Cytomegalovirus (CMV) gB3 Genotype Is Associated with Acute Gvhd and CMV Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients (HSCT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1958-1958
Author(s):  
Débora de Campos Dieamant ◽  
Sandra Helena Alves Bonon ◽  
Francisco J P Aranha ◽  
Gislaine O. Duarte ◽  
Virginio C.O. Fernandes ◽  
...  
Keyword(s):  
Viral Load ◽  
Hematopoietic Stem Cell Transplant ◽  
Acute Gvhd ◽  
Gastrointestinal Disease ◽  
Antiviral Treatment ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Cmv Disease

Abstract Abstract 1958 Based on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). Objectives: The goals of this study were: identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with the CMV disease, acute GVHD and overall survival. Study design: The diagnosis of active CMV infection after allogeneic HSCT was detected by Antigenemia (AGM) and/or Nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using the N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment. Results: Were evaluated 63 allogeneic HSCT recipients, 49/63 patients (78%) presented active CMV infection detected by AGM and/or N-PCR, in a median time of 38 days after the transplant. The distribution of CMV gB genotypes in these 49 patients with active CMV infection was as follow: gB1, 19/49 (38.8%); gB2, 17/49 (34.7%); gB3, 3/49 (6.1%); gB4, 7/49 (14.3%) and three patients (6.1%) had mixed infection with gB1+gB3, gB1+gB4 and gB2+gB4. Acute GVHD grade II-IV occurred in 17/49 (34.7%) patients: 8/19 (gB1-42%), 1/17 (gB2 - 5.9%), 4/4 (gB3 - 100%) and 4/9 (gB4 - 44.4%). The distribution of the frequency of acute GVHD grade II-IV between the genotypes was statistically different (p=0.008). CMV disease occurred in 3/49 (6.1%) patients, characterized for gastrointestinal disease and these three patients had infection with CMV gB3 genotype. This genotype of CMV was also associated with higher viral load during antiviral treatment and worse survival. Conclusions: This study demonstrated that the frequency of active CMV infection in HSCT population was high (78%). The most prevalent genotype in patients with active CMV infection was gB1 and gB3 genotype was associated with acute GVHD grade II-IV, CMV gastrointestinal disease, higher viral load during antiviral treatment and worse survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Real World Outcomes of Letermovir Prophylaxis in Unselected High Risk CMV Seropositive Hematopoietic Stem Cell Transplant Recipients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3269-3269
Author(s):  
Eva Karam ◽  
Justin LaPorte ◽  
Connie Sizemore ◽  
Xu Zhang ◽  
H. Kent Holland ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Stem Cell Transplant ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Hematopoietic Stem ◽  
Clinically Significant ◽  
Cmv Disease

Introduction: Cytomegalovirus (CMV) is a leading cause of morbidity following allogenenic hematopoietic stem cell transplant (HSCT). Letermovir (LTV), an orally available antiviral drug which inhibits the CMV-terminase complex, was recently approved for CMV prophylaxis in CMV-seropositive HSCT recipients due to its ability to significantly reduce the risk of clinically significant CMV infection and its favorable toxicity profile. In the pivotal phase 3 study, subgroup analysis suggested increased benefit of LTV in patients at higher risk for CMV infection (i.e. unrelated or haploidentical donor (HID) vs. matched related donor), however HID transplants represented only 16% of the study population1. Therefore, we conducted a retrospective analysis of CMV reactivation rates, before and after the initiation of routine LTV prophylaxis, to determine the real-world safety and efficacy of LTV in an unselected group of CMV-seropositive high risk HSCT recipients, including a large number of HID transplants. Methods: We conducted a retrospective review of 106 consecutive CMV-seropositive high risk allogeneic HSCT recipients between 2017 and 2019. We compared the incidence of CMV infection immediately prior to the initiation of routine LTV prophylaxis in high risk transplant recipients (pre-LTV) (n=41) to that occurring after the initiation of LTV prophylaxis (post-LTV) (n=63). HSCT recipients were considered high risk if they had received at least one of the following: transplant from a haploidentical donor, matched unrelated donor, umbilical cord blood donor source or received anti-thymocyte globulin. CMV infection was defined as the need for pre-emptive therapy or documented CMV disease. The cumulative incidence (CI) of CMV infection at 100 days and 180 days were calculated to accommodate death as a competing risk. We used the Wald test to compare the CI at 100 and 180 days between the two cohorts. Results: Baseline characteristics of the pre- and post-LTV cohorts were similar, with HID transplants making up the majority of HSCTs in both groups, 65% and 64% respectively. We found a significantly lower CI of CMV infection at both 100 and 180 days in the post-LTV cohort when compared to the pre-LTV cohort (19.4% vs. 68.3% and 27.6% vs. 71% respectively; p<0.001) (Fig. 1). Despite lower CMV incidence following LTV prophylaxis, there was no significant difference in median time to CMV infection when compared to patients not receiving LTV prophylaxis (median [range] 40 [10, 243] vs. 36 [10, 180] days, p=0.72). The CI of CMV disease was 1.6% in the post-LTV cohort vs. 7.3% in the pre-LTV cohort (p=0.186). No significant differences were observed in any other outcome variable including overall survival, non-relapse mortality, relapse, acute graft-versus-host disease (GVHD) or time to neutrophil or platelet recovery. A preplanned subset analysis limited to HID transplant recipients (Fig. 2) again demonstrated a significant decrease in CMV infection in the post-LTV cohort at 100 and 180 days (27.9% vs. 80.8% and 34.6% vs. 84.6% respectively; p<0.001). Conclusion: This single center analysis confirms the benefit of LTV prophylaxis in reducing the risk of clinically significant CMV infection in unselected high risk CMV-seropositive HSCT patients, including a substantial number of HID transplant recipients. We found no significant impact of LTV prophylaxis on any other transplant outcome including hematologic engraftment, GVHD, relapse or mortality. In contrast to the pivotal phase 3 study, we saw few CMV infections occurring past day 100 after discontinuation of LTV prophylaxis. Future planned analyses will include comparisons of antiviral usage and associated toxicities (i.e. cytopenias), overall treatment charges and hospitalization/resource utilization. Disclosures LaPorte: Merck: Speakers Bureau.

scholarly journals 1752. Differential Degree and Duration of Cytomegalovirus (CMV) Viremia Between WHO International Standard-Calibrated Quantitative CMV Nucleic Acid Tests: Implications for Clinical Care

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S642-S643
Author(s):  
Atibordee Meesing ◽  
Joseph D Yao ◽  
Jeffrey Germer ◽  
Michelle Gartner ◽  
Benjamin Digmann ◽  
...  
Keyword(s):  
Viral Load ◽  
Nucleic Acid ◽  
Antiviral Treatment ◽  
Solid Organ ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
International Standard ◽  
Negative Results ◽  
Time To Onset

Abstract Background Quantitative nucleic acid amplification (QNAT) tests are cornerstone for the management of CMV disease after organ transplantation. We assessed the potential impact of viral load results obtained by two commercial WHO international standard-calibrated NAT in solid-organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Methods Sixty-four patients (36 SOT and 28 HSCT) had plasma CMV viral load assessed using the COBAS AmpliPrep/COBAS TaqMan CMV Test (CAP/CTM; lower limit of quantification [LLoQ] at 137 IU/mL) and cobas 6800 System (cobas CMV; LLoQ at 35 IU/mL). Viral load values were correlated with clinical course and outcomes. Results Forty-three of 64 patients (67.2%) had CMV infection or disease (asymptomatic, 67.4%; gastrointestinal disease, 16.3%; pneumonitis 4.7%) at median of 4.4 months (IQR 1.4 to 7.7) from transplantation. At CMV infection diagnosis, viral load results (mean ± SD) were almost two-fold higher when measured by cobas CMV (19,456 ± 51,618 IU/mL) compared with CAP/CTM (10,504 ± 27,744 IU/mL; P = 0.04). Time to onset of CMV viremia was significantly shorter (11.5 days; P < 0.001) while viral clearance was significantly longer (12.75 days; P < 0.001) by cobas CMV when compared with CAP/CTM. Persistent viremia was observed with cobas CMV in 44% of patients at the time of first negative results by CAP/CTM. Patients with negative results by cobas CMV at the end of antiviral treatment had a significantly lower need for re-treatment (OR 0.26, 95% CI 0.04 to 0.99, P = 0.05). Conclusion Our study highlights significant differences between CMV QNAT assays despite calibration to the WHO-international standard. The significant differences in the degree (almost two-fold), time to onset (12 days difference) and clearance (13 days difference) of CMV viremia between two automated commercial QNAT assays have direct implications in the care of transplant recipients. Persistence of low-level viremia was observed in samples that reached negative threshold by CAP/CTM, when tested using the more sensitive cobas CMV. Clearance of CMV viremia, when assessed by the more sensitive cobas CMV, was significantly associated with a lower need for re-treatment. Disclosures All authors: No reported disclosures.

Oral Valganciclovir As Preemptive Therapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5855-5855 ◽  
Author(s):  
Vildan Ozkocaman ◽  
Fahir Ozkalemkas ◽  
Ridvan Ali ◽  
Yasemin Karacan ◽  
Tuba Ersal ◽  
...  
Keyword(s):  
Stem Cell ◽  
Viral Load ◽  
Myeloid Leukemia ◽  
Preemptive Therapy ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Intravenous Ganciclovir ◽  
Hematopoietic Stem ◽  
Cmv Disease ◽  
Cmv Reactivation

Abstract Introduction: Cytomegalovirus (CMV) infection remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (AlloHSCT). Preemptive therapy with oral VGC or intravenous ganciclovir has replaced universal prophylaxis. We investigated the effect of oral VGC as preemptive therapy on CMV reactivation or infection in AlloHSCT. Patient & Methods: We retrospectively studied 30 consecutive adult recipients of HLA-identical sibling allogeneic peripheral blood stem cell transplant from June 2011 through June 2014 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. Among 30 patients we studied the results of 13 patients with CMV DNA positivity. All 13 recipients and their donors were seropositive for CMV Ig G status. Their diagnosis of pretransplantation were as 8 acute myeloid leukemia (61 %) and 5 acute lymphocytic leukemia (39 %). Median age was 39 years (range 21-54). There were 9 men and 4 women (Table-1). The patients received no prophylaxis against CMV. Blood/serum samples from all patients were routinely monitored for CMV-DNA using PCR twice weekly. We iniciated pre-emptive therapy for CMV as the viral load was above and equal to 500 copies/ml in two consecutive samples. VGC was given twice daily 900 mg for 2 weeks, and maintened at a dose daily 900 mg until viral load is undetectable. Results: The PCR test was persistently negative in 17 patients (57 %) and positive at least once in 13 (43%)patients. All patients with CMV reactivations were on immunsupressive treatment. CMV infection was cleared in most patients within 2 weeks, but for those with stable or increasing CMV levels, the induction period was continued. Twelve patients were treated with oral VGC on an outpatient basis and they all became CMV negative after the first week of treatment. Only one patient received intravenous ganciclovir and he was also CMV negative after the first week of treatment. While no positivity was identified in any of the patients who received VGC on day 21, clinically unimportant low titer CMV positivity was noted in three of these patients. VGC was continued at same dose and no positivity was detected after 2-3 weeks. We were obligated interrupt VGC in only four patients for serious side effects namely neutropenia and thrombocytopenia. We did not observe CMV-related mortality. Conclusions: We concluded that VGC therapy could be safely used at outpatient clinics, with frequent monitorization to prevent severe myelotoxicity. In conclusion, based on our findings, oral VGC is effective and safe in the pre-emptive treatment of CMV disease following allo-HSCT. Therefore, preemptive strategy by oral VGC appears preferable to the prevention of CMV disease in alloHSCT with its advantage of effectiveness and usage in outpatient clinic condition. Table- 1: Management and outcome of the patient characteristics with CMV-reactivation Patients with CMV reactivation/Total number of patient 13/30 Median age, years (range) 39 (21-54) Gender Male Female 9 4 Diagnosis AML ALL 8 5 CMV serologic status Donor+/Recipient + 13 Preperative regimen Bu-Cy CY-TBI Flu/Amsc(FLAMSA) 8 4 1 GVHD propylaxis CSA+MTX CSA+MTX+MM 12 1 GVHD prior to CMV reactivation Acute chronic without GVHD 7 1 5 Prednisolone treatment at the time of starting VCG Yes No 8 5 IST at the time of starting VGC Yes No 13 0 Median duration of CMV reactivation (day) 44 (8-330) Viral load before antivial treament (copies/ml) 1153 (78-12800) Treatment VGC (900 mg, twice daily for induction) GC (5 mg/kg, twice daily for induction) VGC+GC 9 (70 %) 1 (7 %) 3 (23 %) Total treatment duration (day) 24 (10-51) CMV DNA at the end of the treatment Conversion to negative Persistently positive (low titer < 50 copies/ml) 10 (77 %) 3 (23 %) Serious side effects Interruption of therapy due to neutropenia Interruption of therapy due to thrombocytopenia Reactivation 3 (23 %) 1 (7 %) 2 (15 %) Abbreviations: AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus,GVHD: graft-versus host disease, CSA: cylosporine, MTX: methotrexate, MMF: mycophenolate mofetil, PDN:prednizolone, IST: Immunosupressive treatment, VGC: valganciclovir, GC: ganciclovir, Bu: Busulfan, Cy: cylophosphamide, TBI: total body irradiation Disclosures No relevant conflicts of interest to declare.

Immunosuppression medication adherence after allogeneic hematopoietic stem cell transplant: Impact of a specialized clinical pharmacy program

2021 ◽  
pp. 107815522110001
Author(s):  
Florent Charra ◽  
Michael Philippe ◽  
Chloé Herledan ◽  
Anne-Gaëlle Caffin ◽  
Virginie Larbre ◽  
...  
Keyword(s):  
Clinical Pharmacy ◽  
Hematopoietic Stem Cell Transplant ◽  
Acute Gvhd ◽  
Intervention Group ◽  
Serum Levels ◽  
Control Group ◽  
Cell Transplant ◽  
Drug Adherence ◽  
Hematopoietic Stem ◽  
Discharge Prescription

This study aims to evaluate the impact of implementing a specialized clinical pharmacy program in patients with allogeneic hematopoietic stem cell transplant (HSCT) on their adherence to the immunosuppression treatment after discharge. A prospective open interventional design using a retrospective control group was used. The intervention was based on pharmaceutical consultations: the first was performed the day before discharge of HSCT unit and the next consultations during day-care follow-up (weeks 2 and 4 after discharge). Proactive medication reconciliation was implemented with a complete list of medications before the discharge prescription. The discharge prescription summarized on a personalized drug schedule was explained to the patient. The importance of optimal adherence and the potential problems related to self-medication were explained to the patient. Immunosuppression drug adherence was assessed by a direct method using serum levels of calcineurin inhibitors. The potential impact on acute GvHD, and infection was investigated. Twenty-six patients were included in the specialized clinical pharmacy program and 35 patients were in the control group. Seventy-nine pharmaceutical consultations were conducted in the intervention group, lasting a mean 25 min and 16 min for the first and following consultations, respectively. Serum levels in the therapeutic target range were higher in the intervention group (61.5% versus 53.0%, p = 0.07), with greater intra-individual variation (p = 0.005). There was no significant intergroup difference in acute GvHD (53.8% versus 50.3%, p = 0.85) or infection (26.9 versus 22.8%, p = 0.72). The implementation of a specialized clinical pharmacy program for patients who have received allogeneic HSCT seems to be beneficial for immunosuppression drug adherence; this now needs to be confirmed in a multicenter study involving a larger number of patients.

A Large Cohort Analysis of CMV Viral Load and Ganciclovir-Related Neutropenia in Nonmyeloablative (NM-HCT) and Myeloablative (M-HCT) Allogeneic Hematopoietic Cell Transplant Recipients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2975-2975
Author(s):  
Hirohisa Nakamae ◽  
Katharine A. Kirby ◽  
Brenda M. Sandmaier ◽  
Lalita Norasetthada ◽  
David Maloney ◽  
...  
Keyword(s):  
Risk Factors ◽  
Viral Load ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
High Grade ◽  
Donor Age ◽  
Cmv Infection ◽  
Significant Difference ◽  
Recipient Age

Abstract Background. The “true” nonmyeloablative allogeneic stem cell transplantation (NM-HCT) allows initial establishment of mixed T-cell chimerism for up to 6 months. The prolonged presence of host memory immune response after NM-HCT may play a role in protection against CMV infection especially early after NM-HCT. Furthermore, we previously reported that the incidence and poor outcome of ganciclovir-related neutropenia (GCV-N) is strongly associated with myelotoxic conditioning. Therefore, non-myeloablative HCT may also contribute to a lower risk of GCV-N. In this to date largest cohort we examined the risk of CMV infection and GCV-N after NM conditioning. Methods. We retrospectively analyzed 537 NM-HCT recipients (median age 54.2 yrs) and 2489 M-HCT recipients (median age 39.8 yrs) transplanted between 1/1995 and 12/2005. The conditionings for NM-HCT mostly consisted of 2 Gy TBI with/without fludarabine. Post-grafting immunosuppression consisted of most commonly mycophenolate mofetil and cyclosporine (CSP) for NM-HCT recipients and methotrexate/CSP for M-HCT recipients. CMV surveillance was performed weekly by antigenemia (AG) or plasma PCR testing. GCV/VGCV was given for CMV AG/PCR positivity. We evaluatedany AG/DNA detection by day 100,AG >10/200,000 PBL or PCR> 1000 copies/ml (high-grade CMV AG/DNA) by day 100 andGCV-N defined as non-relapse-related neutropenia (ANC<500 μL) after AG/PCR positivity with ANC>1000 μL at time of viremia using multivariable Cox regression.In addition, post-engraftment neutropenia, defined as ANC<500 μL occurring after day 28 post HCT among relapse-free patients. Results. There was no significant difference in the incidence of CMV AG/DNA at any level between NM-HCT and M-HCT (39% vs.37%, HR 1.1, P=0.42). However, there was less high-grade CMV infection in NM-HCT compared to M-HCT patients (9% vs. 14%, adj. HR 0.6, P < 0.01). Risk factors for high-grade CMV infection other than M-HCT were advanced recipient age, CMV serostatus, transplantation year and acute GVHD. The incidence of GCV-N was similar between NM-HCT and M-HCT recipients (28% vs. 20%, adj. HR 1.3, P=0.27). Risk factors for GCV-N were advanced recipient age and acute GVHD. On the other hand, the incidence of post-engraftment neutropenia was higher in NM-HCT (29% vs. 13%, adj. HR 2.1, P<0.0001). Other risk factors for post-engraftment neutropenia included advanced recipient or donor age, cord blood, HLA mismatched/unrelated donor, female donor to male recipient, acute GVHD, recipient CMV seropositivity and CMV infection. Conclusion. Our results suggest that the risk of CMV reactivation is not affected by NM conditioning but that progression to higher levels of viral load is reduced. This may be due to residual host memory immunity after NM-HCT. Despite less toxic conditioning, the incidence of GCV-N in NM-HCT was similar to that in M-HCT. Notably, the incidence of post-engraftment neutropenia was more frequent in NM-HCT compared to M-HCT recipients. This may be due to higher recipient and/or donor age, lower capacity to metabolize drugs, or the use of myelotoxic co-medication such as MMF or TMP-SMX.

Prevalence and Patterns of Cytomegalovirus (CMV) Reactivation In Adult Acute Lymphoblastic Leukemia Patients on Chemotherapy: Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2583-2583
Author(s):  
Seema Gulia ◽  
Manju Sengar ◽  
Uma Dangi ◽  
Hari Menon ◽  
Sanjay Biswas ◽  
...  
Keyword(s):  
Viral Load ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Manifestations ◽  
High Dose ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Laboratory Parameters ◽  
Cmv Reactivation

Abstract Abstract 2583 Background: Management of acute lymphoblastic leukemia (ALL) requires use of immunosuppressive agents like high-dose steroids and antimetabolites for prolonged periods which can predispose these patients for CMV reactivation and disease. As opposed to hematopoietic stem cell transplant there has been a real paucity of literature regarding clinical manifestations and management of CMV reactivation in ALL. In countries like India with a background of high CMV seropositivity (>90%), reactivation is a serious concern in ALL patients while receiving chemotherapy. Timely recognition and treatment can avoid the morbidity and mortality as well as help maintaining dose intensity which is the key to achieve cure in ALL patients. Methods: This retrospective case series included adult ALL patients (>14 years) who were being treated with chemotherapy between July 2009 to July 2011 at a tertiary care centre and detected to have CMV viraemia (Real time quantitative PCR with Roche CMV DNA QuantKit). PCR was done in patients with possibility of CMV infection based on clinical suspicion. Case records were analyzed for demography, chemotherapy details, clinical features, laboratory parameters, viral load, antiviral therapy and response. Results: Among 203 adult ALL patients, 23 (males-18, females-5) were detected to have CMV viremia. Median age was 23 years (range, 16–44 years). Occurrence of CMV reactivation was most common during later part of induction or re-induction phase of therapy which includes high dose of steroids (14/23) followed by maintenance therapy with 6-mercaptopurine and methotrexate (5/23) and high dose cytarabine based treatment (4/23). Presenting features were: fever (19/23), fever alone (2/23) respiratory symptoms (9/23), anorexia (10/23), loose stools (8/23), abdominal pain (7/23) and splenomegaly (1/23). Abnormal laboratory parameters were: leukopenia or thrombocytopenia (14/23), deranged liver function tests (12/23). CT thorax was abnormal in 3 patients. Bacterial and fungal co-infection was seen in 5/23 patients. Median CMV viral load was 3.0 ×103 copy numbers (range, 708–1.38×106). Eighteen of these patients were treated with intravenous gancyclovir for a period of 14 days. In remaining 5 patients abnormal clinical and lab parameters improved either with antibiotic therapy or spontaneously. Median time to fever defervescence was 4 days (range, 2–5 days). Blood counts recovered after median period of 5 days (range 3–9 days). Gancyclovir related neutropenia and transaminitis developed in 1 patient. CMV titre became undetectable after a period of 2–4 weeks. Conclusion: Awareness of diverse clinical manifestations of CMV infection and high index of suspicion is important for timely diagnosis. Early diagnosis and treatment with gancyclovir reduces the morbidity, empirical use of other antimicrobials and avoids delays in administration of chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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