bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epistatic Interaction between Fibrinogen alpha and gamma Genes and Factor V Leiden in Children with Venous Thrombosis: Results from a Family-Based Association Study.
Authors: Nowak-Gottl Ulrike , Weiler Hartmut , Seehafer Tanja , Thedieck Sabine , Stoll Monika 
Published: October 2019

Abstract
Background: Fibrinogen, the precursor of fibrin, is an essential component of the hemostatic system. A previous large case-control study showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for VT in adults. Here we investigated the association of haplotypes comprising the fibrinogen alpha (FGA) and gamma (FGG) genes, carriership of the Factor V Leiden mutation and risk for VT in a large family-based study sample for pediatric VT.
Methods: We genotyped 188 pediatric VT families for seven single nucleotide polymorphisms (SNPs) (rs6050, rs2070016, rs2070014 and rs2070011, rs1049636, rs2066861, rs2066860) as well as the G1691A Factor V Leiden (FV) polymorphism. Association was assessed using the Transmission Disequilibrium Test (TDT) and corrected for multiple testing using permutation testing as implemented in HAPLOVIEW. Interaction between FV and FGA and FGG, respectively, was assessed by TDT in families stratified for presence or absence of the FV mutation in the affected child.
Results: rs6050, rs2070016, rs2070014 and rs2070011 located in the FGA gene are in tight linkage disequilibrium (LD) and define 5 common haplotypes (HT) and are linked with the neighboring FGG gene (q= 0.91). rs1049636, rs2066861, rs2066860 located in FGG are in tight LD and define 4 HTs. HTs in both, FGA and FGG are significantly overtransmitted from parents to affected offspring (FGA: HT1 (AACT), HT frequency 0.32, T:U 62: 32, p=0.0025; FGG: HT2 (ATC), HT frequency 0.32, T:U 60:32, p=0.0035). When stratifying for FV status, it became apparent that the association between FGA and FGG and VT was more pronounced in FV-negative families (FGA, HT1, T:U 55:24, p=0.0006; FGG, HT2, T:U 55:24, p=0.0005), while absent in FV-positive families.
Conclusion: Our results indicate that genetic variation in FGA and FGG are risk factors for VT in children, and further that an epistatic interaction between FGA/FGG and FV Leiden influences the risk of FGG and FGA on pediatric VT. Our study highlights the complex nature of VT and the necessity to evaluate gene-gene interactions in association studies of complex, polygenic diseases.
Rates of Guideline-Recommended Venous Thromboembolism Prophylaxis in Surgical Patients among US Hospitals: A Real-World Analysis.
Authors: Amin Alpesh N. , Lin Jay , Yang Guiping , Stemkowski Stephen 
Published: October 2019

Abstract
Background: In spite of the wide availability of evidence-based guidelines for the thromboprophylaxis of venous thromboembolism (VTE), the burden of this syndrome in the US remains high. The improvement of VTE prophylaxis use is a major healthcare goal for the US Joint Commission. We therefore assessed the real-world rate of appropriate thromboprophylaxis in at-risk, hospitalized surgical patients, in accordance with the 7th American College of Chest Physicians guidelines, in hospitals across the US.
Methods: Premier’s Perspective™ inpatient data were used to assess the rate of VTE prophylaxis in discharges undergoing surgical procedures. Discharges aged ≥ 40 years, with a length of stay ≥ 6 days, and without contraindications for anticoagulation were included in the analysis. Appropriate thromboprophylaxis was determined by comparing the daily use of anticoagulants and compression devices, dosage, and duration of prophylaxis with the 7th ACCP recommendations for each surgical procedure. A number of other factors, including geographic region, hospital type and size, and admission source were also investigated for potential influence on the levels of appropriate thromboprophylaxis.
Results: A total of 116,915 surgical discharges from 1,574,320 discharges between January 2002 and December 2006 met the inclusion criteria and were included in this study. VTE prophylaxis rates varied among surgical groups, with an overall mean of only 14.4% of discharges receiving appropriate prophylaxis. Appropriate prophylaxis rates were 68.0% in orthopedic surgery (n = 2,404), 14.9% in vascular surgery (n = 54,170), 13.9% in general surgery (n = 39,072), 12.3% in laproscopic surgery (n = 14,905), 6.5% in gynecological surgery (n = 610), 5.2% in urological surgery (n = 2,640), and 4.0% in neurological surgery (n = 3,114).
Conclusion: There is a significant gap in adherence to the ACCP guidelines in surgical patients, with on average approximately 85% of surgical patients not receiving evidence-based VTE thromboprophylaxis. Although the rates of appropriate prophylaxis for orthopedic surgery patients were considerably higher than in other surgical categories, one-third of these patients still did not receive appropriate prophylaxis. As performance measures evaluating hospital’s VTE thromboprophylaxis use are rolled out across the US, it is important for individual hospitals to increase their awareness and use of the ACCP recommendations for VTE thromboprophylaxis.
Extended-Duration Enoxaparin for Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients: An Evaluation of the EXCLAIM Study Based on a Recently Recommended Composite Efficacy Endpoint.
Authors: Schellong Sebastian M. , Hull Russell D. , Tapson Victor F. , Monreal Manuel , Samama Meyer-Michel , Turpie Alexander G.G. , Yusen Roger D. 
Published: October 2019

Abstract
Introduction The EXCLAIM study has shown that in acutely ill medical patients who have received a standard 10-day period of prophylaxis with enoxaparin, extended-duration prophylaxis with enoxaparin for 4 weeks reduces the relative risk of the primary composite endpoint of asymptomatic proximal deep-vein thrombosis (DVT), symptomatic DVT or pulmonary embolism (PE), and fatal PE by 44% compared with placebo (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the consistency of these results using the composite efficacy endpoint recently proposed for venous thromboembolism (VTE) prophylaxis studies by the European Committee for Medicinal Products for Human Use (CHMP) which, in addition, takes all-cause mortality into account.
Methods Patients enrolled in the EXCLAIM study had a recent reduced mobility (≤3 days) due to a medical illness, were aged 40 years or older, and had anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days. Patients were then double-blind randomized and received either enoxaparin 40mg SC once-daily or placebo for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment period. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Data were analyzed using the CHMP-recommended composite efficacy endpoint of proximal DVT, adjudicated PE and all-cause mortality.
Results Eligible patients enrolled at 370 sites in 20 countries received standard-duration prophylaxis with enoxaparin. Of these, 4114 patients were double-blind randomized and 4040 received extended-duration prophylaxis with enoxaparin (n=2013) and placebo (n=2027), respectively. Extended-duration enoxaparin reduced the relative risk of the CHMP composite endpoint by 26% compared with placebo (5.8% vs 7.9%; RR 0.74; 95% CI 0.58–0.95; p=0.018).
Conclusion The significant reduction in the incidence of the primary efficacy endpoint associated with the use of extended-duration enoxaparin compared with placebo, following standard duration enoxaparin, was consistent when applying both the pre-defined EXCLAIM and the CHMP-recommended composite endpoints, the latter of which included all-cause mortality in addition to proximal DVT and adjudicated PE.
Dose-Escalated Low Molecular Weight Heparin Provides Effective Anticoagulation for Women with Mechanical Heart Valves during Pregnancy: A Single-Centre Experience.
Authors: Quinn John , Brooks Ruth , Walker Fiona , Peebles Donald , Cohen Hannah 
Published: October 2019

Abstract
Effective anticoagulation for women with mechanical heart valves during pregnancy remains a major challenge. The use of standard dosage low molecular weight heparin (LMWH) is associated with an unacceptable incidence of morbidity and mortality for this patient group. In this prospective audit of anticoagulation management, we report pregnancy outcome for a cohort of women with mechanical heart valves, who received anticoagulation with a higher dosage LMWH regimen. We audited 12 consecutive pregnancies in 10 women (mean age 27.8 (18–41) years) with mechanical heart valves (mitral 4, aortic 2, aortic and mitral 2, systemic tricuspid AV valve 2). Past obstetric history (on warfarin) included 6 fetal losses: 2 miscarriages <12 weeks and 4 terminations including one therapeutic at 22 weeks gestation because of an intracerebral fetal haemorrhage. In 11/12 pregnancies treated with LMWH, warfarin was discontinued at <6 weeks and in 1/12 at 8 weeks. LMWH (dalteparin 7, enoxaparin 5) +/− low-dose aspirin (4) was then started at full therapeutic dosage (subcutaneous 12 hourly) with regular monitoring to maintain anti-Xa levels at 1.0–1.2U/mL (0.8–1.2 in the first 4/12 pregnancies). This necessitated stepwise increases in LMWH with median doses (12 hourly) pre-delivery 11,750IU for dalteparin and 95mg for enoxaparin, representing a median 47.7% increase over initial dosage. 11/12 pregnancies on LMWH resulted in live births (median BW 2.5 kg (range 1.0–3.7) at median gestation 36 (range 26–38 weeks) with 1 IUFD at 37 weeks. One patient had non-fatal valve-related thrombosis at 26 weeks associated with a sub-therapeutic anti-Xa level (0.64 U/ml). Of note, she had a past history of pulmonary embolism and was heterozygous for the G20210A prothrombin gene mutation. There were no other valve-related thrombotic events. Minor bleeding occurred during 3 pregnancies. There were 5 major bleeding episodes in 4 patients: 3 antepartum (1 with placenta praevia) and 1 post-partum haemorrhage plus 1 abdominal wound haematoma. Our data suggest that in this patient group escalated dose LMWH provides effective anticoagulation. These patients require meticulous anticoagulant monitoring and close surveillance for bleeding and thrombotic complications within a multidisciplinary setting, with urgent intervention when indicated.
Comparison of the 2-Year Clinical Outcomes of VTE Prophylaxis Options in Medical Patients at Risk of VTE.
Authors: Deitelzweig Steven B. , Lin Jay , Benner Josh , Becker Russ 
Published: October 2019

Abstract
Background: Hospitalized medical patients are at significant risk of venous thromboembolism (VTE). Although evidence-based guidelines exist which provide recommendations for thromboprophylaxis in hospitalized medical patients, the optimum regimen for prophylaxis is not clear. We have therefore created a model, based on established literature, which examines the 2-year clinical outcomes following no prophylaxis, thromboprophylaxis with unfractionated heparin (UFH), or thromboprophylaxis with low-molecular-weight heparin (LMWH) in medical patients at risk of VTE.
Methods: A decision-analytic model was developed that replicates and extends an existing, published VTE model (McGarry et al. Am J Manag Care.2004;10:632–42) from 30 days to 2 years. Hypothetical cohorts of 10,000 medically ill patients at risk of VTE (according to MEDENOX criteria) were assembled, using a Markov chain model with resampling, to compare the rates of primary VTE events and related outcomes at 90 days and VTE complications and recurrent events at 2 years. Clinical outcomes were estimated from published clinical trial and observational data, and compared between three interventions, namely no prophylaxis, UFH, and the LMWH enoxaparin. Outcomes included in the analysis were clinical or venographically detected primary VTE, major and minor bleeds, asymptomatic or symptomatic heparin-induced thrombocytopenia, and death within the first 90 days, as well as VTE recurrence, post-thrombotic syndrome, pulmonary hypertension, and death within 2 years. Sensitivity and threshold analyses were performed to test the general applicability of the model. The simulation model was run using TreeAge software (Williamstown, USA).
Results: VTE rates and death were the lowest in the enoxaparin prophylaxis cohort, followed by the UFH and no prophylaxis cohorts respectively (Table 1). Adverse events were lowest in the no prophylaxis group, followed by the enoxaparin group and the UFH group (Table 1).
Conclusion: In this Markov model, based on robust data from clinical trials and observational studies, prophylaxis with enoxaparin reduced VTE occurrence and mortality over two years when compared with no prophylaxis or UFH prophylaxis in hospitalized medical patients at risk of VTE. Enoxaparin was also associated with a reduced incidence of adverse events when compared with UFH.
Table 1. Two-year outcomes in simulated cohorts of hospitalized medical patients at risk of VTE Outcome (n) Enoxaparin (n=10,000) Unfractionated heparin (n=10,000) No prophylaxis (n=10,000) VTE at 2 years 683 791 1787 DVT 545 633 1426 PE 138 158 361 Death 1573 1600 1745 Adverse events at 90 days 364 725 314 Minor bleed 285 510 244 Major bleed 65 116 55 Asymptomatic HIT 6 45 7 Symptomatic HIT 8 54 8
Downregulation of Mpl Marks the Transition to Lymphoid-Primed Multipotent Progenitors with Gradual Loss of Granulocyte-Monocyte Potential.
Authors: Luc Sidinh , Anderson Kristina , Kharazi Ms Shabnam , Buza-Vidas Natalija , Boiers Charlotta , Jensen Christina T. , Ma Zhi , Wittman Mrs Lilian , Jacobsen Sten Eirik W. 
Published: October 2019

Abstract
Evidence for a novel route of adult hematopoietic stem cell (HSC) lineage commitment through Lin−Sca-1+Kit+Flt3hi (LSKFlt3hi) lymphoid-primed multipotent progenitors (LMPPs) with granulocyte/monocyte (GM) and lymphoid but little or no megakaryocyte/erythroid (MkE) potential was recently challenged, as LSKFlt3hi cells were reported to possess MkE potential. Herein residual MkE potential segregated almost entirely with LSKFlt3hi cells expressing the thrombopoietin receptor (Thpor), whereas LSKFlt3hiThpor− LMPPs lacked significant MkE potential in vitro and in vivo, but sustained combined GM and lymphoid potentials, and co-expressed GM and lymphoid but not MkE transcriptional lineage programs. Gradually increased transcriptional lymphoid priming in single LMPPs from Rag1GFP mice was shown to occur in the presence of maintained GM lineage priming, but gradually reduced GM lineage potential. These functional and molecular findings reinforce the existence of GM-lymphoid progenitors with dramatically downregulated probability for committing towards MkE fates, and support that lineage restriction occurs through gradual rather than abrupt changes in specific lineage potentials.
Single Amino Acid Substitution (Asp111Ala) in Coagulation Factor Va Causes Subunit Dissociation and Disrupted Calcium and Copper Binding.
Authors: Song Jina , Talbot Kimberley , Hewitt Jeffrey , Camire Rodney M. , MacGillivray Ross T.A. , Pryzdial Ed L. 
Published: October 2019

Abstract
Factor V (FV) is the essential inactive precursor of blood coagulation cofactor Va (FVa). FV is synthesized as a single chain protein that is activated at sites of injury by thrombin to FVa. As a ternary complex with the serine protease factor Xa and an anionic phospholipid (aPL) membrane in the presence of calcium (prothrombinase), FVa functions to accelerate the rate of prothrombin to thrombin conversion, the critical step in hemostasis. FVa is a non-covalent heterodimer composed of a heavy (FVaH) and a light subunit (FVaL). It has been well established that FVa requires calcium to stabilize a functional subunit interaction, although copper is also known to bind. A 1:1 divalent cation:FVa stoichiometry has been reported for both metals. Despite the importance of FV few studies have investigated the specific amino acids and divalent cations that mediate the FVaH-FVaL association. In order to understand the role of divalent cations in maintaining the FVa subunit interaction and consequent function, we investigated the effect of mutating FV Asp111 to Ala (D111A), which was suggested by our previous work, others’ crystallography studies and homology to coagulation factor VIII, to potentially participate in calcium binding. Compared to wild type recombinant FV (wtFV), there was no difference in the kinetics of thrombin-mediated conversion of purified FVD111A to FVaD111A assessed by gel electrophoresis. Binding to small unilamellar aPL-containing vesicles was followed by light scattering and also showed no change. However, the cofactor activity of FVD111A was observed in clotting and purified prothrombinase chromogenic assays to be significantly inhibited (39% and 27% reduction, respectively). When the wtFV or FVD111A was pre-activated by thrombin (i.e. 2-stage assay), markedly greater inhibition was observed (94% and 73% reduction, respectively). The 1-stage/2-stage discrepancy seen here can be explained by spontaneous dissociation of subunits in FVD111A upon activation. Indeed, thrombin activation of FVD111A was shown by light scattering to result in rapid dissociation of subunits even in the presence of excess calcium. To quantitatively investigate the direct effect of the mutation on divalent cation coordination, graphite furnace atomic absorption spectrometry was utilized to measure the amount of bound calcium and copper. As predicted, calcium binding to FVD111A was severely inhibited resulting in a stoichiometry of <0.16:1. Interestingly, the stoichiometry of copper binding was also appreciably reduced to ∼0.5:1. These data demonstrate for the first time that a single point mutation can result in the spontaneous subunit dissociation of purified FVa. The finding that mutation of Asp111 disrupted not only the coordination of calcium but also that of copper, suggests that interdependent metal ion binding sites may contribute to FVa configuration and function.
Pegylated Liposomal Doxorubicin (PLD) in Combination with Bortezomib (B) May Provide Therapeutic Advantage for High-Risk Multiple Myeloma Patients Relapsing within 12 Months of Stem Cell Transplant.
Authors: Kumar Shaji , Blade J. , Miguel J. San , Hajek R. , Nagler A. , Sonneveld P. , Spencer A. , Sutherland H.J. , Robak T. , Mundle S.D. , Zhuang S.H. , Harousseau J.L. , Orlowski R.Z. 
Published: October 2019

Abstract
Background: Patients (Pts) with multiple myeloma (MM) who relapse within 12 months of autologous stem cell transplantation (SCT) have a poor prognosis. As reported by Mahmood et al. (ASCO 2007), of 432 pts who received SCT at the Mayo Clinic between 1994–2005, those with early relapse within 12 months (94/432– 22%) showed poorer median overall survival. Kaplan-Meier estimates of 12-month survival from the date of first relapse were 37% for pts relapsing within 12 months after SCT as compared to 85% for those relapsing after 12 months. In that study, pts had received regimens other than B. In a recent report of a large, phase III study (DOXIL-MMY3001), the combination of PLD+B improved time to progression (TTP) as compared to B alone (Orlowski et al. JCO 2007). The present analysis examined the 12-month post-randomization survival of patients who had early (<12 months) vs. late (≥12 months) relapse following SCT, as well as the effect of PLD+B vs. B alone in pts who had relapsed early.
Methods: This was a retrospective analysis of 646 pts who received intravenous B, 1.3 mg/m2 on days 1,4,8 and 11 of every 21-day cycle ± PLD, 30 mg/m2 on day 4.
Results: 359 pts had previously received transplant, 114 (32%) of whom relapsed within 12 months from SCT. The median age, gender distribution, time from diagnosis trial enrollment, measures of disease burden (M-Protein levels and B2M) and renal function were comparable between the early and late relapse groups. There was no difference in overall response rates [complete + partial response (CR+PR)] or very good PR (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early vs. late relapse groups (HR=0.94). 12-month survival from randomization was significantly lower in the early relapse group as compared to late relapse (83% vs. 92% respectively, p=0.009). However, within the early relapse group 12-months post-randomization survival rate was significantly superior following treatment with PLD+B as compared to B alone [52/56 patients (93%) vs. 43/58 patients (74%) respectively, p=0.01]. Correspondingly, TTP was better in this group with PLD+B vs. B alone (276 days vs. 205 days respectively, p=0.13). Overall, the toxicity profiles of the combination and B alone were comparable regardless of early or late relapse following SCT.
Conclusions: The present analysis of the MMY3001 study corroborates the prior Mayo observation of lower survival in MM pts relapsing within 12 months of SCT. Importantly, it demonstrates that PLD+B may provide a therapeutic advantage for high-risk MM pts with early relapse following SCT.
Preferential Proliferation of T Effectors and Tumor Protection by Adoptive Transfer of Primed Anti-Lymphoma Splenocytes into Lymphodepleted Hosts.
Authors: Brody Joshua D. , Goldstein Matthew , Levy Ronald 
Published: October 2019

Abstract
Clinical trials of immunotherapy for lymphoma have demonstrated induction of immunologic anti-tumor responses but only a minority of clinical responses. Possible reasons include tumor-produced factors (e.g. IL10, VEGF, TGFβ) and immune-regulatory mechanisms (e.g. Tregs, immature myeloid cells, tumor-associated macrophages). Immunotherapy in the post-transplant setting could overcome both these obstacles, as it is a state of minimal residual disease and of relative lympho- and myelodepletion. We have previously described a method of CD8 T cell-dependent vaccination against established lymphoma tumors by a combination of chemotherapy and intra-tumoral injection of the TLR9 agonist CpG oligodeoxynucleotides. Herein, we transferred splenocytes from such vaccinated mice into lymphodepleted recipient mice. The transferred tumor-specific T cells proliferate in these “empty” mice at a 30-fold excess over that in normal non-depleted recipients. The lymphodepleted recipients of adoptive transfer were completely protected against challenge with the lymphoma tumor at a 100-fold greater tumor cell dose than that required to kill normal animals. Because the transferred effector lymphocytes may still be contaminated by the same immuno-regulatory elements (e.g. Tregs) present in the donor mice, we asked whether these might proliferate and diminish the effector function of anti-tumor T cells. By tracking the homeostatic proliferation of the transferred cells we observed an apparent preferential proliferative capacity of the tumor-responsive CD8 cells and a relative decreased proliferative capacity of transferred foxP3(+) Treg cells. These data suggest that the post-transplant environment can skew the relative proportion of different T cell subsets, which may be a central mechanism for the dramatic improvement in tumor protection observed.