODS: We conducted a retrospective chart review of patients treated in the classical hematology clinic at Yale Cancer Center (n = 330 consecutive patients) from 2016 to 2021, who received iv ferumoxytol (60.3%), iron sucrose (14.8%), or iron dextran (10.9%). RESULTS: The iv iron IRR was noted in 58 (17.6%) patients, 62.1% of whom had previously tolerated iv iron. The severity of IRR was mild in 22, moderate in 23, and severe in 11 patients. Most (72.4%) patients who experienced IRR tolerated a subsequent iv iron infusion. On multivariable analysis, a history of non-medication allergies was associated with greater odds of IRR (odds ratio [OR] 2.12, 95% confidence interval (CI): 1.16-3.87, p = .01). No patients with type AB blood, and few with type A blood (n = 6), had IRR; compared to type A or AB together, patients with type B (OR 5.00, 95% CI: 1.56-16.06, p = .007) or type O (OR 3.71, 95% CI: 1.44-9.55, p = .007) blood had greater odds of IRR. CONCLUSIONS: This study highlights a possible association of blood type with iv iron IRR; prospective studies with larger patient numbers are warranted to explore this association.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex.

The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIbα or gpIbß. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94.

Severe heart failure after bortezomib treatment in a patient with multiple myeloma: a case report and review of the literature.

BACKGROUND: Bortezomib is a novel, first-in-class peptide which reversibly inhibits the proteasome and is Food and Drug Administration approved for the treatment of multiple myeloma, non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and systemic light chain amyloidosis, among others. CASE REPORT: Very few cases of bortezomib-induced cardiotoxicity have been reported in the literature, and most of them have been confounded by the previous use of anthracyclins. We reviewed the case of a 56-year-old woman with a medical history of well-controlled hypertension who was newly diagnosed with International Staging System stage I multiple myeloma. She presented with new symptoms of exertional dyspnea, paroxysmal nocturnal dyspnea, and orthopnea after a 4th cycle of a bortezomib/dexamethasone-based chemotherapy. Clinical examination was consistent with heart failure. 2-D echocardiogram showed an left ventricular ejection fraction of 25%, abnormal wall motion, severe eccentric mitral regurgitation, and moderate pericardial effusion. Coronary angiogram showed normal coronaries, and cardiac magnetic resonance did not show delayed gadolinium enhancement. CONCLUSION: We reviewed the possible mechanisms involved in cardiotoxicity caused by bortezomib, and the diagnostic methods and importance of early identification of this adverse event. Differential diagnoses such as cardiac amyloidosis and viral myocarditis are also discussed. To our knowledge, this is the first case where pericardial effusion and mitral regurgitation were described after bortezomib treatment.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis.

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. Research Question: How does in-hospital mortality compare with intermediate- versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19? Study Design and Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Mild macrocytosis in Williams-Beuren syndrome.

OBJECTIVE: To evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS). STUDY DESIGN: Complete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives. RESULTS: Just over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated. CONCLUSIONS: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup.

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.

BACKGROUND: An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19. METHODS: In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival. FINDINGS: 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087). INTERPRETATION: Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19. FUNDING: This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.

Acquired deficiency of vitamin K-dependent clotting factors due to brodifacoum ingestion.

Brodifacoum, also known as a superwarfarin, is a four-hydroxycoumarin derivative. It exerts an anticoagulant effect by inhibiting the reduction of vitamin K-2,3 epoxide, thereby decreasing the production of vitamin K-dependent clotting factors. It is a readily available rodenticide that has been associated with accidental ingestions in children. We report the case of a 21-year-old male who was admitted to the hospital with spontaneous bruising, hematuria and abdominal pain secondary to a perinephric hematoma. The patient was found to have a markedly prolonged prothrombin time and activated partial thromboplastin time that corrected with mixing of normal plasma. He had a normal factor V level; however, factors VII and X were less than 1% and factors II and IX were between 2% and 4% of normal. Ingestion of an anticoagulant was suspected, although the patient denied intentional or accidental ingestion. He was treated with FEIBA (Factor VIII Inhibitor Bypass Activity), fresh frozen plasma and oral vitamin K. The patient was stabilized and discharged from the hospital on oral vitamin K 50 mg twice daily. A serum brodifacoum level was later found to be markedly elevated at 320 ng/ml. We followed the brodifacoum level, which decreased to 31 ng/ml approximately six weeks after initial presentation. The exact length of treatment required to prevent recurrence of the coagulopathy was not determined because the patient did not return for follow-up. Superwarfarin ingestion must be suspected and quickly identified in patients with depletion of vitamin K-dependent clotting factors resulting in potentially catastrophic bleeding.

Transient bacteremia induced by dental cleaning is not associated with infection of central venous catheters in patients with cancer.

OBJECTIVE: The aim of this study was to determine the incidence of bacteremia resulting from dental cleaning and of subsequent established bloodstream infection (BSI) caused by oral microorganisms in patients with cancer with central venous catheters (CVCs). STUDY DESIGN: Twenty-six patients with cancer with CVCs and absolute neutrophil count over 1000 cells/µL received dental cleaning without antibiotic prophylaxis. Periodontal status was assessed at baseline by using the Periodontal Screening and Recording (PSR) score. Blood cultures were drawn via the CVCs at baseline, 20 minutes into cleaning, and 30 minutes and 24 hours after cleaning. Medical records were monitored for 6 months. RESULTS: Baseline blood culture results were negative in 25 patients. Nine of 25 patients (36%) had positive blood culture 20 minutes into cleaning, all associated with at least 1 microorganism typically found in the mouth. These 9 patients had significantly higher mean PSR score (3.22) compared with the other 16 (2.56; P = .035). These expected bacteremias did not persist, with blood culture results (0/25) at 30 minutes and 24 hours after cleaning showing no positivity (P = .001). There were no cases of CVC-related infection or BSI attributable to dental cleaning. CONCLUSIONS: Bacteremia resulting from dental cleaning is transient and unlikely to cause CVC-related infection or BSI in patients with absolute neutrophil count greater than 1000 cells/µL.

A case report of therapeutic leukapheresis in an adult with chronic myelogenous leukemia presenting with hyperleukocytosis and leukostasis.

Hyperleukocytosis (>100 x 10(9)/L) is an uncommon presentation of chronic leukemias. It can present with a variety of symptoms secondary to leukostasis, a syndrome caused by the sludging of circulating leukemic blasts in the microvasculature. The management includes hydration, cytoreduction, prevention of tumor lysis and, rarely, leukapheresis in cases complicated by leukostasis and hyperviscosity syndrome. We present a case of severe leukocytosis complicated by leukostasis in which leukapheresis was utilized to bring about a rapid reversal of microvascular sludging.

Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia.

PURPOSE: To test the feasibility, safety, immunogenicity, and clinical efficacy of an autologous vaccine of leukocyte-derived heat shock protein 70-peptide complexes (Hsp70PC), in conjunction with imatinib mesylate, in patients with chronic myeloid leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: Patients had cytogenetic or molecular evidence of disease, despite treatment with imatinib mesylate for all except one patient, at the beginning of study. Hsp70PCs were purified from the leukopheresed peripheral blood mononuclear cells and were administered in eight weekly intradermal injections at 50 microg/dose without adjuvant. Clinical responses were assessed by bone marrow analysis before and after vaccinations. An IFN-gamma enzyme-linked immunospot assay was used to estimate the effect of treatment on natural killer cells and T cells against CML. RESULTS: Twenty patients were treated. The manufacturing of Hsp70PCs was successful and the administration was safe for all patients. Minimal or no side effects were reported. Clinical responses were seen in 13 of 20 patients as measured by cytogenetic analysis of bone marrow Philadelphia chromosome-positive cells in metaphases and/or, when possible, the level of Bcr/Abl transcript by PCR. Immunologic responses were observed in 9 of 16 patients analyzed, characterized by an increase in the frequency of CML-specific IFN-gamma-producing cells and IFN-gamma-secreting natural killer cells in the blood. A significant correlation between clinical responses and immunologic responses was observed. CONCLUSIONS: Autologous Hsp70PC vaccination is feasible and safe. When combined with imatinib mesylate, it is associated with immunologic and possible clinical responses against CML in chronic phase.

Hypercoagulable States: What the Oral Surgeon Needs to Know.

Thrombophilia or hypercoagulable conditions can be thought of as either inherited or acquired. The inherited disorders include deficiencies of antithrombin, protein C, or protein S or the common disorders of factor V Leiden and prothrombin G20210A gene mutation. All these disorders are inherited as autosomal dominant and predispose individuals primarily to venous thrombosis. Acquired thrombophilic conditions are seen in individuals with cancer, phospholipid antibodies, and a whole host of other conditions that alter endothelial function, change blood levels of coagulant or anticoagulant proteins, activate platelets, or have other effects on coagulation proteins, platelet function, or the endothelium.

Predictors of warfarin-associated adverse events in hospitalized patients: Opportunities to prevent patient harm.

BACKGROUND: The optimum international normalized ratio (INR) monitoring frequency for hospitalized patients receiving warfarin is unknown. OBJECTIVE: Assess relationship between daily versus less frequent INR monitoring and overanticoagulation and warfarin-related adverse events. DESIGN: Retrospective cohort study using Medicare Patient Safety Monitoring System data. SETTING: Randomly selected acute care hospitals across the United States. PATIENTS: Patients hospitalized from 2009 to 2013 for pneumonia, acute cardiac disease, or surgery who received warfarin. INTERVENTIONS: None. MEASUREMENTS: (1) Association between frequency of INR monitoring and an INR ≥6.0 or warfarin-related adverse event. (2) Association between the rate of change of the INR and a subsequent INR ≥5.0 and ≥6.0. RESULTS: Among 8529 patients who received warfarin for ≥3 days, for 1549 (18.2%) the INR was not measured on 2 or more days. These patients had higher propensity-adjusted odds ratios (ORs) of having a warfarin-associated adverse event (OR: 1.48, 95% confidence interval [CI]: 1.02-2.17) for cardiac patients and surgical patients (OR: 1.73, 95% CI: 1.20-2.48), with no significant association for pneumonia patients. Cardiac and pneumonia patients with 1 day or more without an INR measurement had higher propensity-adjusted ORs of having an INR ≥6.0 (OR: 1.61, 95% CI: 1.07-2.41 and OR: 1.92, 95% CI: 1.36-2.71, respectively). A 1-day increase in the INR of ≥0.9 occurred in 621 patients (12.5%) and predicted a subsequent INR of ≥6.0 (positive likelihood ratio of 4.2). CONCLUSION: Daily INR measurement and recognition of a rapidly rising INR might decrease the frequency of warfarin-associated adverse events in hospitalized patients.

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation.

Atrial fibrillation (AF) is well known as one of the leading causes of stroke and systemic embolism. Anticoagulation therapy is recommended in all patients at moderate-to-high risk of stroke. The vitamin K antagonist warfarin has traditionally been used in these patients but presents challenges in dosing and monitoring in these patients. The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) was recently approved for use in the US for preventing stroke and systemic embolism in patients with nonvalvular AF. Clinical trials have shown it to reduce the risk of stroke and systemic embolism when compared with warfarin (goal international normalized ratio [INR] 2-3) with a similar risk for severe bleeding. It can be given twice daily, with the dose adjusted for renal function. It does not have any dietary restrictions, has few drug interactions (except involving permeability [P]-glycoprotein [P-gp] agents), and does not require routine laboratory monitoring. Patients may experience significant dyspepsia with its use. Compared with warfarin there is increased risk for gastrointestinal bleeding and perhaps myocardial infarction. Currently, no reversal agent exists for use in situations of overdose or severe bleeding although some strategies have been suggested. Despite its high acquisition cost compared with warfarin, analysis using theoretical models has shown it to be cost-effective. Dabigatran offers a unique alternative to warfarin in patients with nonvalvular AF and can be beneficial in patients requiring anticoagulation therapy.