bluuebunny/crossref_metadata_2025_split huggingface dataset:
The spectrum of Ph-negative disease: CNL and CSF3R-related disorders
Authors: Hasserjian Robert P. 
Published: December 2024

Abstract
Chronic neutrophilic leukemia (CNL) is a very rare myeloid neoplasm characterized by peripheral blood neutrophilia and a hypercellular marrow with increased granulopoiesis. An activating mutation in CSF3R is present in 80% to 90% of cases. CNL displays some biological overlap in terms of clinical presentation and behavior, as well as genetic profile, with several other myeloid neoplasms, particularly myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and other MPN. Distinguishing these related entities can be challenging, requires close attention to peripheral blood and bone marrow morphology, and can be informed by the mutation pattern: CNL is strongly associated with CSF3R mutation, usually lacks JAK2, MPL, or CALR mutations, and, by definition, lacks BCR::ABL1 rearrangement. Pitfalls in diagnosis include subjectivity in assessing neutrophil dysplasia and distinguishing true neoplastic neutrophilia from reactive neutrophilias that may be superimposed upon or occur as a manifestation of the progression of other myeloid neoplasms. Accurate distinction between neutrophilic myeloid neoplasms is important, as it helps guide patient management and may disclose specific genetic lesions amenable to targeted therapy.
Are TP53 mutations all alike?
Authors: Wong Terrence N. , Link Daniel C. 
Published: December 2024

Abstract
TP53 is mutated in 10 to 15% of cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and is associated with a previous exposure to cytotoxic therapy, complex cytogenetic abnormalities, and a poor prognosis. Recent data have established the importance of TP53-mutant allele status, the determination of which requires specific genetic testing. Compared with monoallelic disease, multihit TP53-mutant AML/MDS is associated with chromosomal abnormalities and decreased overall survival. Most TP53 mutations are missense mutations that localize to the DNA binding domain. Hot-spot mutations involving residues R175, Y220, G245, R248, R273, or R282 represent approximately 35% of all TP53 missense mutations in AML/MDS. There is evidence that these hot-spot mutations may have dominant negative or gain-of-function properties. Here we review this evidence and discuss its potential impact on patient outcomes and clinical management.
Nontransplant treatment approaches for myeloid neoplasm with mutated TP53
Authors: Mehta Ansh K. , Konopleva Marina 
Published: December 2024

Abstract
TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a challenging spectrum of clonal myeloid disease with poor prognosis. Recent studies have shown that in AML, MDS, and MDS/AML with biallelic TP53 loss, the TP53-mutated clone becomes dominant. These are highly aggressive diseases that are resistant to most chemotherapies. The latest 2022 International Consensus Classification categorizes these diseases under “myeloid disease with mutated TP53.” All treatment approaches have not improved survival rates for this disease. Many newer therapies are on the horizon, including chimeric antigen receptor T/NK-cell therapies, mutated p53 reactivators, Fc fusion protein, and monoclonal antibodies targeting various myeloid antigens. This review summarizes the current approaches for myeloid disease with TP53 mutation and provides an overview of emerging nontransplant approaches.
End-of-life care for people with sickle cell disease: barriers to and facilitators of high-quality care
Authors: Patel Rushil V. , Johnston Emily E. 
Published: December 2024

Abstract
End-of-life (EOL) care is a critical part of sickle cell disease (SCD) management. However, barriers to high-quality EOL care remain, including (1) disease-related barriers (prior opioid exposure, risk of vaso-occlusive crises, chronic conditions with conflicting needs, and limitations of receiving disease-directed therapy on hospice); (2) communication-related barriers (challenges of identifying and responding to religious and spiritual concerns, limited health literacy, and previous health care system experience); (3) systemic issues (social determinants of health, structural racism, and mistrust of the medical system). However, palliative care and interdisciplinary collaboration can overcome many of these barriers. In addition, we can improve EOL care by accounting for opioid exposures, multimodal symptom management, and exploring (1) who people want involved in decision-making, (2) the role of religion and spirituality in decision-making, and (3) previous experiences with EOL. Systemic barriers can be addressed through the social determinants of health screening, minimizing financial burdens of care, and building longitudinal relationships with people with SCD. This requires the continued education of SCD providers about primary palliative care and palliative care providers about SCD. With such strategies, high-quality EOL care is possible for this vulnerable population.
Heavy menstrual bleeding clinics for adolescents
Authors: Baldwin Maureen , Haley Kristina M. , Staber Janice M. 
Published: December 2024

Abstract
Heavy menstrual bleeding (HMB) is a common symptom in adolescence, often leading to significant disruptions in daily life, such as school absences, shame caused by the stigma surrounding menstruation, and symptoms from iron deficiency. Further, HMB may be the first and/or only sign of an underlying bleeding disorder. Navigating the symptoms, effects, and treatments of HMB during adolescence requires a collaborative approach between the patient, caregivers, and healthcare providers. This work can be effectively and efficiently conducted in interdisciplinary clinics, where patients see hematology, gynecology, and adolescent providers. In these settings, healthcare providers exchange knowledge and expertise, after which they can reach a consensus for diagnostic evaluation and therapeutic intervention. Development and implementation of an interdisciplinary hematology and gynecology clinic can be challenging; however, the crucial rationale is that established clinics improve patient outcomes. Using an example interdisciplinary adolescent clinic, we outline the critical components needed to execute a successful clinic for adolescents with HMB and share key takeaways.
Approaches to management of HIT in complex scenarios, including cardiac surgery
Authors: Adeoye Oluwatayo , Zheng Guoliang , Onwuemene Oluwatoyosi A. 
Published: December 2024

Abstract
Although heparin-induced thrombocytopenia (HIT) presents management challenges for any population, it adds complexity to the management of certain patient populations, including those undergoing cardiac surgery and those with refractory HIT and/or acute bleeding. For each of these scenarios, we review alternative management strategies when standard therapies—heparin cessation and the initiation of a nonheparin anticoagulant—are either insufficient or not practicable. In patients with HIT undergoing cardiac surgery, we review the clinical experience for heparin reexposure using therapeutic plasma exchange (TPE) or antiplatelet therapy. In patients with refractory HIT despite adequate nonheparin anticoagulation, we address the use of intravenous immune globulin, TPE, and rituximab. Finally, in patients with active bleeding, we discuss bleeding management and the risks associated with platelet transfusion. Although they may facilitate a patient-centered approach, most of these strategies are supported by limited evidence.
Luspatercept: a treatment for ineffective erythropoiesis in thalassemia
Authors: Musallam Khaled M. , Taher Ali T. 
Published: December 2024

Abstract
Patients with β-thalassemia continue to have several unmet needs. In non–transfusion-dependent patients, untreated ineffective erythropoiesis and anemia have been associated with a variety of clinical sequelae, with no treatment currently available beyond supportive transfusions. In transfusion-dependent forms, lifelong transfusion and iron chelation therapy are associated with considerable clinical, psychological, and economic burden on the patient and health care system. Luspatercept is a novel disease-modifying agent targeting ineffective erythropoiesis that became recently available for patients with β-thalassemia. Data from randomized clinical trials confirmed its efficacy and safety in reducing transfusion burden in transfusion-dependent patients and increasing total hemoglobin level in non–transfusion-dependent patients. Secondary clinical benefits in patient-reported outcomes and iron overload were also observed on long-term therapy, and further data from real-world evidence studies are awaited.
The evolving frontline management of CLL: are triplets better than doublets? How will we find out?
Authors: Rogers Kerry A. , Woyach Jennifer A. 
Published: December 2024

Abstract
Frontline therapy for chronic lymphocytic leukemia (CLL) has substantially advanced in the previous decade. While monotherapy with a Bruton's tyrosine kinase (BTK) inhibitor is an excellent option for many patients, combination therapies are of high clinical interest as they can induce deep responses and durable remissions, and in many cases allow discontinuation of therapy. There are several doublet therapies that are currently in clinical use. These include combinations of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or BCL2 inhibitors (venetoclax) with anti-CD20 monoclonal antibodies, and combinations of BTK and BCL2 inhibitors. While BTK inhibitors with anti-CD20 monoclonal antibodies still typically require indefinite therapy, combinations involving the BCL2 inhibitor venetoclax have allowed for successful therapy discontinuation. Triplets, which combine all 3 of these paradigms, are of interest especially for patients with higher-risk disease. While triplets have been mainly studied in single-arm trials with excellent outcomes, comparative data to doublets are limited. In this article, we outline the doublet and triplet regimens that have been evaluated in CLL as well as the data from trials comparing doublets and triplets.
Identifying Castleman disease from non-clonal inflammatory causes of generalized lymphadenopathy
Authors: Nijim Sally , Fajgenbaum David C. 
Published: December 2024

Abstract
Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening subtype of Castleman disease (CD), which describes a group of rare, polyclonal lymphoproliferative disorders that demonstrate characteristic histopathology and variable symptomatology. iMCD involves a cytokine storm that occurs due to an unknown cause. Rapid diagnosis is required to initiate appropriate, potentially life-saving therapy, but diagnosis is challenging and impeded by clinical overlap with a wide spectrum of inflammatory, neoplastic, and infectious causes of generalized lymphadenopathy. Diagnosis, which requires both consistent histopathologic and clinical criteria, can be further delayed in the absence of close collaboration between clinicians and pathologists. A multimodal assessment is necessary to effectively discriminate iMCD from overlapping diseases. In this review, we discuss a pragmatic approach to generalized lymphadenopathy and clinical, laboratory, and histopathological features that can aid with identifying iMCD. We discuss diagnostic barriers that impede appropriate recognition of disease features, diagnostic criteria, and evidence-based treatment recommendations that should be initiated immediately following diagnosis.
Estrogen, progestin, and beyond: thrombotic risk and contraceptive choices
Authors: Skeith Leslie , Bates Shannon M. 
Published: December 2024

Abstract
Hormonal contraceptive therapy (estrogens and/or progestogens) includes different formulations associated with varying venous thromboembolism (VTE) risks. The thrombogenicity of combined hormonal contraceptives (CHCs) is due at least in part to multiple changes in clotting factors and the vasculature and is dependent on both estrogen dose and type of progestin. Transdermal patch and vaginal ring users have similar or higher VTE risk as combined oral contraceptive users. Progestin-only agents have varying VTE risk. While depot medroxyprogesterone acetate appears to increase VTE risk, the levonorgestrel-based intrauterine system and low-dose progestin-only pills have no additional VTE risk. There are less data for the subdermal progestin-only implant. This article reviews contraceptive-related VTE risk by agent and by clinical scenario, including in patients with inherited thrombophilia, systemic lupus erythematosus with or without antiphospholipid antibodies or antiphospholipid syndrome, and sickle cell disease. Relevant clinical practice guidelines are reviewed. A multidisciplinary approach to counseling is needed for patient-focused decision-making.
Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk
Authors: King Hannah , Kelley Thalia Padilla , Shatzel Joseph J. 
Published: December 2024

Abstract
Research regarding the hematologic sequelae of estrogen and testosterone therapy for transgender people is an emerging area. While estrogen therapy has been widely studied in cisgender women, studies in transgender individuals are limited, revealing variable adverse effects influenced by the dose and formulation of estrogen used. Thrombotic risk factors in transgender and gender-diverse individuals are multifactorial, involving both modifiable and nonmodifiable factors. Management of venous thromboembolism (VTE) in individuals receiving gender-affirming estrogen entails standard anticoagulation therapy alongside shared decision-making regarding hormone continuation and risk factor modification. While data and guidance from cisgender women can offer a reference for managing thrombotic risk in transgender individuals on hormone therapy, fully applying these insights can be challenging. The benefits of gender-affirming hormone therapy include significantly reducing the risk of suicide and depression, highlighting the importance of a contemplative approach to the management of hormonal therapy after a VTE event. Although limited, the available data in the literature indicate a low thrombotic risk for transgender individuals undergoing gender-affirming testosterone therapy. However, polycythemia is a common adverse effect necessitating monitoring and, occasionally, adjustments to hormonal therapy. Additionally, iron deficiency may arise due to the physiological effects of testosterone or health care providers' use of phlebotomy, an aspect that remains unstudied in this population. In conclusion, while the set of clinical data is expanding, further research remains vital to refine management strategies and improve hematologic outcomes for transgender individuals undergoing gender-affirming hormone therapy.
Insights on treatment of adult ITP: algorithm for management and role of multimodal therapy
Authors: Ghanima Waleed , Cuker Adam , Michel Marc 
Published: December 2024

Abstract
The management of immune thrombocytopenia (ITP) is continuously evolving with the development and introduction of newer therapies and a better understanding of the disease. Corticosteroids still represent the cornerstone of first-line treatment. Patients who fail to achieve remission with a short course of corticosteroids require subsequent therapy. Most guidelines recommend starting with either a thrombopoietin receptor agonist (TPO-RA), rituximab, or fostamatinib since these agents have been investigated in randomized trials and have well-characterized efficacy and safety profiles. Patients' involvement to reach a shared decision regarding choice of therapy is essential as these treatments have different modes of administration and mechanisms of action. Less than 10% will fail to respond to and/or be intolerant of multiple second-line therapeutic options and thus be considered to have refractory ITP and require a third-line therapeutic option. Such patients may require drugs with different targets or a combination of drugs with different mechanisms of action. Combining a TPO-RA and an immunomodulatory agent may be an appropriate approach at this stage. Many studies have been conducted during the last 2 decades investigating the efficacy and safety of combinations strategies for first and later lines of therapies. Yet none of these are recommended by current guidelines or have gained wide acceptance and consensus.
When should we use it? The role of brentuximab vedotin in 2024
Authors: Schroers-Martin Joseph G. , Advani Ranjana 
Published: December 2024

Abstract
The CD30-directed antibody-drug conjugate brentuximab vedotin (BV) was FDA approved in 2011 for the treatment of relapsed classic Hodgkin lymphoma (cHL), in 2015 for maintenance after autologous transplantation in high-risk patients, and in 2018 for frontline therapy with doxorubicin, vinblastine, and dacarbazine for advanced stage cHL. Although the role of BV in cHL had been reasonably well-established, it is currently being challenged by the changing landscape of other highly effective novel agents, such as checkpoint inhibitor immunotherapies. In this review, we discuss the evolving role of BV in the management of cHL and ongoing studies attempting to define the optimal usage of this effective agent.
Cognitive engagement as a predictor of learning gain in Python programming
Authors: Singh Daevesh , Rajendran Ramkumar 
Published: December 2024

AbstractThe relationship between cognitive engagement and learning gains in computer programming has not been well-studied. This study examined the relationship between students’ cognitive engagement and learning gains in the context of Python programming. Cognitive engagement, defined by the Interactive, Constructive, Active, Passive (ICAP) framework, refers to the level and depth of mental effort and involvement a learner invests in an educational activity. In this paper, we provide details about how students’ actions were classified into three levels of cognitive engagement. We studied these actions’ frequency and duration differences and performed regression analysis. The results revealed significant student diversity regarding frequency and time allocation to these engagement categories and highlight the complex interplay between students’ cognitive activities and their corresponding time investments. Further, the regression analysis results showed that the constructive and passive levels of engagement were significant predictors of students’ learning gains in the case of Python programming.These findings offer actionable insights into why some students may have lower learning gains. By examining the specific levels of cognitive engagement that lead to better learning outcomes, this study hopes to inform the development of more effective learning environments that support student engagement and improve programming education.
Single-cell transcriptome profiling of m6A regulator-mediated methylation modification patterns in elderly acute myeloid leukemia patients
Authors: Wang Zhe , Du Xin , Zhang Peidong , Zhao Meiling , Zhang Tianbo , Liu Jiang , Wang Xiaolan , Chang Doudou , Liu Xiaxia , Bian Sicheng , Zhang Xialin , Zhang Ruijuan 
Published: December 2024

AbstractMillions of people worldwide die of acute myeloid leukaemia (AML) each year. Although N6-methyladenosine (m6A) modification has been reported to regulate the pathogenicity of AML, the mechanisms by which m6A induces dysfunctional hematopoietic differentiation in elderly AML patients remain elusive. This study elucidates the mechanisms of the m6A landscape and the specific roles of m6A regulators in hematopoietic cells of elderly AML patients. Notably, fat mass and obesity-associated protein (FTO) was found to be upregulated in hematopoietic stem cells (HSCs), myeloid cells, and T-cells, where it inhibits their differentiation via the WNT signaling pathway. Additionally, elevated YT521-B homology domain family proteins 2 (YTHDF2) expression in erythrocytes was observed to negatively regulate differentiation through oxidative phosphorylation, resulting in leukocyte activation. Moreover, IGF2BP2 was significantly upregulated in myeloid cells, contributing to an aberrant chromosomal region and disrupted oxidative phosphorylation. m6A regulators were shown to induce abnormal cell-cell communication within hematopoietic cells, mediating ligand-receptor interactions across various cell types through the HMGB1-mediated pathway, thereby promoting AML progression. External validation was conducted using an independent single-cell RNA sequencing (scRNA-Seq) dataset. The THP-1 and MV411 cell lines were utilized to corroborate the m6A regulator profile; in vitro experiments involving short hairpin RNA (shRNA) targeting FTO demonstrated inhibition of cell proliferation, migration, and oxidative phosphorylation, alongside induction of cell cycle arrest and apoptosis. In summary, these findings suggest that the upregulation of m6A regulators in HSCs, erythrocytes, myeloid cells, and T-cells may contribute to the malignant differentiation observed in AML patients. This research provides novel insights into the pathogenesis of AML in elderly patients and identifies potential therapeutic targets.
Chronic Kidney Disease and Thyroid Hormones
Authors: Cheng Yuan , Hu Haofei , Li Wangyang , Nie Sheng , Zhou Shiyu , Chen Yuna , Cao Tao , Xu Hong , Liu Bicheng , Chen Chunbo , Liu Huafeng , Yang Qiongqiong , Li Hua , Kong Yaozhong , Li Guisen , Zha Yan , Hu Ying , Xu Gang , Shi Yongjun , Zhou Yilun , Su Guobin , Tang Ying , Gong Mengchun , Wan Qijun 
Published: December 2024

Abstract

Context
Thyroid dysfunction is prevalent in chronic kidney disease (CKD) patients and significantly impacts renal outcomes and mortality.

Objective
This study investigated the associations between thyroid function and clinical outcomes, and also the therapeutic effects of thyroid hormone replacement therapy (THRT) in CKD patients.

Methods
We conducted a retrospective cohort study using data from the China Renal Data System. The primary endpoints were composite renal failure and all-cause mortality. The secondary endpoint was the impact of THRT on renal outcomes. Associations were analyzed using multivariable Cox proportional hazards regression models and Kaplan-Meier survival analyses, with adjustment for relevant clinical and demographic covariates.

Results
Among 30 804 CKD patients enrolled, 26 673 (86.6%) had normal thyroid function, 2291 (7.4%) had hypothyroidism, and 1840 (6.0%) had hyperthyroidism. Hypothyroidism independently predicted increased risk of renal failure (adjusted HR = 1.29; 95% CI, 1.15-1.45; P &lt; .001). Both hypothyroidism (adjusted HR = 1.24; 95% CI, 1.11-1.39; P &lt; .001) and hyperthyroidism (adjusted HR = 1.20; 95% CI, 1.07-1.33; P &lt; .01) were associated with increased all-cause mortality. Notably, THRT was associated with significantly reduced risk of renal failure (adjusted HR = 0.65; 95% CI, 0.52-0.82; P &lt; .001) in hypothyroid patients.

Conclusion
This large-scale cohort study demonstrates that hypothyroidism accelerates CKD progression, while both hypo- and hyperthyroidism increase mortality risk in CKD patients. THRT appears to attenuate the adverse effects of hypothyroidism on renal function. Regular thyroid function monitoring and appropriate THRT should be considered in CKD management.