bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombotic Complications in Inflammatory Bowel Disease: The Role of Coagulation Markers and Family History
Authors: Algahtani Farjah , Altuwaijri Mansour , Saeed Maria , Aljebreen Abdulrahman , Aleem Aamer , Sewaralthahab Sarah , Alotaibi Ghazi S , Alanazi Abdulelah , Azzam Nahla , Almadi Majid , AlHarbi Othman 
Published: December 2023

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized mainly by intestinal pathology. The risk of thrombosis increases in IBD patients, increasing overall disease morbidity and mortality. We aim to investigate the role of coagulation markers in determining the risk of thrombotic complications in IBD patients compared to healthy controls.
Methods: The study was approved by the institutional review board. All patients aged 16 or over, diagnosed with IBD and followed at our center from January 2012 -2022, were included. We investigated the family history and the hemostatic profiles of these patients. Descriptive statistics were computed for continuous variables, including means, standard deviations (SDs), minimum and maximum values, as well as 95% confidence intervals (CIs), where appropriate, and frequencies for categorical variables. Fisher exact test was used for categorical variables. Student t-test was used for continuous variables.
Results: A total of 100 patients were included in the study, comprising of 51 (24%) females and 158 (76%) males. 73% of patients were diagnosed with Crohn's disease (CD), and 27% with ulcerative colitis (UC). Deep vein thrombosis (DVT) was observed in 5 (2.3%) of patients. In patients with a family history of DVT, 1.9% had developed a thrombotic event. Among continuous variables, prothrombin time, thrombin clotting time, and fibrinogen levels had mean values significantly different for patients with thrombosis than those without thrombosis ( p-values 0.01, 0.01, and 0.03, respectively).
Conclusions: Patients with both UC and CD are at an increased risk of thrombosis. A family history of IBD can increase the risk of these events. The coagulation markers, including PT, TTC, and fibrinogen levels, can be used as biomarkers to predict the risk of thrombosis and the evaluation of the hemostatic profiles of IBD patients regularly, which can help prevent serious thrombotic complications and thus reduce morbidity and mortality resulting from these events. Therefore, such evaluation should be included in the routine examination protocols of high-risk IBD patients. This study may help better understand the biology of disease.
Development of a Novel, Allogeneic GPRC5D-Directed CAR for Treatment of Multiple Myeloma Patients
Authors: Kinder Jeremy , Estrada Chanel Athena , Granger Brian , O'Rourke Allison , Liang Ouwen , Lampano Aaron , Zipp Garrett , Chaturvedi Vandana , Hu Xiaomeng , Young Chi , van Hoeven Neal , Schrepfer Sonja , Fry Terry J. 
Published: December 2023

Despite the success of BCMA-targeted therapy in advanced multiple myeloma, the disease is still considered incurable. Relapse following BCMA-directed cellular and antibody-based therapies is commonly associated with decreased surface expression of BCMA on malignant plasma cells. The G protein-coupled receptor, class C group 5 member D (GPRC5D) represents an additional target whose expression is limited to bone marrow and hair follicles, with selectively increased expression on malignant plasma cells. Thus far, the use of GPRC5D-targeted CAR T cells has provided a strong clinical benefit in multiple myeloma with limited on-target, off-tumor effects. To this end, we have validated novel, fully human GPRC5D-specific CARs for use with our hypoimmune (HIP), allogeneic CAR T cell platform. This will allow rapid delivery of allogeneic GPRC5D CAR T cells from healthy donors that simultaneously circumvent “non-self” recognition through TCR, B2M and CIITA gene disruption and promote persistence through innate immune evasion by leveraging CD47 overexpression.
For early selection of candidate GPRC5D binders, T cells from healthy donors were transduced with VSV-G pseudotyped lentivirus containing second-generation, fully-human GPRC5D CARs. A clinically validated GPRC5D CAR was produced in similar fashion and used as benchmark control for initial characterization experiments. Transduction efficiency of GPRC5D CARs was analyzed via flow cytometry. GPRC5D CAR efficacy was analyzed in vitro via 24-hour luciferase or long-term Incucyte cytotoxicity assays against RPMI-8226 and MM.1S multiple myeloma target cells. Systemic MM.1S in vivo tumor models were performed in NSG mice to further assess efficacy of lead CAR candidates.
Here we show our candidate GPRC5D CARs demonstrate in vitro cytotoxicity and effector cytokine production that is comparable to clinically validated benchmark controls. In 5-day Incucyte cytotoxicity assays, GPRC5D CAR T cells expand up to 10-fold and reduce tumor cell counts at starting E:T ratios of 1:8. Furthermore, in MM.1S in vivo tumor challenge models, these GPRC5D CARs significantly reduce flux and prolonged survival relative to tumor only controls with tumor clearance that was in line with clinical benchmark controls.
Using ex vivo VSV-G production, our GPRC5D CAR T cells control multiple myeloma tumor cells both in vitro and in vivo, demonstrating efficacy that is on par with GPRC5D clinical benchmark CAR T cells. Studies to further define the efficacy of HIP-modified GPRC5D CAR T cells are ongoing. Moving forward, further interrogating GPRC5D CAR activity against multiple myeloma tumor cells with varying levels of target antigen expression will be critical to understanding the benefit of deploying GPRC5D CAR T cells within the multiple myeloma clinical landscape.
Effect of Hydroxyurea Treatment on Body Composition in Children with Sickle Cell Anemia in Uganda Using Bioelectrical Impedance Analysis (BIA)
Authors: Kalibala Dennis , Nabaggala Catherine , Turyagyenda Lynnth , Mboizi Vincent , Naggayi Shubaya Kasule , Kabatabaazi Maxencia , Rosano Caterina , Munube Deogratias , Kasirye Phillip , Ssenkusu John , Opoka Robert , Bangirana Paul , Green Nancy S. , Idro Richard , Mupere Ezekiel 
Published: December 2023

Introduction
Children with sickle cell anemia (SCA) experience severe illness and risk of malnutrition in sub-Saharan Africa. Treatment with hydroxyurea (HU) decreases SCA complications. In high-income regions, hydroxyurea also improves pediatric growth and overall quality of life. We assessed the effects of hydroxyurea on growth and body composition of children with SCA in Uganda.
Methods
This study was nested in an open-label, single-arm pediatric clinical trial of hydroxyurea 20-30mg/kg/day for prevention of neurological and cognitive impairment. In all, 267 study participants with SCA, ages 3-9 years, initiated hydroxyurea treatment at the Mulago Hospital SCA Clinic in Kampala, Uganda. Anthropometric measurements (weight, height) were obtained at enrollment and at month 18 of therapy; age- and sex-specific z-scores were assigned, per World Health Organization (WHO) international standards. Non-invasive bioelectric impedance analysis (BIA), was used to estimate total body fat mass (FM) and fat-free mass (FFM) at both timepoints. A control sample of110 siblings/family members without SCA, aged 3-12 years, established local z-scores for BIA assessments.
Results
Among SCA participants and controls, 50.6% and 57.3% were female, respectively. Mean age was younger foror the SCA sample: 5.1±0.1 and 7.1±0.3 years ( p&lt;.001). At trial month 18, mean hydroxyurea dose 25.4mg/kg, SCA hemoglobin rose from 7.8±1.2 to 8.9±1.5 g/dL( p&lt;.001), remaining lower than mean hemoglobin level of non-SCA controls 12.5±1.1 ( p&lt;.001). Using the World Health Organization definition of “wasting,” SCA participants at enrollment had a higher proportion of low weight-for-height than controls: 9.8% vs 3.8%, p=.009). By body composition, the SCA sample also had lower FFM (-0.67±0.56 vs. 0.00 ±1.00, p &lt; .001) and FM (-0.68±0.60 vs. 0.00 ±1.00, p&lt;.001) than controls. At month 18, for the 254 active SCA participants (95.1%), the proportion with wasting was unchanged. In contrast, z-scores for FFM (-0.65±0.57 to -0.16±0.57, p &lt; .001) and FM (-0.66±0.61 to -0.18±0.61, p&lt;.001) significantly increased (Figure) to near control levels.
Conclusion
Hydroxyurea therapy in children with SCA increased hemoglobin yet did not reduce the proportion with wasting after 18 months. Nonetheless, treatment led to significantly improved FM and FFM to near normal levels. These results suggest that hydroxyurea therapy may play a crucial role in enhancing body composition of children with SCA in the region. The ongoing hydroxyurea trial will enable assessment of longer-term impact on health-related growth and body composition in children with SCA in Uganda.
Epidemiological Insights into Large Granular Lymphocyte Leukemia: A Nationwide SEER Database Study
Authors: Yadukumar Lekha , Gogtay Maya 
Published: December 2023

Background: Large granular lymphocytic (LGL) leukemia is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T-LGL) or natural killer (NK) cells. LGL leukemia accounts for 2% to 5% of chronic lymphoproliferative disorders in the United States of America. LGL leukemia can either present as an indolent type or an aggressive type. Most patients remain asymptomatic and often have associated autoimmune diseases, such as rheumatoid arthritis and hematologic dyscrasias. We analyzed the demographic characteristics of LGL leukemia patients and investigated the influence of social determinants on their survival.
Methods: We performed a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with LGL leukemia between years 2000 and 2020. Patient demographics, year of diagnosis, and timeline of treatment were analyzed by descriptive statistics. Cox proportional hazards regression analysis was performed to identify the factors influencing the survival of these patients.
Results: A total of 2589 patients were diagnosed with LGL leukemia. Median age of diagnosis was 67 years. 59.4% were aged more than 65 years of age at the time of diagnosis, 52.7% were males, 81.5% were Caucasians, 64% had an annual income of more than $65,000, and 84.2% lived in metropolitan areas. 91.8% were diagnosed in the past decade after 2010. It is worth noting that 64.5% of the patients received treatment more than six months after diagnosis of LGL leukemia. 81.5% of patients were Caucasians, 9.6% were African Americans, 5.3% were Asians/Pacific Islanders, followed by 2% Hispanics and 1.5% American Indians. At the time of the last follow-up, 65.5% of patients were alive, with an overall median survival of forty months. 70% of patients had LGL leukemia as the only primary malignancy. Age less than 65 years had better outcomes than the older age group (HR 0.32). Female gender was protective (HR 0.69). Poor outcomes were seen in patients with an annual income of less than $65,000 (HR 1.21). The year of diagnosis and residence had no significant effect on survival. Marriage improved the outcomes of patients (HR 0.78) (Table 1). Patients receiving treatment within six months of diagnosis had higher mortality (HR 1.43) than the rest of the population. Caucasians comprised majority of the patient population and had better prognoses (HR 0.11) than Asians/Pacific Islanders (HR 0.49), Hispanics (HR 0.82), and African Americans (HR 0.97) (Figure 1).
Conclusion: We present a population-based analysis and the determinants of survival in patients with LGL leukemia, a rare malignancy. The number of cases has increased in the past decade. Significant patient factors influencing survival in LGL leukemia patients include younger age at diagnosis, female gender, marriage and higher annual income.
Recurrent Thromboembolism in Patients with Congenital Heart Disease and Prior Thromboembolism: A Prospective Cohort Study
Authors: Kiskaddon Amy L , Betensky Marisol , Do Nhue , Stock Arabela , Quintessenza James , Goldenberg Neil 
Published: December 2023

Introduction:
Patients with congenital heart disease (CHD) are at increased risk of thromboembolism (TE) due to changes in blood flow, type of cardiac lesion, exposure to cardiopulmonary bypass, and cardiac catheterization. There are limited data describing the rate of and risk factors associated with recurrent TE in pediatric patients with CHD and prior TE. Therefore, the primary aim of this study was to describe the rate of recurrent TE in pediatric patients with CHD and a prior episode of TE. Secondary aims included: characterize the type of index and recurrent TE and site, as well as compare characteristics and risk factors of patients with CHD and history of index TE who developed recurrent TE versus to those who did not develop a recurrent TE.
Methods:
Patients in this study were enrolled and prospectively followed in the Johns Hopkins All Children's (St. Petersburg, FL) Institution-wide Prospective, Inception Multi-Cohort Study of Pediatric TE anytime between 2013 to present. For this analysis, patients were eligible for inclusion if they were &lt;21 years of age, presented with an index TE, and had a diagnosis of CHD. Data collection included patient characteristics, clinical laboratory testing, radiologic results, type and site of TE, acute and chronic risk factors, and treatment agents. Frequencies/proportions were compared between groups by chi-squared or Fisher's exact test, as appropriate.
Results:
Thirty patients with CHD and index TE were included in this study. Of these, 11 (36.7%) patients had a total of 23 recurrent TEs. Five (45.5%) patients had one recurrent TE, 3 (27.3%) had two recurrent TEs, and another 3 patients had &gt;2 recurrent TEs. Of the 23 recurrent TE, 3 events (13%) were arterial and 20 (87%) were venous. All 3 (100%) arterial TEs were provoked, and catheter related. Of the 20 venous TEs, 16 (80) were provoked and of these, 15 (93.8%) were catheter related. When compared to those who did not develop recurrent TE, patients who developed recurrent TE were more likely to have immobility (p=0.005), an arterial TE (p=0.041), or a lower extremity deep venous thrombosis (p=0.045) at the time of index TE. A greater proportion of patients with recurrence had a central catheter-associated TE compared to those with no recurrent TE but this difference was not statistically significant (73% vs 55%, p=0.057).
Conclusions:
In this single center prospective cohort we describe a high rate of recurrent TE (37%) among children with CHD and history of prior TE, and identified risk factors for TE recurrence. The vast majority of recurrent TE was provoked and catheter associated. Identified risk factors include immobility, and type and location of the index TE. Future multicenter prospective cohort studies are needed to validate these findings and identify additional risk factors.
Interleukin-17A Directly Signals to Bone Marrow-Derived Hematopoietic Stem and Progenitor Cells to Promote Their Expansion and Differentiation in Vitro
Authors: Losada Cristobal González , Poon William Wai Lam , Salaciak Matthew , Amghar Samy , Johnson Nathalie A. , Sharif-Askari Bahram , Mercier Francois E. 
Published: December 2023

Rationale: IL-17 is a family of six pro-inflammatory cytokines (named from A to F) with distinct patterns of cellular expression. Among these, IL-17A is secreted by lymphoid subsets such as T-helper 17 cells and innate lymphoid cells type 3. Through its action on many tissues, IL-17A is recognized as a key mediator of response to infection and pathogenic states such as cancer and auto-immunity. Until now, the main effect of IL-17A on hematopoiesis has been attributed to an indirect loop through IL-17RA signaling on bone marrow stromal cells, which stimulates secretion of hematopoietic factors such as G-CSF. However, we hypothesized that IL-17A can directly signal to hematopoietic stem and progenitor cells (HSPCs) to determine their self-renewal and differentiation.
Methodology: We analyzed the expression of the IL-17 signaling pathway in publicly available human and mouse hematopoietic single-cell RNAseq datasets. Mouse HSPCs were isolated using FACS to perform clonogenic and differentiation assays in Methocult (StemCell Technologies) and StemPro-34 (Gibco). Spectral flow cytometry (SONY ID7000) was used for analysing IL-17RA expression and differentiation of mouse HSPCs. IL-17A levels were measured in blood and bone marrow serum using ELISA (Invitrogen).
Results: IL-17RA is expressed at the surface of mouse HSPCs, with greatest levels in common lymphoid progenitors and granulocyte-monocyte progenitors. mRNA expression of IL-17RA signaling pathway is also detectable in human HSPCs, with greatest levels in young individuals. IL-17A supplementation leads to an increase in clonogenic capacity of mouse HSPCs in methylcellulose colony-formation assays. In liquid culture, supplementation with IL-17A leads to a greater expansion of sorted Lin -/s-kit +/Sca-1 + progenitors, accompanied by an increased proportion of myeloid-committed cells.IL-17A is also detected in the bone marrow serum, with possible production from subsets of cells expressing RORγt, a master regulator in development of T helper 17 (Th17) cells.
Conclusions: Our work suggests the ability of IL-17A to directly promote clonogenic potential of HSPCs and drive a myeloid-biased lineage commitment in progenitor subsets. Additional studies are required to characterize the response of HSPCs to direct IL-17A signaling in vivo. Considering the important role of IL-17A as a mediator of immune response, and tissue repair, further studies are warranted to elucidate whether modulation of this pathway may be therapeutic in the context of hematopoietic failure or malignancy.
Risk and Outcomes of Hospitalizations in Patients with Anti-Phospholipid Syndrome Admitted with Autoimmune Hemolytic Anemia: A Nation-Wide Analysis
Authors: Mahmoud Amir , Orakzai Abdullah , Jain Tripti , Kharel Himal , Srivastava Arnav , Neupane Niraj , Yassin Heba , Eltaher Basant , Abdelhay Ali 
Published: December 2023

Introduction: Autoimmune hemolytic anemia (AIHA) can occur as a primary disorder or as a secondary manifestation of an underlying autoimmune condition. The coexistence of anti-phospholipid syndrome (APS) and AIHA can be very complex and challenging to manage given the intertwining of the prothrombotic and hemolytic states. In this study, we explored the outcomes of underlying antiphospholipid syndrome in autoimmune hemolytic anemia hospitalizations.
Method: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for AIHA and then the data was subclassified into hospitalizations with and without APS. Demographics, comorbidities, and outcomes were identified using appropriate ICD 9/10 codes. Propensity score matched cohorts were generated for APS status and adjusted for age, race, sex, smoking, obesity, DM, CHF, CKD/ESRD, and liver disease.
Results: A total of 7,609 AIHA hospitalizations were included, with 76 patients having underlying APS and 7,533 did not have APS. Mean age was younger in the APS cohort and there were also more females, blacks and Hispanics compared to the non-APS cohort. Propensity score matching was used to generate two cohorts, adjusting for age, race, sex, and for co-morbidities including obesity, smoking, DM, CHF, CKD/ESRD and liver disease. The adjusted analysis showed an 8.59 times higher risk of developing venous thromboembolic events (VTE) in AIHA with APS as compared to those hospitalizations without APS (Odds ratio (OR): 8.59, CI: 1.05-70.5; p=0.03). There was also a statistically significant increase in mean hospitalization cost in the APS group (p=0.001). A trend towards more arterial athero-embolic events (AAE), major bleeding events, and AKI as well as longer length of stay was seen in hospitalizations with APS, but it did not reach statistical significance. No significant difference in in-hospital mortality was seen between the two groups. The results are summarized in the Figure 1.
Conclusion: APS confers additional risk to AIHA hospitalizations with significantly higher VTE events and added costs. Further studies should address the complex management of anticoagulation and prothrombotic risk in APS in the setting of active hemolytic anemia.
A Co-Reactivation Model of Cytomegalovirus and Epstein-Barr Virus after Allogeneic Hematopoietic Stem Cell Transplantation Was Constructed to Predict Mortality after Transplantation
Authors: Ren Jinhua , Chen Shaozhen , Hu Jianda , Yang Ting 
Published: December 2023

Abstract
Objective: The aim of this study was to create a predictive model for the occurrence of co-reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods: The study included 373 patients who underwent allo-HSCT. The patient population was randomly divided into two groups: a training cohort comprising 70% of patients (n=261) and a validation cohort comprising 30% of patients (n=112). The predictive model was developed using several variables, including the time of reactivation of CMV and EBV, patient age and gender, presence of hepatitis B core antibody (HbcAb), type of transplant, use of anti-thymocyte globulin (ATG), and the occurrence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively).
Results: The developed predictive model was expressed as y = -6.21338339 + 0.01923832 × (CMV reactivation time) + 0.00362628 × (EBV reactivation time) - 0.57604523 × (patient gender) + 0.01974136 × (patient age) + 0.85514424 × (presence of HbcAb) + 1.13782872 × (transplant type) + 0.95376138 × (use of ATG) - 0.62393602 × (aGVHD) - 1.09485262 × (cGVHD). The model demonstrated a g-mean value of 0.685 and a probability threshold of 0.297, allowing for the classification of patients into high-risk and low-risk groups.
The incidence of co-reactivation of CMV and EBV over 100 days was significantly higher in the high-risk group compared to the low-risk group. In the high-risk group, the incidence was 49.3%, while in the low-risk group, it was 16.9% (P&lt;0.0001, HR 95%CI 3.693(2.493,5.47)). For patients with aGVHD, the incidence was 41.7% in the high-risk group and 17.9% in the low-risk group (P=0.00026, HR 95%CI 2.7473(1.560,4.839)). In patients without aGVHD, the incidence was 53% in the high-risk group and 14.0% in the low-risk group (P&lt;0.0001, HR 95%CI 4.9439(2.347,10.4)). Additionally, the model was able to predict post-transplant mortality and survival.
Conclusion: Overall, the findings of this study suggest that the developed model is a valuable tool for predicting the risk of CMV and EBV co-reactivation following allo-HSCT. By identifying high-risk patients, clinicians can take proactive measures to prevent or manage viral infections, ultimately improving patient outcomes. Therefore, this model can potentially enhance clinical decision-making and optimize post-transplant care.