bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor VIII Half-Life and Clinical Characteristics of Severe Hemophilia A.
Authors: van Dijk Karin , van der Bom Johanna G. , Mauser-Bunschoten Eveline P. , Roosendaal Goris , Lenting Peter J. , de Groot Philip G. , van den Berg H. Marijke 
Published: April 2020

Abstract
Introduction
Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with clinical characteristics has not been reported. The aim of this study was to describe the effect of half-life on the clinical characteristics of patients with severe hemophilia.
Patients and Methods
Patients were selected from a single-centre cohort of 214 patients with severe hemophilia, born between 1944 and 1995. To improve efficiency we measured factor VIII half-life in the patients with the most severe and the mildest clinical phenotypes of severe hemophilia. Patients were selected according to age at first joint bleed, annual joint bleed frequency, clotting factor consumption and radiological Pettersson scores.
A first blood sample was taken after a period of 72 hours in which the patient did not use factor VIII. After infusion with 50 IU factor VIII/kg, blood was collected at 15, 30 minutes and 1, 3, 5, 24, 30, 48 and 60 hours. From 1972 onwards, data on joint bleed frequency, clotting factor use and age at first joint bleed were collected from the patients’ files. Pettersson scores were performed at five-year intervals. For calculations of annual clotting factor use (IU/kg/yr) and number of joint bleeds per year, the last 5 years of follow-up were used. Linear regression analysis was used to assess the relation between clinical characteristics and factor VIII half-life.
Results
Factor VIII half-life was measured in 42 patients and ranged from 7.4–20.4 hours, with a median of 11.8 hours. One hour increase in factor VIII half life was associated with a decrease of 96 (SD 45) IU clotting factor use per kg per year (p&lt;0.05). Joint bleed frequency was similar in patients with a shorter and a longer factor VIII half-life. Median number of joint bleeds was 2.9 per year (interquartile range (IQR) 1.1–4.4) in patients with a factor VIII half-life shorter than 12 hours and 2.6 per year (IQR 1.0–4.8) in patients with a factor VIII half-life longer than 12 hours (p=0.84). Patients with a factor VIII half-life shorter than 12 hours had a median Pettersson score of 52 points (IQR 12–61) and patients with a factor VIII half-life longer than 12 hours had a median Pettersson score of 29 points (IQR 16–52; p=0.90).
Conclusion:
Patients with a shorter factor VIII half-life need more clotting factor to prevent joint bleeds and subsequent arthropathy than patients with a longer factor VIII half-life.
A Non-Human Primate Model for Lentivirus-Mediated Anti-HIV RNAi Strategies.
Authors: Beagles Karen , Beard Brian , Rossi John , Yee Jiing-Kuan , Hu Shiu-lok , Trobridge Grant , Kiem Hans-Peter 
Published: April 2020

Abstract
AIDS remains a significant health problem worldwide despite the advent of highly active antiretroviral therapy (HAART). Although substantial efforts have been made to develop a vaccine there is still no cure and alternative strategies are needed to treat HIV infection and to control its spread. Our goal is to evaluate lentiviral vectors that inhibit HIV replication by RNA interference (RNAi) in a non-human primate SHIV model to develop a hematopoietic stem cell (HSC) gene therapy for AIDS. SHIV89.6 P is a chimeric virus comprised of an SIV genome that contains the tat, rev and env genes of HIV and infects both T lymphocytes and macrophages. Infection of non-human primates with SHIV89.6P results in significant decreases in CD4+ T cells as early as 4 weeks post infection, and is currently the best large animal model available to test gene therapy strategies for AIDS. We present here data showing efficient transduction of M. nemestrina CD34+ cells with an HIV-based lentiviral vector and RNAi-mediated inhibition of SHIV89.6 P replication in a hybrid T/B lymphocyte cell line (CEMx174). Although others reported a block to transduction of M. mulatta CD34+ cells with an HIV-based lentiviral vector, we observed efficient transduction rates (» 50%) of M. nemestrina CD34+ cells, comparable to transduction rates observed in human CD34+ cells (» 60%). To determine effectiveness of anti tat/rev shRNA to inhibit SHIV89.6P in vitro, a human T cell/B cell hybrid cell line (CEMx174) was transduced with a lentiviral vector expressing a short-hairpin RNA (shRNA) targeted to both HIV tat and rev sequences that also contained either a GFP reporter gene or a MGMT(G156A) resistance gene at MOIs of 1.3 and 3 respectively. Polyclonal populations of CEMx174 cells transduced with the GFP and MGMT(G156A) vectors were challenged with a 2.15x103 TCID50 dose of SHIV 89.6P. One week post challenge, expression of both tat and rev transcripts was reduced 88% and 97% respectively in these cultures as measured by real-time PCR. In summary, we have shown efficient HIV-based lentiviral transduction of M. nemestrina cells and efficient inhibition of SHIV infection by shRNA against HIV tat and rev thus providing a useful model to test lentiviral-mediated anti-HIV RNAi stem cell gene therapy in vivo.
Anemia and Cardiovascular Disease (CVD) Synergistically Interact To Increase the Risk of Frailty in Community-Dwelling Older Women.
Authors: Chaves Paulo H.M. , Woodman Richard C. , Fried Linda P. 
Published: April 2020

Abstract
Background: Moderate-to-severe anemia has been shown to adversely affect health outcomes in patients with cardiovascular disease (CVD). Less is known about the potential conjoint impact of mild anemia and CVD on frailty status in community-dwelling older adults. The objectives of this cross-sectional study were two-fold: (1) to assess the risk of frailty associated with mildly low Hb in community-dwelling older women with and without CVD, and (2) to test whether the association between Hb and frailty differed according to CVD status.
Methods: Data from women 70–80 years old who participated in the baseline assessments of the Women’s Health and Aging Studies (WHAS) I and II were analyzed. Analysis was restricted to those with Hb &gt;/= 10g/dL, and known frailty and CVD status. CVD was defined as angina, myocardial infarction, and/or congestive heart failure. Frailty was defined according to previously validated criteria; i.e., 3 or more of the following: slowness (walking speed&lt;20th percentile), unintentional weight loss &gt;10%, weakness (grip strength &lt;20th percentile), low energy expenditure (bottom 20th percentile of Kcal estimated using the Specific Activity Scale), and self-reported low energy. A fully-adjusted logistic regression model that controlled for demographics, diseases (including depression), renal function and cognition was used to determine the probability of being frail as a function of Hb and/or CVD.
Results: In the analytic sample of 670 community-dwelling older women, 14% were frail, 12.8% had WHO-defined anemia (Hb &lt;12 g/dL), 23.6% had CVD, and 17.1% had both anemia and CVD. Those with CVD were more likely to have anemia, though statistical significance was only borderline (OR 1.6, 95%CI 1.0–2.5, p=.077). Both anemia and CVD were independently associated with frailty in the fully-adjusted model (respectively, OR 2.3, 95%CI 1.1–4.8; and OR 2.2, 95%CI 1.2–4.2). When Hb was treated as a continuous variable, even mildly low Hb such as 11.5 g/dL (OR 3.0; 95%CI 1.5–6.0, p=.002), and low-normal Hb such as 12.5 g/dL (OR 1.3; 95%CI 1.0–1.8, p=.044) were independently associated with frailty, as compared to mid-normal Hb such as 13.5 g/dL. The relationship between frailty status and Hb varied according to CVD status (p-value for multiplicative interaction &lt;.035) (Figure below).
Conclusion: In community-dwelling older women, mildly-low/low-normal Hb and CVD were independently associated with frailty status. More importantly, presence of both of these risk factors was associated with a synergistic increase in frailty risk above that expected on the basis of their independent effects. These results are particularly relevant for the development of novel screening and intervention approaches to prevent frailty in older adults.
Figure Figure
Developing National Estimates of the Out-of-Pocket Costs of Cancer: The Importance of Including Patients with Lymphoma.
Authors: McCaffrey Kathryn R. , Carson Kenneth R. , Kutikova Lucie , Fisher Matt , Pickard Simon , Schumock Glen , Bowman Lee , Bennett Charles L. 
Published: April 2020

Abstract
Background: While Congress has mandated that the NIH provide a national estimate of the cost of cancer, almost all cancer cost studies have focused exclusively on breast cancer. No study has reported comparison data for persons with Hodgkin’s disease (HD) or non-Hodgkin’s lymphoma (NHL). These illnesses have a high cure rate, and affected persons are likely to experience significant economic hardships. Many participate in the workforce during treatment and long after the treatment is complete. Herein, we report preliminary results from an ongoing study on the out-of-pocket direct medical and non-medical costs for a cohort of patients with lymphoma and provide contextual comparison with a cohort of breast cancer patients who received care at the same cancer center (Arozullah, Supportive Oncology, 2004).
Methods: 178 breast cancer and lymphoma patients provided information on out-of-pocket costs for the preceding 3-month period; 12% had a diagnosis of HD or NHL. In total, 120 lymphoma patients will be interviewed for this study. Direct medical costs are costs related to medical care such as medications, procedures, and doctor visits. Direct non-medical costs are costs related to cancer, but not medical care, such as costs for meals, transportation, parking, and phone calls.
Results: The majority of both lymphoma and breast cancer patients were &lt; 65 years old, married, and employed. All patients had healthcare insurance coverage, with the majority insured with private plans. In comparison to women with breast cancer, persons with HD/NHL had similar mean monthly out-of-pocket cost expenditures, $635 versus $728. For lymphoma patients, factors associated with high direct medical costs included ≤ 12th grade education ($1,585/month) and HD ($1,133/month).
Conclusion: Mean monthly out-of-pocket expenditures are similar for HD/NHL and breast cancer. Direct medical out-of-pocket expenditures for lymphoma vary. Direct medical expenditures are greatest for HD ($1,130), intermediate for aggressive NHL and breast cancer ($512–$597), and lowest for indolent NHL ($180). Comprehensive economic analyses of cancer should include a range of malignancies.
Average Monthly Out-of-Pocket Costs for Lymphoma and Breast Cancer Patients.
Direct Medical Cost Direct Medical Cost Direct Non-Medical Cost Direct Non-Medical Cost Lymphoma Breast Lymphoma Breast Household Income &lt; $60,000 $381 $664 $40 $111 ≥ $60,000 $599 $553 $159 $161 Education ≤ 12th grade $1,585 $610 $72 $118 &gt; 12th grade $437 $653 $141 $122 Diagnosis &lt; 6 Months $577 $487 $114 $135 ≥ 6 Months $333 $660 $128 $130 Total Lymphoma $516 .. $119 .. HD $1,133 .. $155 .. AggressiveNHL $512 .. $167 .. Indolent NHL $180 .. $166 .. Total Breast Cancer .. $597 .. $131
The Critical Role of the NKG2D Receptor in CD8+CTL and CD8+CD56+ NKT Cell Cytotoxicity.
Authors: Wu Jia-Yan , Hill John M. , Ernstoff Marc , Meehan Kenneth R. 
Published: April 2020

Abstract
We previously demonstrated the ability to grow and ex vivo expand mobilized peripheral blood mononuclear cells (PBMNC) from myeloma patients into aggressive cytotoxic effector cells (Blood102; 422b, 2003). These experiments were designed to test the function and mechanism of tumor cell killing of these cells. Peripheral blood stem cells (PBSC) were collected from myeloma pts after mobilizing with cyclophosphamide and rhG-CSF and cultured in Aim-V serum-free medium at 37 and 5% CO2. After 2 hrs, the non-adherent cells were removed and placed in culture with Aim-V, IL-2 (50 IU/ml) and OKT-3 (50 ng/ml) for 7 days. Cytotoxicity of the expanded cells was tested on Day 0 and Day 7 using a chromium release assay. To identify the cytotoxic potential of cell subsets, cell populations were depleted using the Auto MACS Magnetic Cell Sorter (Miltenyi Biotec Auburn, CA) and cytotoxicity assays were repeated. Since the CD8+ cell(s) were the most cytotoxic, the CD8+ cells were isolated and their mechanisms of tumor cell killing were evaluated by testing killing through MHC Class I, T cell receptor or the NKG2D receptor. The ex vivo expanded population was extremely cytotoxic and killed RPMI 8226 myeloma cells at 60% lysis (+/− 1.6%) (E:T of 100:1) when compared to 3.9 % on day 0 (+/− 0.8%). CD8+ or CD8+CD56+ cell subsets contributed to &gt; 83.3 % (+/− 1.5%) of the killing. Blocking the TCR pathway (Redirected Cytotoxicity Assay) had no effect on killing and blocking the MHC Class I molecules decreased cytotoxicity by only 6%. When the NKG2D receptor was blocked, cytotoxicity by the CD8+ cells decreased by 48% (+/− 2%), demonstrating the critical role of the NKG2D in these CD8+ cell populations. The expanded cytotoxic effector cells aggressively lyse myeloma tumor cells in a MHC and non-MHC restricted fashion. These ex vivo expanded CD8+ cells likely acquire the NKG2D receptor and kill tumor cells in a non-MHC restricted manner. Since MHC expression is often low or absent on myeloma cells and the NKG2D ligands are fairly specific to tumor cells, the infusion of these ex vivo expanded cells following transplant may improve clinical outcomes.
Ceftazidime Versus Levofloxacin for Antibacterial Prophylaxis in Allogeneic Hematopoietic Cell Transplant (HCT) Recipients.
Authors: Frieze Deborah A. , Guthrie Katherine A. , Nichols William G. 
Published: April 2020

Abstract
Antibacterial prophylaxis for patients with neutropenia after HCT may decrease morbidity and mortality. We sought to determine whether levofloxacin prophylaxis is as effective as ceftazidime (which has been utilized at our center for the past decade) for this indication. Consecutive cohorts of allogeneic HCT recipients received ceftazidime (2 g IV q8h, N=221) or levofloxacin (750 mg PO or IV, N=103) as antibacterial prophylaxis during neutropenia (absolute neutrophil count &lt; 500 cells/μL). The two groups were comparable with regards to age, gender, underlying disease, conditioning regimen, and donor match. Compared to the levofloxacin cohort, significantly more patients in the ceftazidime cohort received bone marrow rather than peripheral blood stem cells (p=0.007). Overall, 71 (32%) of patients in the ceftazidime cohort had at least one bacterial infection as compared to 31 (30%) in the levofloxacin cohort; time to first infection was similar as well. Eleven percent of ceftazidime patients and 8% of levofloxacin patients experienced 2 or more infectious episodes. In total, the ceftazidime cohort had 104 infections (mean 0.47 infections per patient) and the levofloxacin cohort had 44 infections (mean 0.43 infections per patient). Breakthrough infections with skin-colonizing gram-positive cocci were modestly more prevalent in the levofloxacin cohort than in the ceftazidime cohort (38.6% of infections vs. 34.6%), as were enteric gram-negative rods (6.8% vs. 5.8%). Oral and gastrointestinal gram-positive cocci (22.7% vs. 30.8%), and environmental gram negative rods (11.4% vs. 12.5%), were more prevalent in the ceftazidime cohort. Of the seven viridans streptococci infections isolated in the ceftazidime cohort, only one was resistant to levofloxacin, yet all of the five isolates in the levofloxacin cohort were resistant. Patients in the levofloxacin cohort had a significantly higher probability of having a fever, as compared to patients in the ceftazidime cohort (p=0.004). Changes in antibiotic regimen were more likely to occur in the levofloxacin cohort (87 of 103 patients) as compared to the ceftazidime cohort (154 of 220 patients), p=0.0002. Relapse-free survival in the first 200 days after HCT, however, did not differ by prophylaxis regimen. Our data demonstrates that levofloxacin is an appropriate alternative to ceftazidime for use as antibacterial prophylaxis in allogeneic HCT recipients, and may be more cost effective given its oral bioavailability. Prospective, randomized trials are needed to elucidate the ideal prophylaxis regimen.
Herpes Zoster (HZ) Infection in the Post-Hematopoietic Stem Cell Transplant Pediatric Population May Be Preceded by Transaminitis.
Authors: Berman Jason N. , Berry Winter , Wang Molin , Neuberg Donna S. , Guinan Eva C. 
Published: April 2020

Abstract
HZ infection is a common complication following hematopoietic stem cell transplantation (HSCT). We reviewed the incidence, complications, and associated risk factors in a post-HSCT pediatric population at a single center and examined whether antecedent blood counts or transaminase levels (AST, ALT) might predict the onset of infection prior to the development of skin manifestations. Seventy-eight children between the ages of 2 months and 21 years developed HZ among the 309 patients, on whom data was available, who underwent HSCT from January 1995 to December 2002. Underlying diagnoses included: acute leukemia (n=108), chronic myelogenous leukemia (n=22), myelodysplastic syndrome (n=24) and other conditions (n=155). Two hundred patients underwent an allogeneic HSCT (98 sibling donor, 102 unrelated donor) and 109 underwent an autologous HSCT. The incidence of HZ was 25% by 10 months and 40% by 70 months post-HSCT. Post-herpetic neuralgia occurred in 21/73 (29%; 95% CI=19%, 41%) evaluable patients, disseminated skin involvement in 15/74 (20%; 95% CI= 12%, 31%) patients and visceral organ involvement in 6/75 (8%; 95% CI= 3%, 17%) patients. Acyclovir prophylaxis for cytomegalovirus (CMV) antigen positivity was given for 21 days post-BMT in 49/75 (65%) patients and had no impact on the incidence or onset of HZ, nor did immune compromise (defined as history of chemotherapy or underlying primary immune deficiency) prior to HSCT. Risk factors for development of HZ included: patient age-greater than 10 years (p&lt;0.0001), allogeneic HSCT (p&lt;0.001), and conditioning with total body irradiation (TBI) (p&lt;0.059). Type of allogeneic donor did not add significantly to the model. Graft-versus-host-disease (GVHD) increased the interval to HZ infection (p&lt;0.0018). There was insufficient evidence to attribute this surprising result to CMV prophylaxis. However, prior GVHD did increase the risk of disseminated skin involvement (p&lt;0.016). There was a significant change in ALT level in the month preceding diagnosis of HZ (p&lt;0.02), with 22/37 (59%) evaluable patients having a progressive increase. This rise in ALT level was not associated with GVHD (p=0.60). Changes in AST levels, white blood cell and platelet counts were not significant. Forty-four patients were admitted to hospital for HZ infection for a median of 6 days (range 2–39). Length of stay for allogeneic patients was significantly affected by skin dissemination and visceral involvement (p&lt;0.023 and p&lt;0.034, respectively) and not by donor type, prior immune status, GVHD or TBI. Inclusion of HZ infection post-HSCT in the differential diagnosis of patients with a rising ALT level, particularly if &gt; 10 years of age after allogeneic HSCT with TBI conditioning may allow for earlier initiation of therapy with less morbidity and decreased need for hospital admission.
Short-Term Foamyviral Transduction with Virions Encoding Recombinant Corrects the Mitomycin C Hypersensitivity of Fancc −/− Progenitor Cells In Vitro and Restores Long Term Repopulating Activity of Fancc −/− Stem Cells In Vivo.
Authors: Si Yue , Leurs Cordula , Srour Edward , Ciccone Samantha , Hanenberg Helmut , Clapp D. Wade 
Published: April 2020

Abstract
Fanconi anemia (FA) is a complex autosomal recessive genetic disorder characterized within the hematological system by progressive bone marrow aplasia, a high propensity to develop acute myeloid leukemia, and hypersensitivity to alkylating agents including mitomycin c. The identification of individual FA genes raises the potential of using gene transfer technology to express/introduce the functional cDNA in/into deficient autologous stem cells. We have previously shown that in the absence of genetic correction with a retroviral mediated Fancc transgene, ex vivo culture of Fancc−/− stem/progenitor cells (HSPC) predisposes uncorrected Fancc−/− HSPC cells to clonal hematopoiesis (Haneline, Blood 2003). Therefore we examined the potential of a helper-free human foamy virus (HFV) derived construct that encodes both the human FANCC and EGFP transgenes to transduce murine Fancc−/− HSC in the absence of prestimulation. In initial experiments, we determined that 40–80% of progenitors were transduced following a single overnight HFV infection using a 20:1 moiety of infection. Subsequent studies demonstrated that HFV efficiently transduced primitive hematopoietic progenitors in G0 and G1 phases of the cell cycle as evidenced both by using multicolor fluorescence activated cell sorting and subsequent culture of sorted cell populations in high proliferating potential (HPP-CFC) and low proliferating potential colony forming assays. Aliquots of HFV transduced cells that were transduced with the construct encoding both Fancc and EGFP, or the reporter transgene only were transplanted into irradiated recipient mice. Four months following transplantation, bone marrow cells were isolated from the reconstituted recipients and clonogenic assays were established in a range of mitomycin c (MMC) concentrations. In these experiments, the MMC hypersensitivity of Fancc−/− progenitors was corrected to wild-type levels. To assess quantitatively the potential of HFV expressed FANCC to correct stem cell repopulating ability, we next utilized the competitive repopulating assay. In two replicate experiments, we determined that the repopulating activity of HFV-transduced Fancc−/− stem cells was comparable to wildtype controls six months following transplantation in primary and secondary recipients. Collectively, these data provide in vivo evidence that the HFV vector is an efficient vehicle for introducing a functional hFANCC transgene into quiescent Fancc−/− HSC in the absence of prestimulation and for complementing the cellular FA defect in vitro and in vivo.