bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental and Socioeconomic Factors Influence the Live‐Born Incidence of Congenital Heart Disease: A Population‐Based Study in California
Authors: Peyvandi Shabnam , Baer Rebecca J. , Chambers Christina D. , Norton Mary E. , Rajagopal Satish , Ryckman Kelli K. , Moon‐Grady Anita , Jelliffe‐Pawlowski Laura L. , Steurer Martina A. 
Published: April 2020

BACKGROUND

The development of congenital heart disease (
CHD
) is multifactorial with genetic and environmental influences. We sought to determine the relationship between socioeconomic and environmental factors with the incidence of
CHD
among live‐born infants in California and to determine whether maternal comorbidities are in the causal pathway.

METHODS AND RESULTS

This was a population‐based cohort study in California (2007–2012). The primary outcome was having significant
CHD
. Predictors included socioeconomic status and environmental exposure to pollutants determined by U.S. Census data. A social deprivation index and environmental exposure index was assigned based on neighborhood socioeconomic variables, categorized into 4 quartiles. Quartile 1 was the best with the least exposure to pollutants and social deprivation, and quartile 4 was the worst. Multivariate logistic regression and mediation analyses were performed. Among 2 419 651 live‐born infants, the incidence of
CHD
was 3.2 per 1000 live births. The incidence of
CHD
was significantly higher among those in quartile 4 compared with quartile 1 (social deprivation index: 0.35% versus 0.29%; odds ratio [OR], 1.31; 95% CI, 1.21–1.41; environmental exposure index: 0.35% versus 0.29%; OR, 1.23; 95% CI, 1.15–1.31) after adjusting for maternal race/ethnicity and age and accounting for the relationship between the 2 primary predictors. Maternal comorbidities explained 13% (95% CI, 10%–20%) of the relationship between social deprivation index and environmental exposure index with the incidence of
CHD
.

CONCLUSIONS

Increased social deprivation and exposure to environmental pollutants are associated with the incidence of live‐born
CHD
in California. Maternal comorbidities explain some, but not all, of this relationship. These findings identify targets for social policy initiatives to minimize health disparities.
Extreme disruption of heterochromatin is required for accelerated hematopoietic aging
Authors: Keenan Christine R. , Iannarella Nadia , Naselli Gaetano , Bediaga Naiara G. , Johanson Timothy M. , Harrison Leonard C. , Allan Rhys S. 
Published: April 2020

Abstract
Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell types. However, a comprehensive analysis of hematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in hematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on hematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced hematopoietic stem cell function, thymic involution and decreased lymphoid output with a skewing toward myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied by molecular changes consistent with aging, including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the hematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire hematopoietic system from changes associated with premature aging.
The CXCR4 Score: A New Prognostic Marker in Acute Myelogenous Leukemia.
Authors: Spoo Anke C. , Wierda William G. , Burger Jan A. 
Published: April 2020

Abstract
Despite major improvements in the understanding and treatment of certain leukemias during the past years, the overall survival of patients with acute myelogenous leukemia (AML) remains poor and new prognostic markers and therapeutic strategies are urgently needed. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play key roles in retention of hematopoietic cells in the marrow microenvironment and release into the circulation. Rambouts and colleagues recently reported that CXCR4 expression on AML cells correlates with Flt3 mutations and prognosis (Blood 104: 550-57, July 2004). The aim of our study is to evaluate the prognostic significance of CXCR4 surface expression by AML blasts. Ninty newly diagnosed patients with AML were were divided into three groups based on expression of CXCR4 by AML blasts (CXCR4 score A–C). Group A contains patients with a mean fluorescence intensity ratio (MFIR) for CXCR4 &lt;5 (n=32), group B: MFIR 5–10 (n=26), and group C: MFIR &gt;10 (n=32). MFIR was calculated by divding the mean flourescence intensity for CXCR4 by that for the non-specific isotype control of the respective sample and indicates the level of CXCR4 expression. The characteristics for each group are summarized in Table 1.
Previously, we demonstrated that CXCR4 receptors on AML cells mediate adesion and induce migration beneath marrow stromal cells (Burger JA,et al., Br J Haematol. 122: 579–89, August 2003). Because adhesion to stromal elements can affect survival and induce adhesion-mediated drug resistance, antagonists of the CXCR4/SDF-1 axis may increase the efficacy of current treatments. We conclude that CXCR4 expression at time of diagnosis correlates with leukocytosis, LDH, blast persistence after first therapy, relapse rate, and survival. Therfore, CXCR4 expression in AML may be an important progostic factor for complete remission and survival. As such, CXCR4/SDF-1 interaction may provide the basis for a novel therapeutic approach in AML.
Characteristic Score A (N=32) Score B (N=26) Score C (N=32) Median CXCR4 MFIR (range) 2.8 (1.0–4.9) 6.9 (5.1–9.4) 17.2 (10.3–73.4) Median Age (range) 62.0 (21–89) 59.5 (18–80) 65.0 (32–93) Median WBC (range) 2.3 (1.0–14.0) 10.2 (10.2–17) 30.0 (2.7–240) Median PLT (range) 56.0 (8–211) 86.0 (13.6–265) 82.5 (4–218) Median LDH (range) 251.5 (140–2637) 368.0 (187–1489) 357.0 (144–2760) Unfavorable Cytogenetics 4/28 10/24 7/27 blast persistence after first therapy N=6, 22.2% N=13, 65% N=14, 73.7% Relapse Rate 13.8% 52.4% 40% Total Deaths N=7, 21.9% N=13, 50% N=17, 53.1% Mean overall survival (months) 12.4±11.9 10.3±9.8 8.3±7.4 Mean follow-up (months) 12.0±19.7 Median Overall Survival (months) 9.0 (2–52) 6.5 (0–42) 7.0 (0–25) Median follow-up (months) 7.0 (0–52)
Table
Favorable Outcome of High-Risk Mediastinal Diffuse Large B-Cell Lymphoma (DLBCL) after Dose-Intensive Chemotherapy, Rituximab and Autologous Transplant (ASCT).
Authors: Pytlik R. , Kubackova K. , Kozak T. , Belada D. , Pirnos J. , Jankovska M. , Pukyova J. , Papajik T. , Siffnerova H. , Zak P. , Vasova I. , Hamouzova M. , Trneny M. 
Published: April 2020

Abstract
Background. According to the gene expression profiling studies, mediastinal variant of DLBCL is closely related to classical Hodgkins lymphoma (HL). As dose-intensive chemotherapy markedly improves survival in advanced HL, we investigated whether the same is true for high-risk mediastinal DLBCL.
Methods. Since 1998, three studies utilising dose-intensive chemotherapy with ASCT for high-risk DLBCL (aaIPI 2–3) were conducted by Czech Lymphoma Study Group. From 1998–1999, patients were induced with 3–4 cycles of MegaCHOP every 3 weeks (Cyclophosphamide, 3 g/m2 d 1, Vincristin 2 mg d 1, Doxorubicin 75 mg/m2 d 1, Prednison 60 mg/m2 d 1–5, G-CSF 5 ug/kg from day 6) and consolidated with BEAM and ASCT (Protocol 1). From 2000–2002, patients received 3 cycles of MegaCHOP, followed by 3 cycles of ESHAP and BEAM with ASCT (Protocol 2). From 2002, 4–6 doses of Rituximab 375 mg/m2 were added to the previous regimen (Protocol 3). Outcome of patients with mediastinal DLBCL was compared with outcome of other DLBCL patients treated by the same protocols with log-rank test.
Results. 24 patients with mediastinal DLBCL with at least 12 months follow-up were identified. Their median age was 26 years (range, 21–59) and 15 of them were women (62%). 88% of patients had stage IV disease based on extensive pulmonary, pleural or pericardial involvement and 25% of patients had subfrenic disease. LDH was elevated in 88% of cases. Nine patients were aaIPI 2 (38%) and 14 patients aaIPI 3 (58%). Five patients were treated with Protocol 1 (21%), 9 with Protocol 2 (37%) and 10 with Protocol 3 (42%). 22 patients (92%) were successfully mobilized after one of the induction cycles with median 8.03x106 CD34+ cells/kg collected and 21 of them were transplanted as a part of primary treatment (88%). After chemotherapy and ASCT, there were 18 CR (75%) and 4 PR (17%). Twenty patients (84%) were further consolidated by mediastinal radiotherapy because not being in CR or because of bulky disease at diagnosis. Overall, 21 patients achieved CR and one achieved PR at the end of the treatment (ORR, 92%). Two patients progressed on treatment and two other relapsed; three of these were salvaged by additional therapy. After median follow-up of 31 months (12–70), the 3-year FFS is 87% and OS is 95%. Compared with other DLBCL patients, patients with mediastinal DLBCL had significantly better 3-year survival (95% v. 64%, p = 0.007).
Conclusion. Dose-intensive chemotherapy in high-risk mediastinal DLBCL patients leads to equally good results as in advanced Hodgkins lymphoma patients. Further studies are needed with aim to reduce the treatment burden while maintaining the efficacy of the therapy.
Phase 1 Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Concomitant Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine (HDAra-C) Consolidation in Newly Diagnosed Patients with AML.
Authors: Giles Francis , Schiffer C. , Kantarjian H. , Fischer T. , Paquette R. , Pelov D. M. , Resta D. J. , Cohen P. S. , Wang Y. F. , Stone R. 
Published: April 2020

Abstract
The Fms-like tyrosine kinase 3 (FLT3), a receptor expressed in 80% of AML patients, is constitutively activated in 25–35% of adult AML patients due to mutations, in the form of either ITDs or activating loop point mutations, most commonly at D835Y. PKC412 is an oral multi-targeted tyrosine kinase inhibitor known to potently inhibit both activated wild type (WT) and mutated (mut) FLT3 kinase. PKC412 (100 mg po bid) was tested in a phase IB study in newly diagnosed AML patients between 18 and 60 years of age (both WT and mut FLT3) in combinations with DA for induction therapy (up to 2 cycles) and HDAra-C for consolidation (up to 3 cycles).
Study design: PKC412 was given daily beginning on Day 8 (Arm 1) or Day 1 (Arm 2) of induction chemoRX in cycle 1. Primary endpoints were PK, tolerability, and safety as defined by fewer than 2 drug-related deaths in the initial cohort of 6 pts per arm (stage 1) and fewer than 4 drug-related deaths among the total 20 pts per arm (stage 2) during induction.
Results: 15 pts were enrolled (median age 50; 1 FLT3 ITD+, 14 WT; ): 7 in Arm 1 and 8 in Arm 2. Cytogenetic prognostic categories of the 15 patients were: 0 (good), 9 (intermediate) and 6 (bad). Of the 15 pts, 14 were evaluable for toxicity; 1 pt did not receive PKC412; no drug-related deaths were observed during induction therapy. The most common G3 drug-related toxicities included: nausea (46%), vomiting (32%), transaminitis (18%), and hyperbilirubinemia (18%), all were transient and/or reversible. 13/15 patients were evaluable for response: 2 pts were not evaluated: one pt never received PKC412 and one pt did not complete the full-course of induction chemoRx; 3/7 (43%) achieved a CR in Arm 1 and 3/6 (50%) achieved a CR in Arm 2. 3 pts have completed the study (Days 143, 141, 132) and one pt is ongoing (Day 127). Because of the high rate of G3 nausea and vomiting, the study was amended, (5 patients are ongoing) such that PKC412 is given with each cycle of chemoRx on either Days 1–7 and 15–21 (Arm 1), or on Days 8–21 (Arm 2).
Conclusions: PKC412 can be given safely in newly diagnosed AML patients in combinations with DA and HDAra-C chemoRx. An update of this study, along with PK data of PKC412, daunorubicin, and Ara-C levels will be presented.
Possible Relation of Crohn’s Disease and Hereditary Thrombophilia: Detection of ASCA Seropositivity. (Preliminary Results).
Authors: Lazaraki Georgia , Girtovitis Fotios , Dokas Stefanos , Pithara Eleftheria , Tsaousidou Maria , Spartali Aikaterini , Makris Pantelis 
Published: April 2020

Abstract
Introduction: Hereditary thrombophilia (Factor V Leiden mutation -FV G1691A, FVL, FII G20210A -prothrombin mutation), has been reported to be correlated to Crohn’s disease (CD) by some studies. The determination of anti- Saccharomyces Cerevisiae IgA and IgG Antibodies (ASCA) have been described as important serological marker for the differential diagnosis of CD. The aim of the study was to evaluate ASCA seropositivity in a high-risk population (i.e. thrombophilic patients, pts) for CD.
Material-Methods: From April to July 2004, 37 patients (16 men, 21 women, mean age 52,5± 9.6 years old) with hereditary thrombophilia and 28 healthy control subjects (16 men, 12 women, mean age 51,3 ± 8.5 years) were included in the study. Fasting blood samples were drawn from patients and control subjects were examined for serum p-ANCA, ASCA IgA and IgG titers. Pts and control subjects were matched for age, sex and smoking and had to fill a questionnaire concerning history of rectal bleeding, diarrhea lasting longer than 4 weeks, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).Colonoscopy or flexible sigmoidoscopy was proposed to all patients and controls when reported an alarm symptom. ASCA IgA and IgG titers were measured with quantitative enzyme immunoassay method (Medizym ASCA IgG, Medizym ASCA IgA, and MEDIPAN, GERMANY).
Results: In the patient group 8 pts reported IBS symptoms, 2 had history of rectal bleeding while none IBD or chronic diarrhea. In the control group 6 patients reported IBS symptoms while none IBD, rectal bleeding or chronic diarrhea (p&gt;0,05). Ten and 15 pts were found to be positive for ASCA IgG and IgA respectively. In the control group, 6 and 10 subjects were found to be positive for ASCA IgG and IgA respectively (p&lt;0,05 and p&lt;0,1 respectively).
Conclusions: Thrombophilic pts, a high-risk population for CD, present an important rate of ASCA IgG and IgA seropositivity. Although these are preliminary results, thrombophilic pts should be screened for ASCA and some of them with colonoscopy. ASCA seropositivity in the control group was found to be greater than in the literature but this may be explained by the small sample.
A Detailed Phenotypic Analysis Using Six Color Flow Cytometry of Lymphocyte Subsets Mobilized with AMD3100 Compared to G-CSF.
Authors: Takahashi Yoshiyuki , Chakrabarti S. , Sriniivasan R. , Lundqvist A. , Read E.J. , Khuu H. , Leitman S. , Bolan C. , Barrett A.J. , Calandra G. , Childs Richard 
Published: April 2020

Abstract
AMD3100 (AMD) is a bicyclam compound that rapidly mobilizes hematopoietic progenitor cells into circulation by inhibiting stromal cell derived factor-1 binding to its cognate receptor CXCR4 present on CD34+ cells. Preliminary data in healthy donors and cancer patients show large numbers of CD34+ cells are mobilized following a single injection of AMD3100. To determine whether AMD3100 mobilized cells would be suitable for allografting, we performed a detailed phenotypic analysis using 6 color flow cytometry (CYAN Cytometer MLE) of lymphocyte subsets mobilized following the administration of AMD3100, given as a single 240mcg/kg injection either alone (n=4) or in combination with G-CSF (n=2: G-CSF 10 mcg/kg/day x 5: AMD3100 given on day 4). Baseline peripheral blood (PB) was obtained immediately prior to mobilization; in recipients who received both agents, blood was analyzed 4 days following G-CSF administration as well as 12 hours following administration of AMD3100 and a 5th dose of G-CSF. AMD3100 alone significantly increased from baseline the PB WBC count (2.8 fold), Absolute lymphocyte count (ALC: 2.5 fold), absolute monocyte count (AMC: 3.4 fold), and absolute neutrophil count (ANC: 2.8 fold). Subset analysis showed AMD3100 preferentially increased from baseline PB CD34+ progenitor counts (5.8 fold), followed by CD19+ B-cells (3.7 fold), CD14+ monocytes (3.4 fold), CD8+ T-cells (2.5 fold), CD4+ T-cells (1.8 fold), with a smaller increase in CD3−/CD16+ or CD56+ NK cell counts (1.6 fold). There was no change from baseline in the % of CD4+ or CD8+ T-cell expressing CD45RA, CD45RO, or CD56, CD57, CD27, CD71 or HLA-DR. In contrast, there was a decline compared to baseline in the mean percentage of CD3+/CD4+ T-cells expressing CD25 (5.5% vs 14.8%), CD62L (12.1% vs 41.1%), CCR7 (2.1% vs 10.5%) and CXCR4 (0.5% vs 40.9%) after AMD3100 administration; similar declines in expression of the same 4 surface markers were also observed in CD3+/CD8+ T-cells. A synergistic effect on the mobilization of CD34+ progenitors, CD19+ B cells, CD3+ T-cells and CD14+ monocytes occurred when AMD3100 was combined with G-CSF (Figure). In those receiving both AMD3100 and G-CSF, a fall in the % of T-cells expressing CCR7 and CXCR4 occurred 12 hours after the administration of AMD3100 compared to PB collected after 4 days of G-CSF; no other differences in the expression of a variety activation and/or adhesion molecules on T-cell subsets were observed. Whether differences in lymphocyte subsets mobilized with AMD3100 alone or in combination with G-CSF will impact immune reconstitution or other either immune sequela (i.e. GVHD, graft-vs-tumor) associated with allogeneic HCT is currently being assessed in an animal model of allogeneic transplantation.
Are There Potential Predictors for Response to Enoxaparin in the Neonatal Population?.
Authors: McCusker Patricia J. , Punter Fiona A. , Israels Sara J. , Seshia Mary M.K. , Seifert Blair W. 
Published: April 2020

Abstract
The recognition of thromboembolic events (TE) in the pediatric population is increasing. Recently, effort has been directed at determining the correct dosing of low molecular weight heparins necessary to achieve the therapeutic heparin concentration. It has been noted by our group and others that a higher dose of enoxaparin is required for the neonatal population than was originally proposed in the literature. Currently, the reason for this is not understood. Retrospectively, we examined our population of neonates for possible factors that may affect the dose requirements: the presence of sepsis (sepsis is felt to increase the need of heparin by an as yet unknown mechanism), level of antithrombin (AT; it is the protein whose action is accelerated by the presence of heparin and is normally low in the neonate), FVIII (elevated levels &gt;200% have been associated with increased risk of TE) and fibrinogen (an acute phase reactant).
Results: Twenty-five neonates were treated with subcutaneous enoxaparin for venous and arterial TE over a two year period. A total of 84% (21/25), had antithrombin (AT), Factor VIII and fibrinogen levels measured. All AT levels were drawn at the time of diagnosis, prior to initiating enoxaparin. The majority of, but not all, FVIII and fibrinogen levels were drawn at diagnosis. A starting dose of at least 1.6 mg/kg/dose of enoxaparin was received by 18/25 (72%). Therapeutic heparin levels (0.5 –1.0 aXa units/mL) at first measure were achieved in 12/18 (67%) patients. The range of enoxaparin dosages needed to achieve therapeutic heparin levels was 1.42–2.2 mg/kg/dose. The above factors were each compared to the dosage (mg/kg) required to attain a therapeutic heparin concentration. None of these factors appeared to clearly predict for a higher enoxaparin dosage in our population. It is interesting to note that those patients with sepsis seem to need a higher than usual dosage of enoxaparin to achieve a therapeutic heparin level. However, the number of patients in this group is too few to verify this observation.
Conclusions: Higher doses of enoxaparin are needed to treat neonates with TE. We recommend an initial dosage of enoxaparin of 1.65–1.75 mg/kg/dose based on actual body weight for neonates with TE. AT levels at the beginning of therapy, as well as FVIII and fibrinogen levels, are not predictive of the need for higher dosage requirements of low molecular weight heparin in the newborn. A greater number of patients are necessary to substantiate the observation that sepsis may be an important predictor of initial enoxaparin dosage in the neonatal population.
Resolution of Catastrophic Anti Phospholipid Antibody Syndrome with Acute Renal Failure after Treatment with Rituximab.
Authors: Shurafa Muhammad S. , Babbar Nidhika , Khairullah Quresh 
Published: April 2020

Abstract
Antiphospholipid antibody syndrome (APS) is a thrombophilic disorder defined by the presence of recurrent thrombosis associated with anticardiolipin antibodies (ACA). To date, there is no effdective therapy for this condition. Rituximab, a chimeric monoclonal antibody B Cells has been shown to be effective in autoimmune disorders. Sporadic abstracts have reported the disappearance of ACA after Rituximab treatment. We have successfully treated a patient with primary catastrophic APS and renal failure with Rituximab. Case Report: A thirty seven year old male with history of DVT, ischemic cardiomyopathy and cerebrovascular accident was admitted to the Hospital for the treatment of acute renal failure and thrombocytopenia. Physical examination was significant for cognitive deficits, mild hepatomegaly, generalized livido reticulairs, and acrocyanosis. Laboratory data revealed platelet count of 97000, creatinine 3.4 mg/dl, IgG ACA titer of 43.8 and negative IgM ACA and ANA. He had proteinuria with benign urinary sediment. Kidney biopsy showed thrombotic microangiopathy. Plasmaphersis was initiated and hemodialysis for the rapidly progressing renal failure. He continued his treatment in an outpatient hemodialysis unit while on Coumadin. Four weekly cycles of Rituximab were given as an outpatient. Serial laboratory investigations showed gradual normalization of the platelet count and disappearance of the IgG ACA. Gradually renal function recovered and hemodialysis was discontinued after three months. He remains in remission with no further thrombotic events.Conclusion: Rituximab is promising in the treatment of APS and must be considered in the first;line treatment of catastrophic APS. A clinical trial is necessary to test the feasibility of discontinuing anticoagulation in these patients.
PERTINENT LABORATORY DATA
DATE HEMOGLOBIN PLATELETS CREATININE ACA TITER 03/21/02 1.4 11/15/03 14.4 97 3.4 11/21/03 12.5 100 6.2 43.8 12/01/03 12.2 222 ON DIALYSIS 16.1 01/01/04 14.1 276 ON DIALYSIS 20.9 03/17/04 14.1 276 ON DIALYSIS 05/05/04 11.3 330 3.3 NEGATIVE