bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemophilia and the Dynamics of Hemostasis.
Authors: Brummel-Ziedins Kathleen E. , Branda Richard F. , Butenas Saulius , Mann Kenneth G. 
Published: April 2020

Abstract
The conversion of fibrinogen to fibrin and cross-linking to form a stable clot are key processes in effective hemostasis. We investigated fibrinopeptide (FP) A and FPB release, factor XIII (FXIII) activation and fibrin mass in tissue factor initiated coagulation in whole blood from individuals with hemophilia (n=8) and healthy subjects (n=35). For hemophilia whole blood, the rates and patterns of fibrin formation are altered when compared to blood from healthy individuals. The rate of FPA release is decreased from 2.3μ M/min in healthy individuals to 1.5μ M/min in hemophilia and more significantly the rate of FPB release is decreased from 1.3μ M/min to 0.19 μ M/min in hemophilia whole blood. The activated form of FXIII in hemophilia whole blood is formed at a rate of 4nM/min versus healthy individuals where the rate is accelerated to 7nM/min. Prior to clot time in hemophilia whole blood, FPB release is reduced. Whereas more FPA is released in hemophilia whole blood prior to clot time than in whole blood from healthy individuals, 67% versus 47%, respectively. FXIII activation is delayed relative to FPA release. Around clot time in hemophilia whole blood, FPB levels are only ~1μ M and FPA levels are 8 fold higher. In normal whole blood at clot time, FPA release is only 2.5 fold higher than FPB release, potentially suggesting that there is an essential correlation of time dependence between FPA, FPB and FXIII activation to form a stable clot. Whereas, this pattern of fibrin formation is altered in the hemophilia state. Clots from hemophilia whole blood are more soluble as evidenced by a 43% decrease in fibrin mass compared to clots from healthy individuals. Overall, data indicate that hemophilia clots are weaker due to decreased lateral association (FPB release) and are mostly composed of fibrin units that are only partially cross-linked. Thus, suggesting that FXIII activation and FPB release play crucial roles in the pathology of hemophilia and the fragile nature of blood clots in hemophiliacs.
National Responses to HIV Versus HCV-Infection from Virally Contaminated Blood Products among Persons with Hemophilia (PWH): More Different Than Alike.
Authors: Bennett Charles L. , Frohlich Lauren E. , McCaffrey Kathryn R. , McKoy June M. , Ramsey Glenn E. , Lindenberg Julia S. 
Published: April 2020

Abstract
Background: 95% of HIV- and HCV-infections among PWHs occurred with use of contaminated blood products prior to 1985. Overall, 20% to 90% of PWHs in developed countries have HIV- and/or HCV-infection. We compared country-specific public health approaches, judicial activities, and compensation for these viral infections.
Methods: Reports from hemophilia organizations, national ministries of health, published articles, and the World Federation of Hemophilia were reviewed.
Results: Except for the United States, the number of PWHs who developed HCV-infection from contaminated blood products was 1.5 to 3-fold as great as for HIV-infection- as a result of delayed use of heat-treated blood products, importation in late 1984 of HCV-infected non-heat treated blood products from the United States, and failure to use surrogate laboratory marker hepatitis screening tests. Compensation funds for HIV-infected PWHs were established in Japan ($521,000 at Dx); France ($305,000 at Dx; $102,000 for AIDS); the United States ($115,000 at Dx); Ireland ($106,000 at Dx); the United Kingdom ($55,000 at Dx); Australia ($48,000 at Dx); Canada ($13,000 at Dx/$18,000/yr); Germany ($12,000/yr for HIV; $24,000/yr for AIDS); and Italy ($6,000/yr; $82,000 at death). Compensation has also been provided to HCV-infected PWHs in Ireland ($266,000 at Dx); Canada ($251,000 at Dx); the United Kingdom ($33,000 at Dx; $42,000 if w/liver damage); and Italy ($10,000/yr; $37,000 at death).
Conclusions: In most developed countries, despite a greater number of HCV-versus HIV-infected PWHs, markedly less attention has been paid to HCV-infected PWHs. All countries should review HCV-related blood safety decisions made in the 1980s and consider providing compensation to HCV-infected PWHs.
A comparison of national responses to HIV and HCV infections from blood products Country -PWH (thousands) % PWH with HIV:HCV Man-dated HIV ELISA (date) Man-dated heat Rx factor (date) Anti-HBc marker screening (date) Nat’l Funds for HIV/HCV among PWHs (year) Nat’l Panels for HIV/HCV decisions (year) USA-20 50%:30% Mar 85 Oct 84 Oct 84 96/none 95/none Italy- 8.7 23%:55% Mar 85 Jul 85 None 92/98 92/05 GDR- 6 47%:90% Oct 85 Oct 85 None 95/none 94/none UK-6 28%:80% Oct 85 Jun 85 None 88/03 87/05 France-4 50%:90% Aug 85 Oct 85 None 89/none 91/none Japan-3.4 60%:90% Nov 86 Jun 86 None 88/none 96/none Canada-2 40%:88% Nov 85 Jul 85 None 89/98 97/none Australia-1.5 31%:90% May 85 Jan 85 None 89/none 88/none Ireland-0.3 36%:76% Oct 85 Feb 85 None 91/97 91/97
Anti-HCV Agent, Ribavirin, Decreases Events of Bleeding in Hemophilia Patients, Possibly by Elevating the Clotting Activity of Factor VII.
Authors: Yamamoto Koji , Honda Takashi , Suzuki Satoshi , Toyoda Hidenori , Matsushita Tadashi , Kojima Tetsuhito , Goto Hidemi , Takamatsu Junki 
Published: April 2020

Abstract
Ribavirin has been used in combination with interferon-alpha (IFN-α) to treat chronic hepatitis C. This combination therapy has been reported to be more effective than IFN-α monotherapy for eradicating hepatitis C virus (HCV), including patients with concomitant hemophilia. Eight consecutive hemophilia patients were treated for HCV infection with IFN-α and ribavirin between June 2002 and May 2005 at Nagoya University Hospital as outpatients.
Characteristics of patients and responses to anti-HCV treatment Patient Age (yrs) Hemophilia type Severity of hemophilia HIV infection Ribavirin load (mg/day) HCV genotype Eradication of HCV The eradication of HCV was considered positive when the absence of serum HCV RNA was maintained for 24 weeks after treatment was completed. 1 28 A moderate N 800 3a Yes 2 61 A severe N 800 3a Yes 3 50 A severe N 600 --&gt; 400 1b No 4 42 B mild N 800 2a +1b Yes 5 44 A severe N 800 3a Yes 6 52 A mild N 600 2b Yes 7 37 A mild P 800 --&gt; 600 1a No 8 44 B moderate N 800 1a Yes
All patients were men with a mean age (SD) of 44.8 (10.0) years. Seven patients had hemophilia A, and 2 had hemophilia B. Hemophilia was severe in 4 patients, moderate in 2 and mild in 3. Four patients had been previously treated with IFN-α-2b alone (Intron A®, Schering Plough, K.K., Osaka, Japan) but HCV had not been eradicated. During this study, all patients were treated with the same 24-week regimen of IFN-α. Oral ribavirin (Rebetol, Schering-Plough, Kenilworth, N.J.) was administered at a dose of 600 mg/day for patients who weighed 60 kg or less and 800 mg/day for those who weighed more than 60 kg during 24 weeks. We observed the reduction of the frequency and dose of infusion with clotting factors as a hemostatic therapy in HCV-positive hemophilia patients who were administered with ribavirin.
Figure Figure
(Use of clotting factor concentrates 6 months before, during and 6 months after combination therapy with ribavirin and IFN-α. Use of clotting factors is presented as the average use per month.) In order to investigate the mechanism of this prophylactic effect of ribavirin to bleeding in hemophiliacs, we analyzed ribavirin-induced changes in the activity of factor VII in patients’ plasma. The clotting activity of factor VII in plasma has been elevated at 15% on an average in 9 HCV-positive hemophilia patients during treatment with ribavirin (without ribavirin: 86.3±7.6%; with ribavirin: 102.0±10.3%). Furthermore, a significant induction of factor VII mRNA was demonstrated in cultured normal human hepatocytes or HepG2 cells when treated with ribavirin at the therapeutic concentration. These observations indicate that ribavirin can elevate factor VII procoagulant activity in plasma, possibly due to the induction of factor VII in hepatocytes, thus, contributing to decreased events of bleeding in HCV-positive hemophiliacs.
A Multi-Institution Retrospective Case Report Analysis of Emergence of Breakthrough Zygomycoses in Patients on Prior Voriconazole Therapy.
Authors: Trifilio Steven M. , Balasubramanian Lakshmi , Mehta Jayesh , Tallman Martin S. , Kennedy LeAnne , Bennett Charles L. , Kontoyiannis Dimitrios P. 
Published: April 2020

Abstract
Background: The incidence of Zygomycete infection has been increasing, almost exclusively in patients with hematologic malignancy with or without history of stem cell transplantation. In a single institution case control study, voriconazole was identified as an independent risk factor for the development of Zygomycete infections. A small number of single institution case reports have also been noted.
Methods: Investigators for The Research on Adverse Drug Events and Reports (RADAR) project requested collaboration from cancer centers regarding the identification and characterization of Zygomycete infections in patients with prior exposure to voriconazole. 12 centers participated in this study project. Medical records were reviewed and data collected on a standard case report form including diagnosis, transplant type, concomitant risk factors, exposure times, concurrent infection and outcomes. A minimum of 5 days exposure was noted between clinical diagnosis and confirmation with either tissue or histology.
Results: 54 cases were identified from 12 centers and with notably almost 75% mortality rate in individuals who were diagnosed with Zygomycoses with prior exposure to voriconazole.Of interest 31/54 cases received voriconazole for prophylaxis. Presenting characteristics were similar to those reported previously with lung as major site of infection. Concomitant risk factors included steroid use, immunosupression, GVH, neutropenia and diabetes. Simultaneous co-infections from diverse bacterial, viral and fungal infections were noted in 60% of patients signifying a compromised immune status. Drug therapy with an amphotericin product used to treat the identified Zygomycosis was highly ineffective with failure in 26/32 patients with resultant mortality.
Conclusion: Rates of breakthrough zygomycoses with high mortality rates with prior voriconazole therapy are on the increase. Appropriateness of prophylactic use as well as early diagnosis and institution of antifungal therapy in these patients with Zygomycoses is essential to combat this devastating infection.
Induction and Capture of CD4+ Cytotoxic Adenoviral Specific T-Cells in Response to pan-DR Binding Adenoviral Epitopes; towards Immunotherapy.
Authors: Haveman Lianne M. , Prakken Berent , Klein Mark R. , Albani Salvo , Bierings Marc 
Published: April 2020

Abstract
In the immunocompromised host adenovirus may cause fatal infections, especially after stem cell transplantation. No effective antiviral medication exists for severe adenoviral infection. Adoptively transferring adenoviral (Adv) specific T-cells from the donor into the patient may be a promising treatment, but requires the identification of these cells. The aim of the study was to induce Adv-specific cells in response to recently detected pan-DR binding CD4+ T-cell epitopes of adenovirus serotype 5. Epitopes were selected by using a computer algorithm designed to predict HLA pan-DR binding T-cell epitopes. Peripheral blood mononuclear cells (PBMCs) of 26 healthy adults were incubated with 19 different 15-mer peptides. Proliferation expressed as Stimulation Index (SI) was determined. Five peptides with highest SI derived from fiber protein, E1B protein, hexon protein (2 peptides) and DNA-polymerase were selected. To induce Adv-specific T-cells PBMCs from healthy subjects were either cultured with complete inactivated adenovirus for 11 days and restimulated with the different peptides for 3 days (n=10) or directly cultured with the peptides for 7 days (n=10). The cytokine profile induced by these epitopes was determined with multiplex immunoassay (MIA). By using the T-cell capture (TCC) method1 and FACS-sorting it was possible to capture the Adv-specific T-cells for further characterization by PCR and FACS analysis. In comparison with medium and irrelevant Adv-peptides PBMCs cultured with the 5 selected Adv-peptides induced significant larger amounts of Adv-specific CD4+ T-cells and showed a predominant pro-inflammatory cytokine profile. This suggests that peptides are naturally processed. By using TCC Adv-peptide specific CD4+ T-cells were identified and sorted. The Adv-specific T-cells displayed a high expression of TGF-1b, IFNg and Tbet (Th1 response), but also in lesser extent GATA3 and IL10 (Th2 response). A majority of the CD4+ Adv-specific cells expressed perforin and granzyme B, indicating that these CD4+ T-cells play an essential role in adenoviral infections. The induction of a specific immune response to adenovirus and subsequent capture of the Adv-specific T-cells is an important step towards adoptive immunotherapy in case of Adv-infections in the immunocompromised host.
Figure 1. Induction of adenoviral specific T-cells (CD4, CTB double positive cells) in response to Adv-peptides. 1A) Induction of CD4+ Adv-specific in response to medium stimulated PBMCs and 1B) in response to a peptide derived from hexon protein. Figure 1. Induction of adenoviral specific T-cells (CD4, CTB double positive cells) in response to Adv-peptides. 1A) Induction of CD4+ Adv-specific in response to medium stimulated PBMCs and 1B) in response to a peptide derived from hexon protein.
Fatal Infectious Complications Developing Late after Allogeneic Stem Cell Transplantation.
Authors: Bjorklund Andreas , Aschan Johan , Ringden Olle , Winiarski Jacek H. , Ljungman Per T. 
Published: April 2020

Abstract
Background and aim: The procedure of allogeneic stem cell transplantation (SCT) has evolved during the past decades. Infectious complications are still a major problem contributing to the transplantation related mortality (TRM). The epidemiology and outcome of early infections after SCT are well described. However, less is known has about late infections after SCT. Thus, the aim of this study was to determine risk factors for fatal infections occurring later than 6 months after allogeneic SCT.
Material and methods: Our study is based on 938 consecutive SCT patients transplanted 1976–2003 of whom 688 (73%) had survived for at least 6 months after SCT. A retrospective chart review was performed identifying 44 (6.4%) patients surviving for at least 6 months, having died from infection. Patients who had relapsed in their malignant disease were excluded. A control group of 176 patients (4 per case) was identified using relapse-free survival for at least 6 months and year of SCT as the matching criteria. Five controls were excluded leaving 171 patients in the control population. Risk factors for death from late infections were identified by logistic regression.
Results: 29 patients (66%) developed their fatal infection within 18 months and 37 (84%) within 5 years after SCT. 37 patients (84%) had ongoing chronic graft versus host disease (GVHD) and 36/44 (82%) had ongoing immunosupression at the time of death. 57 controls had died after 6 months from SCT; 32 of 57 from relapse. Comparing patients and controls in univariate analyses, the mean age was 30.6 years in the cases and 26.5 years in the controls (p=.13). 22/44 (50%) cases had been transplanted from an unrelated or mismatched donor, compared to 57/171 (33%) controls, p=.053; and 35/44 (80%) cases had received a conditioning regimen including myeloablative dose of TBI compared to 113/171 (66%) in the control group, p&lt;.05). Regarding post-transplant complications 40/44 (91%) cases had experienced cGVHD compared with 101/171 (59%) controls, p&lt;.001. 21/44 (48%) cases had developed obstructive respiratory dysfunction compared with 46/171 (27%) controls, p=.01; and more cases (33/44; 75%) than controls (85/171; 50%;) had experienced CMV infection. In multivariate analysis chronic GVHD (OR 9.2; p&lt;.001), use of a mismatched or unrelated donor (OR 4.8; p&lt;.001), and having had a CMV reactivation (OR 8.3; p=.004) increased the risk. Age, acute GVHD, TBI or obstructive respiratory dysfunction had no significant impact on the risk for late fatal infection.
Conclusion: Infections later than 6 months after SCT are important contributors to late TRM. Risk factors for late fatal infections include chronic GVHD, use of alternative donors and CMV infection.
CMV-Seropositive Patients Allografted with a CMV-Seronegative Donor Show Delayed or Missing CMV-Specific T-Cell Immune Response and Are at Higher Risk for CMV-Viremia and CMV-Disease.
Authors: Ganepola Susanne , Gentilini Chiara , Hilbers Urte , Hartung Goetz , Lange Thoralf , Hofmann Joerg , Liebert Uwe G. , Hammer Markus , Engelmann Elisabeth , Niederwieser Dietger , Thiel Eckhard , Uharek Lutz 
Published: April 2020

Abstract
The human cytomegalovirus (CMV) is an important cause for mortality and morbidity after allogeneic stem cell transplantation (allo SCT) especially in patients without a CMV-specific T cell response. CMV seropositive patients allografted with a CMV seronegative donor do not rise up specific CMV-T cell immunity posttransplant and are therefore at great risk for CMV viremia and disease. In a prospective manner, we analyzed blood samples of 38 HLA-A2+ patients with different haematological malignancies for CMV specific T cells.
Methods: Frequency of T cells with reactivity against the pp65-peptide (NLVPMVATV) was assessed by ELISPOT assay in 38 patients at defined time points after allo SCT. In patients with high CMV specific T cell frequencies, the T cell phenotype was determined by flow cytometry. Surveillance of CMV viremia was carried out by routine PCR-technique or pp65 Ag staining.
Results: In high-risk patients (donor-/recipient+) viremia was observed in 7/9 patients, 3/7 developed clinical severe CMV-disease. In this group, only one patient presented a weak CMV-specific T cell response in the first year after transplantation, although CMV-specific T cells were demonstrated in 5/9 patients before transplantation. In contrast, 64% (11/17) of the CMV seropositive patients having had a CMV seropositive donor showed CMV-specific T cells around day 30. Their T cell frequencies remained stable at a relative high level during the whole time of our investigation period and no CMV disease was observed. CMV seronegative patients allografted with either a CMV seronegative or seropositive donor also remained disease-free. CMV specific T cells were detectable in 2/7 patients of the d+/r− group. FACS analysis revealed that most of the responding cells were of the activated effector phenotype CD8+/CD45RA+/HLA-DR+ with a low expression of CCR7 and CD27.
Conclusion: CMV-seropositive patients receiving graft from a seronegative donor are at a high risk and therefore prone for CMV-viremia and -disease. The development of CMV-specific T cells i.e. immune reconstitution in high risk patients remains delayed or is completely missing during the first year post transplant. In contrast, seropositive recipients grafted with a seropositive donor develop a durable T cell response within 3–4 weeks and show no viremia at all. New strategies as donor vaccination and adoptive T cell transfer are warranted to prevent CMV-disease in CMV seropositive patients for whom only a seronegative donor can be found.
CMV Reactivation after Allogeneic Stem Cell Transplantation Is Associated with a Preponderance of Circulating Late-Stage CMV-Specific CD8+ T Cells.
Authors: Komanduri Krishna V. , St. John Lisa S. , Shpall Elizabeth J. , Champlin Richard E. , Molldrem Jeffrey J. , Ozdemir Evren 
Published: April 2020

Abstract
CMV reactivation remains a major cause of morbidity after after allogeneic stem cell transplantation. Using HLA-peptide tetramer staining and cytokine flow cytometry, we previously demonstrated that higher CD4+ and CD8+ T cells specific for CMV were found in the peripheral circulation of individuals who experienced CMV reactivation, but that more of these cells were dysfunctional in subjects experiencing viral reactivation. Recent studies have examined the role of maturation status of virus-specific T cells in the setting of of cleared, persistent and progressive viral infections. CD57 is a marker of replicative senescence that is expressed on a subset of human CD8+ memory T cells that generally lacks CD28 expression, and that is characterized by downregulation of the naïve and central memory T cell markers CD45RA and CCR7. To examine whether CMV reactivation after SCT was associated with late-stage differentiation of CMV-specific CD8+ T cells specific for viral proteins, we first examined the fraction of CD57-expressing CD8+ T cells in patients stratified by the occurrence of post-SCT viral reactivation. In 87 patients examined with HLA-peptide tetramer staining at approximately 3 months after allogeneic SCT, we found that individuals experiencing CMV reactivation within the first 100 days after SCT had significantly higher absolute numbers of circulating CD57+ tetramer-stained CD8+ T cells specific for CMV than those who did not experience viral reactivation (mean 11.8 vs. 1.6 CD57+ tetramer-stained cells/μl, median 3.3 vs. 0.08 cells/μl, p&lt;0.0001). In individuals in whom &gt;75% of tetramer-stained CD8+ T cells were CD57+, the incidence of CMV reactivation was 83%, in contrast to 52% of others. In other experiments, we found that CD57+ tetramerstained CD8+ T cells failed to expand following co-culture with autologous monocyte-derived dendritic cells pulsed with CMV peptide pools, confirming that CD57+ CMV-specific CD8+ T cells may have impaired proliferative capacity. Taken together, these results suggest that late-stage differentiation of memory CD8+ T cells may be indicative of an exhausted antigen-specific immune response, and that optimal post-SCT immune restoration should consider the differentiation status and not simply the numbers of antigen-specific T cells targeted.
Figure Figure