bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterial Infections in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study in a High Endemic Area
Authors: Yao-Chung Liu , Wu Chi-Jung , Chien Sheng-Hsuan , Fan Nai-Wen , Hu Ming-Hung , Gau Jyh-Pyng , Liu Chia-Jen , Yu Yuan-Bin , Hsiao Liang-Tsai , Chiou Tzeon-Jye , Liu Jin-Hwang 
Published: October 2019

Abstract
Background
Mycobacterial infection is an important and potentially life-threatening complication of patients receiving organ transplantations. Notably, for the recipients of allogeneic hematopoietic stem cell transplantation (HSCT), there are few supporting results to explore post-transplant mycobacterial infections. Taiwan is a high endemic area of the infection. We therefore aim to investigate the incidence, risk factors, and survival of post-transplant mycobacterial infections, including mycobacterium tuberculosis (MTB) and nontuberculous mycobacterium (NTM).
Patients and Methods
We included in this study 422 adult patients undergoing allogeneic HSCT at an Asian tertiary medical center between January 2003 and December 2013. A total 26 subjects who developed post-transplant mycobacterial infections were identified. Risk factors, clinical features, and survival for post-transplant mycobacterial infections in recipients of HSCT were collected and analyzed.
Results
Post-transplant mycobacterial infections occurred in 26 (6.2%) of 422 HSCT patients. Two-year cumulative incidences in MTB and NTM were 1.4 % and 5.4%. In the multivariate analysis, being age > 45 years (adjusted HR 2.21, 95% CI 1.01-4.83)) and extensive chronic graft-versus-host disease (cGVHD) (adjusted HR 4.95, 95% CI 2.14-11.46) were identified as independent risk factors of post-transplant mycobacterial infections. There was a trend as a risk factors in relapsed patients (P=0.088). For patients with cGVHD, there was a significant difference of post-transplant survival between mycobacterial infections and none (median: 6.82 months versus not reached, P=0.036). Pneumonia with or without other infections contributed most to mortality (n = 11, 42.3%).
Conclusion
The 2-year cumulative incidence is higher in NTM (5.4%) than TB (1.4%) in recipients of allogeneic HSCT. Patients with age > 45 years, and extensive cGVHD are at risk of mycobacterial infections. Poor post-transplant survival in cGVHD patients developed mycobacterial infections and 42.3% patients in our study died of pneumonia. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection and treatment of infections.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Increase of Regulatory γδ T Cells Reduces the Incidence of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Gao Li , Xuan Li , Wu Xiuli , Fan Zhiping , Huang Fen , Yi Zhangshan , Li Yangqiu , Liu Qifa 
Published: October 2019

Abstract
Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the primary means for treatment of hematologic and non-hematologic malignancies. Acute graft-versus-host disease (aGVHD) is a major complication associated with high morbidity and mortality after transplantation. Regulatory γδ T cells (γδ Tregs), as a novel subset of γδ T cells with Foxp3 expression and immunosuppressive effect, are found to effectively alleviate aGVHD in mice model. However, whether γδ Tregs involve in the occurrence of aGVHD in recipients of allo-HSCT remains unclear. Therefore, the aim of this study is to investigate the effect of γδ Tregs in the occurrence of aGVHD in recipients of allo-HSCT.
Methods The immunophenotyping of γδ Tregs was analyzed in peripheral blood from 24 aGVHD and 24 paired non-aGVHD patients (undergoing transplantation at the same time, basic data matched), using flow cytometry. The expression levels of immunoregulatory-associated molecules (Foxp3, CD25, CTLA-4, GITR, TLR8, RORc, STAT-1 and STAT-3) were analyzed in peripheral blood, using real-time RT-PCR with SYBR GreenⅠstaining. Liquichip technology was used to analyze the concentration of interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-10, IL-17 and tumour necrosis factor-α (TNF-α) in cultural supernatant.
Results The proportions of total γδ T and Vδ2 T cells in non-aGVHD patients were significantly higher than that in aGVHD patients (P=0.044, P=0.000), and the proportion of Vδ1 T cells was similar between the two groups (P=0.061). Compared with aGVHD patients, the proportions of Foxp3+γδ T, Foxp3+Vδ1 T, Foxp3+Vδ2 T cells and Tregs were increased in non-aGVHD patients (P=0.005, P=0.014, P=0.026 and P=0.000). There was a negative correlation between the incidence of aGVHD and the percentages of Foxp3+γδ T, Foxp3+Vδ1 T and Foxp3+Vδ2 T cells (P=0.014, rs=-0.477; P=0.001, rs=-0.610; P=0.040, rs=-0.405). The mRNA expression levels of Foxp3 and TLR8 genes were significantly increased in non-aGVHD patients compared with aGVHD patients (P=0.042, P=0.002). There were no significant difference in the expression levels of CD25, RORc, CTLA-4, GITR, STAT-1 and STAT-3 genes (P=0.234, P=0.194, P=0.056, P=0.524, P=0.142 and P=0.775). In addition, the concentrations of IL-10 and TNF-α were significantly increased in aGVHD patients (P=0.002, P=0.036), and the concentrations of IL-4, IL-17 and IFN-γ were similar between the two groups (P=0.379, P=0.414, P=0.170).
Conclusions Increase of γδ Tregs might reduce the incidence of aGVHD after allo-HSCT.

Disclosures
No relevant conflicts of interest to declare.
Does Cell Size Matter?: Utilizing Mean Cell Volume in Hospitalized Patients As a Screen to Determine Common Causes of Anemia Including Iron Deficiency Anemia, Vitamin B12 and Folate Deficiency
Authors: Gupta Manika , Copley Kathleen , Keeney Michael , Chin-Yee Ian 
Published: October 2019

Abstract
Background: The approach to anemia is traditionally based on the Mean Cell Volume. Based on this approach anemia is subdivided into microcytic, normocytic and macrocytic causes. This approach may not accurately discern common causes of anemia in hospitalized patients. Previous studies suggest the MCV may not be a sensitive measurement to differentiate iron deficiency anemia (IDA) and megaloblastic anemia due to vitamin B12 or folate deficiency.
Methods: In a retrospective, single-centre study at London Health Sciences Center, all adult patients (age 18 years or older) with confirmed IDA, vitamin B12 and folate deficiency and their associated MCV and RDW values at LHSC over a one year period were reviewed. IDA was defined as hemoglobin less than 115 g/l and ferritin less than 30 (M) and 10 (F). Vitamin B12 deficiency was defined as a value of less than 145.
Results: 1119 patients were identified with confirmed IDA, B12 or Folate deficiency. 894 patients had IDA of which 564 patients had low MCV (sensitivity 63.1%) and 797 patients had low MCV or high RDW (sensitivity 89.1%). Of the 96 patients with vitamin B12 deficiency anemia, 12 patients had high MCV (sensitivity 12.5%) and 70 patients had high MCV or high RDW (72.9%). Only one of 2244 patients who had RBC folate measured had an actual folate deficiency.
Conclusion: Our results confirm that a normal MCV does not exclude IDA or vitamin B12 deficiency. Clinicians need to be aware of the low sensitivity of the MCV as a screen. The sensitivity of MCV for IDA or vitamin B12 deficiency is improved with indices such as RDW. Folate deficiency is rare in North America and should not be routinely ordered for assessment of nutritional anemia.

Disclosures
No relevant conflicts of interest to declare.
Wait Times and Bed Capacity for Hematopoietic Cell Transplantation in Ontario: A System Dynamics Model
Authors: Wang Jonathan , Vahid Saba , Sherrie Hertz , Kouroukis C. Tom 
Published: October 2019

Abstract
Objectives: Cancer Care Ontario (CCO) is the provincial governmental organization responsible for planning hematopoietic cell transplantation (HCT) services in Ontario, Canada. The objective of this project is to develop a capacity planning model to investigate the effects on wait times of adding extra bed capacity for allogeneic transplant (ALLOHCT) in HCT centers.
Approach: A high-level process flow diagram was generated to understand patient flow at a 6-bed HCT unit within a hospital in Ontario and validated through consultation. This flow diagram was used to construct a system dynamics model to simulate patient flow. The model was parameterized with data from CCO, Discharge Abstract Database, and with hospital and clinical expert input. The effects at six months were projected for five scenarios: 1) current state; 2) increase bed capacity by 1 bed; or 3) increase bed capacity by 2 beds; 4) increasing patient demand by 20 patients per year; 5) combination of scenarios 3 and 4. Provincial clinical consensus established a benchmark wait time of 42 days for ALLOHCT from ready to transplant to the transplant date. In addition, the estimated number of beds required to reduce the wait times to the provincial benchmark within 1 year was calculated.
Results:The addition of 1 ALLOHCT bed resulted in a reduction of 22% and 11% to the ALLOHCT wait times and wait lists, respectively. The addition of 2 beds resulted in a reduction of 38% and 22% to the wait times and wait lists, respectively. If the demand increases by 20 patients per year, the addition of 2 beds resulted in a reduction of 16% in the wait times and while the wait list may experience a brief reduction, after 6 months, the wait list size will have increased by 9% as a result of the increased demand. In order to reduce the wait times to the provincial benchmark within 1 year, an additional 8 beds are needed.
Considerations: Concurrent planning for additional health human resources (physicians, nurses, etc…) needs to be done to ensure the additional beds are adequately staffed. This model also only considers the effects of adding beds within 1 year. There may be instances where bed space cannot be immediately opened and new capital is required. Additionally, the demand for ALLOHCT continues to increase, which in turn drives up the number of arrivals to the queue. A multi-year model will be built to account for timing of bed openings and increasing demand for ALLOHCT.
Conclusion:Using a system dynamics model, we are able to quantify the relationship between ALLOHCT bed capacity and wait times at an HCT center. This model can be used to estimate the ALLOHCT bed requirements for sites in other jurisdictions where ALLOHCT demand and wait time benchmarks are known.

Disclosures
Kouroukis: Janssen: Research Funding; Karyopharm: Research Funding.
Splenectomy Protects Humans from Red Cell Alloimmunization
Authors: Evers Dorothea , van der Bom Johanna G , Tijmensen Janneke , de Haas Masja , Middelburg Rutger A , de Vooght Karen , van de Kerkhof Daan , Visser Otto , Pequeriaux Nathalie , Hudig Fransisca , Zwaginga Jaap Jan 
Published: October 2019

Abstract
Background and aim
Being the primary organ that clears and processes ageing and damaged red cells, the spleen has been suggested to play a central role in red cell alloimmunization in mice experiments. We evaluated the effect of splenectomy on the occurrence of red cell alloimmunization in humans.
Methods
We performed a nested case-control study among a source population of 24,063 patients who received their first and subsequent red cell transfusion in one of six participating hospitals in the Netherlands between 2005 and 2013. Cases were defined as patients who developed a first transfusion-induced clinically relevant red cell alloantibody. Each case was matched to two non-alloimmunized control patients, based on the number of (lifetime) transfusions and the hospital. Using multivariate logistic regression analyses, we evaluated the association between (a history of) splenectomy and the risk for alloimmunization.
Results
Among a source population of 24,063 patients, 505 patients (2.1%) developed red cell alloantibodies and were matched to 1,010 controls. Splenectomy had been performed in one case and 19 controls. In 12 patients, splenic injury was caused by severe trauma or complicated abdominal surgery. No patient underwent a splenectomy in the context of an autoimmune disease.
Using multivariate logistic regression analysis with conditioning on identified potential confounders, we found that splenectomized patients had a 20-fold reduced risk of alloimmunization as compared to patients lacking a history of splenectomy (adjusted RR 0.05, 95% confidence interval (CI) 0.01-0.55).
With the assumption that the red cell exposure patterns of the 19 splenectomized controls represented the red cell exposure pattern of all splenectomized patients within the source population we estimated that the total number patients with alloimmunization after splenectomy was 24; yielding a RR of 0.04 which confirms our logistic regression based RR.
Interpretation
In conclusion, in accordance with the findings in mice, our findings suggest that splenectomized patients are strongly protected from primary red cell alloimmunization.

Disclosures
No relevant conflicts of interest to declare.
Gut Colonization with Carbapenem Resistant Enterobactriaceae (CRE) Adversely Impacts the Outcome in Patients with Hematological Malignancies: Results of a Prospective Surveillance Study
Authors: Jaiswal Sarita Rani , Gupta Satyanker , Sherawat Amit , Vinod Seena , Jacob Hensey , Abraham Sajin V , Chaturvedi Anushree , Chakrabarti Suparno 
Published: October 2019

Abstract
CRE is the major concern in the patients suffering from hematological malignancy but the data on the impact of colonization in such patients is scarce. We conducted a prospective surveillance study of CRE on 225 patients of haematological malignancies (HM), who required hospital admission between October 2013 to January 2016. The median age of the cohort was 45 years(range,2-84). The cohort included a broad representation of diseases; AML (n=58), ALL(n=44), Lymphoma (n=76), Myeloma(n=22), CML(8) and Others (n=17). Rectal swabs were taken for cultures in all patients during first day of admission and repeated subsequently on weekly basis for continuous hospital stay or in subsequent admissions.47 (21%) patients were colonized with CRE on admission. This increased to 45% on prolonged hospital stay/ contact for more than 4 weeks with 72 (32%) patients being colonized overall. The highest number of patients colonized with CRE at diagnosis was those with AML (30%). The non-relapse mortality (NRM) of the cohort at 6 months was 10.3%. This was 14% in those with acute leukemia compared to 5.8% in others (p=0.02). Furthermore, this was highest in patients with AML (22.9% vs 6.1% in others; p=0.001). CRE related events accounted for 77% of mortality. NRM was 29.6% in those colonized with CRE during hospitalization compared to 10.5% in those colonized at admission with no NRM in those not colonized with CRE (p=0.0001). Amongst patients with AML, colonization with CRE during hospitalization was associated with a NRM of 54.9%(95%CI 32.4-67.4%) compared to those colonized at admission(11.8; 95%CI 4.0-19.6) and those not colonized(0%)(p=0.0001). This trend was true for patients without AML as well (27.3% vs 10.3% vs 0%; p=0.0001). On multivariate analysis, colonization with CRE during hospitalization was the most important risk factor for NRM in patients with hematological malignancies (HR-7.1; 95%CI 3.1-16.1). Our data demonstrates that a substantial proportion of patients with HM are colonized with CRE without prior hospitalisations but those with nosocomial colonization have the highest risk of mortality, particularly in those with AML.
Figure Figure.

Disclosures
No relevant conflicts of interest to declare.
Adenosine A2B Receptor Promotes Erythrocyte Oxygen Release to Counteract Tissue Hypoxia and Injury
Authors: Peng Zhangzhe , Luo Renna , Song Anren , Sun Kaiqi , Liu Hong , Zhang Yujin , Adebiyi Morayo G. , Xia Yang , Kellems Rodney E. , Huang Aji 
Published: October 2019

Abstract
Insufficient tissue oxygen (O2) availability (hypoxia) is commonly seen in patients with cardiovascular diseases (CVD), chronic kidney diseases (CKD), respiratory diseases, hemolytic disorders and certain cancers. Without interference, pathological hypoxia is dangerous because it promotes disease progression, organ damage and failure. Although erythrocyte is the only cell type responsible for delivering O2, its function in pathological tissue hypoxia remains largely unknown. Here using unbiased high throughput metabolomic profiling, we found that 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite enhancing O2 delivery, was significantly induced in the erythrocytes of mice infused with angiotensin II (Ang II), a potent vasopeptide commonly increased in the circulation of CVD and CKD patients to induce tissue hypoxia and injury via vasoconstriction. Mouse genetic studies demonstrated that Ang II induced local tissue accumulation of adenosine and that elevated adenosine-mediated erythrocyte A2B adenosine receptor (ADORA2B) activation was beneficial by inducing 2,3-BPG production, triggering O2 release to prevent multiple tissue hypoxia, inflammation and kidney damage. Mechanistically, we revealed that AMPK is an intracellular signaling molecular functions downstream of ADORA2B underlying elevated 2,3-BPG production by inducing BPG mutase activity. Finally, we translated our mouse study to human and confirmed that the levels of 2,3-BPG and P50 were elevated in erythrocytes of mild CKD patients compared to healthy individuals and further increased in severe CKD patients compared to mild CKD patients. Taken together, we demonstrate that erythrocyte ADORA2B plays a key protective role in Ang II-induced tissue damage by increasing 2, 3-BPG and oxygen release to counteract tissue hypoxia.

Disclosures
No relevant conflicts of interest to declare.
Haptoglobin and Hemopexin Infusion Efficiently Activates the Nrf2/HO-1 Axis and Inhibits Inflammation and Vaso-Occlusion in Murine Sickle Cell Disease
Authors: Belcher John D , Chen Chunsheng , Nguyen Julia , Abdulla Fuad , Nguyen Phong , Nguyen Hao , Zhang Ping , Brinkman Nathan , Vercellotti Gregory M 
Published: October 2019

Abstract

Free hemoglobin and hemin, released by red blood cells during intravascular hemolysis, promote vasculopathy, inflammation, thrombosis, and renal injury. Plasma haptoglobin and hemopexin tightly bind free hemoglobin and hemin, respectively, thwarting these clinical sequelae. In sickle cell disease (SCD), chronic hemolysis can deplete plasma haptoglobin and hemopexin in humans and mice. To explore mechanisms mediating this protection and provide a basis for supplementation in SCD patients, dorsal skin fold chambers were implanted onto Townes-SS mice and microvascular stasis (% non-flowing venules) was measured in response to a hemoglobin challenge. Human haptoglobin, hemopexin, or albumin was co-infused with hemoglobin or 1 hour after hemoglobin at equimolar concentrations. Sickle mice co-infused with hemoglobin/haptoglobin, hemoglobin/hemopexin or hemoglobin/haptoglobin/hemopexin had less stasis 1 to 4 hours after infusion, compared to albumin- and saline-treated mice (*p<0.01, Figure A). Haptoglobin, hemopexin, or haptoglobin/hemopexin given to Townes-SS mice 1 hour after hemoglobin, decreased stasis 2 and 3 hours after supplementation, while the venules of mice treated with albumin remained static (*p<.01, Figure B). Plasma hemoglobin and heme levels in Townes-SS mice were not different between treatment groups 3 and 4 hours after supplementation. Haptoglobin or hemopexin infusion increased hepatic Nrf2 and HO-1 and decreased pro-inflammatory NF-ĸB phospho-p65 expression relative to albumin 3 and 4 hours after supplementation (p<.05). The combination of haptoglobin/hemopexin was similar to either scavenger alone. Inhibition of the enhanced HO-1 activity afforded by haptoglobin or hemopexin with tin protoporphyrin blocked the stasis protection, confirming the critical cytoprotective role of HO-1. Haptoglobin and hemopexin, but not albumin, are cytoprotective in part by efficiently delivering heme to CD163 and CD91 and activating the Nrf2/HO-1 axis.
Figure Figure.

Disclosures
Belcher: CSL-Behring: Research Funding; Imara: Research Funding. Chen:Imara: Research Funding. Brinkman:CSL-Behring: Employment. Vercellotti:CSL-Behring: Research Funding; Imara: Research Funding.
Novel Lyn-Mediated Regulation of CLEC-2 Signaling By Gq-Coupled Receptors in Platelets
Authors: Badolia Rachit , Inamdar Vaishali , Manne Bhanukanth , Dangelmaier Carol , Kunapuli Satya P. 
Published: October 2019

Abstract
The CLEC-2 agonist, rhodocytin, elicits powerful platelet activation signals in conjunction with Src family kinases, Syk, and PLCg2. Previous reports have shown that rhodocytin-induced aggregation is dependent on secondary mediators. However, the role of secondary mediators in CLEC-2 signaling is not defined. In this study we report that CLEC-2-induced Syk activation is aspirin-sensitive and that TxA2 plays an important role in the most proximal events such as CLEC-2 phosphorylation and Syk activation. We also show that the activation of other GPCRs, such as the ADP receptors and PARs, can also potentiate CLEC-2 signaling. By using the Gq-inhibitor, UBO-QIC, or P2Y1/P2Y12 antagonists, we show that the Gq-signaling, but not G12/13 or Gi, is essential for GPCR-induced Syk phosphorylation downstream of CLEC-2. We further elucidated the signaling involved in Gq-mediated Syk phosphorylation and identified an important role for PKCs downstream of PLCb regulating SFK activation (Figure 1A). Using Lyn-knock out murine platelets we identified a potential role for Lyn downstream of the Gq-pathway in potentiating CLEC-2 signaling by using. We suggest that, at low concentration of CLEC-2 agonist, the unclustered CLEC-2 receptors are phosphorylated by the Gq-activated Lyn resulting in the potentiation of the initial CLEC-2 signal (Figure 1B). However, Gq receptors by themselves cannot phosphorylate CLEC-2 receptors and require minimal levels of ITAM-containing receptor stimulation in order to initiate unclustered CLEC-2 receptor phosphorylation. Together, these results provide evidence for a novel Lyn-mediated regulation of CLEC-2 signaling by Gq-coupled receptors thereby leading to potentiation of CLEC-2-induced signaling (Figure 1C).
Figure 1 A) Western blot showingeffect Gq-pathway inhibitors on CLEC-2 signaling. B) Effect of low concentration of CLEC-2 agonist in Lyn-knock out murine platelets. C) Model showing role of Gq-activated Lyn in CLEC-2 signaling. Figure 1. A) Western blot showingeffect Gq-pathway inhibitors on CLEC-2 signaling. B) Effect of low concentration of CLEC-2 agonist in Lyn-knock out murine platelets. C) Model showing role of Gq-activated Lyn in CLEC-2 signaling.

Disclosures
No relevant conflicts of interest to declare.