bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management, in people with hemophilia A or B
Authors: Pipe Steven W. , Lissitchkov Toshko , Georgiev Pencho , Mangles Sarah , Hegemann Inga , Trinchero Alice , Chowdary Pratima , Forbes Adam , Feng Liqi , Menapace Laurel A. , Kichou Salim , Andersson Shauna , Demissie Marek , Ragni Margaret V.
Published: December 2024

Fitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here, we present the results of a completed phase 2 open-label extension study, which evaluated the long-term safety and efficacy of fitusiran in participants with moderate or severe hemophilia A or B, with or without inhibitors. Male participants who had completed the phase 1 study (ClinicalTrials.gov identifier: NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, after which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15% to 35%. Thirty-four participants (hemophilia A, n = 27; hemophilia B, n = 7) were enrolled in the phase 2 study and treated with fitusiran for a median exposure of 4.1 years. Adverse events reported on the original and the AT-based dose regimen were consistent with the identified risks of fitusiran. After implementation of the AT-based dose regimen, there were no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events was reported. The observed median annualized bleed rate (ABR) on the AT-based dose regimen (0.87) was comparable with the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared with baseline and provided successful hemostatic control during surgical procedures and invasive interventions. Overall, fitusiran was well tolerated, and effective bleeding control was maintained on an AT-based dose regimen. This trial was registered at www.clinicaltrials.gov as #NCT02554773.
Targeting hardship: poverty as a modifiable risk factor in childhood leukemia and lymphoma treatment
Authors: Umaretiya Puja J. , Aziz-Bose Rahela , Kelly Colleen , Bona Kira
Published: December 2024

Racial, ethnic, and socioeconomic survival disparities have been well-demonstrated across population-based and clinical trial datasets in pediatric hematologic malignancies. To date, these analyses have relied on trial-collected data such as race, ethnicity, insurance, and zip code. These exposures serve as proxies for factors such as structural racism, genetic ancestry, and adverse social determinants of health (SDOH). Systematic measurement of SDOH and social needs—and interventions targeting these needs—are feasible in pediatric oncology. We use these data to present a roadmap for the next decade of health equity research to identify actionable mechanisms and develop a portfolio of interventions to advance equitable outcomes across pediatric hematologic malignancies.
Ph+ ALL: new approaches for upfront therapy
Authors: Luskin Marlise R.
Published: December 2024

Philadelphia chromosome-positive (Ph+) ALL is the most common genetic subtype of ALL and primarily affects adults. Ph+ ALL is characterized by the constitutively active ABL1 kinase and is resistant to conventional chemotherapy. Thus, Ph+ ALL was historically associated with a dismal prognosis, particularly among patients who did not undergo allogeneic hematopoietic stem cell transplantation (alloHCT) in first complete remission (CR). Imatinib, the first tyrosine kinase inhibitor (TKI) effective against ABL1, transformed the treatment and prognosis of Ph+ ALL, allowing more patients to achieve CR and become eligible for alloHCT, thereby improving outcomes. In recent years, there has been an improved understanding of the biology of Ph+ ALL, including recognition of distinct subtypes (multilineage and lymphoblast-only Ph+ ALL). There has also been a dramatic expansion of effective therapeutic and diagnostic tools for management of Ph+ ALL, including more potent TKIs, which have activity against ABL kinase–resistance mutations; refinement of the chemotherapy and alloHCT regimens that accompany TKI therapy; introduction of immunotherapy (blinatumomab); and better assays for measurable residual disease monitoring. This article reviews recent advancements and future directions for the initial treatment of Ph+ ALL in adults.
Late complications and long-term care of adult CAR T-cell patients
Authors: Bishop Michael R.
Published: December 2024

The success of chimeric antigen receptor (CAR) T-cell therapy in adult patients with hematologic malignancies has resulted in a large number of long-term survivors who may experience late complications distinct from those in the early CAR T-cell treatment period. These late complications, defined as occurring more than 90 days after CAR T-cell infusion, include cytopenias, infections, secondary malignancies, and delayed neurotoxicities. Late cytopenias may be from prolonged recovery after lymphodepleting (LD) chemotherapy or arise anew, raising concerns for recurrent primary disease or a secondary malignancy. Cytopenias are treated with supportive care, hematopoietic cytokines, and, occasionally, hematopoietic stem cell support. LD chemotherapy profoundly affects B, T, and natural killer cells. CD19 and B-cell maturation antigen are expressed on normal B cells and plasma cells, respectively, and the targeting of these structures by CAR T-cell products can result in prolonged lymphopenias and hypogammaglobulinemia, making infection an ongoing risk. Late infections are predominantly due to respiratory viruses, reactivation of herpes viruses, and Pneumocystis jirovecii. Patients may require ongoing prophylaxis and immunoglobulin replacement therapy. Although responses may be blunted, vaccinations are generally recommended for most adult CAR T-cell patients. Both hematologic and solid secondary malignancies are a known risk of CAR T-cell therapy; retroviruses used to produce CAR T-cell products have resulted in T-cell cancers secondary to insertional oncogenesis. It is essential to monitor for late complications in adult patients receiving CAR T-cells by using a multidisciplinary approach between referring hematologist oncologists and cell therapy centers to improve the outcomes and quality of life for these patients.
Common variable immunodeficiency: autoimmune cytopenias and advances in molecular diagnosis
Authors: Cunningham-Rundles Charlotte , Casanova Jean-Laurent , Boisson Bertrand
Published: December 2024

Common variable immunodeficiency (CVID) is one of the most common groups of human inborn errors of immunity. In addition to infections resulting from insufficient levels of immunoglobulins and antibodies, a significant proportion of patients develop autoimmune cytopenias, especially immune thrombocytopenia, hemolytic anemia, or neutropenia. They may be the initial manifestation of CVID in a patient who has not had significant infections, and similar episodes may recur at intervals over time. Treatment of these hematologic complications includes the use of corticosteroids or other medications, often including rituximab; splenectomy is discouraged. Here we outline the overall occurrence of these blood cytopenias in a cohort of 408 patients, as well as the clinical and genetic associations noted in these individuals.
The spectrum of Ph-negative disease: CNL and CSF3R-related disorders
Authors: Hasserjian Robert P.
Published: December 2024

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

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

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

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

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

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

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

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

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

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

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

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

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

The 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

Millions 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

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 < .001). Both hypothyroidism (adjusted HR = 1.24; 95% CI, 1.11-1.39; P < .001) and hyperthyroidism (adjusted HR = 1.20; 95% CI, 1.07-1.33; P < .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 < .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.
Incident Vertebral Fractures During Romosozumab Treatment in a Patient With a Pathogenic LRP5 Variant
Authors: van Velsen Evert F S , Wijnen Mark , Muradin Galied S R , Zillikens M Carola
Published: December 2024

A defect in the canonical Wnt-β-catenin pathway may lead to reduced bone strength and increased fracture risk. Sclerostin is a key inhibitor of this pathway by binding to low-density lipoprotein (LDL) receptor–related protein (LRP)-5/6, thereby reducing bone formation. The effectiveness of romosozumab, a human monoclonal antibody that binds sclerostin and prevents this inhibitory effect, has been questioned in patients with inactivating genetic variants in LRP5 or LRP6. We present a 67-year-old woman with severe osteoporosis with 4 grade 2 vertebral fractures due to a heterozygous pathogenic variant in LRP5. She was treated with romosozumab for 1 year, after which a routine follow-up spine x-ray revealed 5 new vertebral fractures, despite a strong increase in bone mineral density (BMD) (lumbar spine [LS] + 58%; femur neck [FN] + 23%), although overestimated at LS because of the vertebral fractures. This suggests that in patients with loss-of-function LRP5 variants, romosozumab is able to increase BMD. However, it is unclear whether the progressive vertebral fractures are due to the severe osteoporosis in relation to the start of romosozumab or a diminished responsiveness related to her LRP5 variant. Further evaluation is needed on the effect of romosozumab on BMD and fracture outcomes in patients with a likely defective LRP5/6 receptor.
Down in the Metamodernist Plain: Tracing a Twenty-First-Century Structure of Feeling in the Reception of NW and How to Be Both
Authors: Kersten Dennis , Wilbers Usha
Published: December 2024

This article investigates how the manifestation of the structure of feeling labeled “metamodernism” by academics is recognized and interpreted by readers outside academia, represented by reviewers in established (print) media and on personal blogs and online platforms such as Goodreads. It focuses on the question of how two contemporary British novels (Zadie Smith's NW and Ali Smith's How to Be Both) that have been explicitly discussed in relation to metamodernism by literary scholars are read by readers who do not participate in the current academic debate about the supposed demise of postmodernism and who may not be familiar with the theorization of the new cultural dominant. The aim is to discover how readers recognize, interpret, and describe the novels’ processing of the legacies of modernism and postmodernism in an effort to move beyond both—a characteristic of literary metamodernism according to the scholars working in the field. The authors believe that a qualitative investigation of the reception of the two novels will advance the (academic) discussion aimed at conceptualizing metamodernism as well as contribute to a deeper understanding of the structure of feeling itself.
Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation
Authors: Siddiqui Sahiba , Liu Fang , Kanthasamy Anumantha G. , McGrail Maura
Published: December 2024

The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.
Stem cell expression of CXCR4 regulates tissue composition in the vomeronasal organ
Authors: Dietz André , Senf Katja , Neuhaus Eva M.
Published: December 2024

The vomeronasal organ (VNO) detects signaling molecules that often prompt innate behaviors, such as aggression and reproduction. Vomeronasal sensory neurons, classified into apical and basal lineages based on receptor expression, have a limited lifespan and are continuously replaced from a common stem cell niche. Using a combination of single-cell RNA sequencing data, immunofluorescence staining and lineage tracing, we identified CXCR4 expression in proliferative stem cells and the basal neuronal lineage. Mice with a conditional knockout of Cxcr4 showed an increased number of SOX2-positive proliferative stem cells and enhanced basal neuronal lineage maturation. In addition, computational gene perturbation analysis revealed 87 transcription factors that might contribute to neurogenesis, among which was SOX2. Conditional knockout of Cxcr4 did not only disturb neuronal maturation, but also affected non-neuronal cell types, resulting in a decrease of basal lamina lining quiescent stem cells and an increase in sustentacular support cells. Together, these findings enhance our understanding how a common pool of stem cells can give rise to different cell types of the VNO, highlighting the distinct role of CXCR4 in this process.
Bir Siyasal İmkan Olarak Anayasayı Tartışmak: 1990’lı Yıllarda İslamcılık Söylemi
Authors: Büyükkaradoğan İsmail
Published: December 2024

Bu çalışma, Türkiye’de 1990’lı yıllarda İslamcılık söyleminin yürüttüğü anayasa tartışmalarına odaklanmaktadır. Bu doğrultuda Altınoluk, Panel, Yeni Zemin ve Yörünge dergilerinden elde edilen yazılardan hareketle, İslamcılık söyle- minin anayasa ile ilişkisi irdelenmektedir. Çalışmanın birinci ve ikinci bölümlerinde İslam siyaset teorisinde anayasanın yeri ve İslamcılığın tanımlanmasına ilişkin kavramsal ve teorik tartışmalarla birlikte İslamcılık söyleminin Türkiye’de kuruluşundan itibaren geçirdiği çeşitli dönemler incelenmektedir. Buna göre İslam siyaset teorisinde anayasa; Kur’an, sünnet ve İslam devleti etrafında Allah’ın egemenliğini tesis etmek için bir araç olarak değerlendirilmektedir. İslamcılık söyleminin Türkiye izleğine bakıldığında ise anayasa, 1960 ve 1980 yılları arasında Allah’ın egemenliği, İslam devleti gibi temalarla tartışılırken 1990’lı yıllarla birlikte Allah’ın egemenliğini tesis etmekten ziyade ulus devlet içerisinde bir siyasal arayış olarak ortaya çıkmaktadır. Bu minvalde İslamcılık söylemi için 1990’lı yıllarda anayasayı tartışmak, büyük ideallerini gerçekleştirmekten ziyade kendi yerini makul kılarak siyasal ve toplumsal düzen içerisinde konumlanma girişimleridir. Çalışmanın son bölümünde ise bahsedilen dergilerdeki anayasa tartışmaları; “toplumsal mutabakat”, “temel hak ve hürriyetler” ve “laiklik ve devletin dini denetimi” olmak üzere üç başlık altında tasnif edilerek İslamcılık söyleminin anayasa tartışmalarına hangi bağlamlarda katıldığı ortaya çıkartılmaktadır.
İsim, Büro, Reklam: Avukatlıkta Simgesel Sermaye Biçimleri
Authors: Koytak Elyesa
Published: December 2024

Hukukun formel yanıyla yaşanan toplumsal gerçeklik arasındaki ilişkiye dair özgün bir olgu avukatlık mesleğidir: Mevzuata ve meslek kurallarına göre bir yandan bu mesleğin güven, saygınlık ve itibar uyarınca yapılması gerekir, diğer yandan iş elde etmek için hangi eylemlerin makbul ve meşru olduğu tanımlanmamıştır. Oysa avukatların yeni iş alma ve mesleki yetkinliklerine yönelik rağbet ve itimat kazanma yolları toplumsal etkiler altında gerçekleşir. Bu makalenin amacı, avukatların dünyasında tanınırlık ve güvenirlik inşa ve icra etme biçimlerinin nasıl oluştuğunu, Bourdieu’nün simgesel sermaye kavramı ışığında keşfetmektir. Meslek dünyasında geçerli simgesel sermaye biçim- lerinin neler olduğunu avukatların anlam ve deneyim dünyaları üzerinden keşfetmek adına, farklı kıdemlerde ve çalışma şartlarında 14 avukatla derinlemesine mülakat yapılmıştır. Yapılan analiz sonucunda avukatlık mesleğinde simgesel sermayenin birbiriyle alakalı dört boyutu olduğu tespit edilmiştir. İsim ve çevre yapmak, güven ve yetkinlik kurmak, büronun kurumsallaşmış simgesel sermayesi ve reklam bu dört boyutu oluşturur. İlk üç boyutun ortak noktası avukatlıkta mesleki rağbet ve itimat inşa etmenin sürekli performans gerektirdiği ve toplumsal etkilere açık bir süreç olduğudur. Reklam ise rağbet ve itibarın kendiliğinden birikeceği yönündeki meslekte yerleşik inancın karşısında yer alır ve simgesel sermaye kazanmanın makbul sürecine kısa devre yapar. Reklamda esasen ilk üç boyutta da içerilen tanınma performansının ve dış etkilerin aleni olması söz konusudur.
Unraveling China’s Aid Strategy Towards Central Asian Countries: The Case of Kyrgyzstan and Tajikistan
Authors: Nurdun Rahman
Published: December 2024

China’s burgeoning influence in Central Asia, particularly in economically disadvantaged nations like Kyrgyzstan and Tajikistan, presents a multifaceted phenomenon deserving of deeper analysis. This article delves into the impact of Chinese involvement in these two Central Asian countries, shedding light on the instruments employed by China, such as development aid and the Belt and Road Initiative (BRI). Despite their economic challenges, Kyrgyzstan and Tajikistan have emerged as key recipients of Chinese aid, receiving grants, concessional loans, and infrastructure projects that have reshaped their socio-economic landscapes. At the heart of China’s engagement lies the ambitious Belt and Road Initiative, which has positioned Kyrgyzstan and Tajikistan as pivotal nodes in China’s quest for regional connectivity. As Kyrgyzstan and Tajikistan navigate their relationship with China, they face the delicate task of leveraging economic opportunities while safeguarding their national interests amidst evolving geopolitical dynamics in Central Asia. This article aims to analyze Chinese influence through development aid and the BRI in Kyrgyzstan and Tajikistan, illuminating both the opportunities and challenges of this relationship.
Como criar valor conjuntamente e capturá-lo individualmente
Authors: Dos Santos Carlos Alberto Frantz , Zen Aurora Carneiro
Published: December 2024

Objetivo: analisar como ocorre a criação e captura de valor em ecossistema de inovação.
Estado da arte: a literatura de inovação tem pesquisado principalmente os mecanismos de criação de valor, em detrimento dos mecanismos de captura de valor. O artigo argumenta que os dois processos devem ser analisados conjuntamente paracompreender o desenvolvimento do ecossistema.
Escopo: foi realizado estudo de caso em 14 organizações do ecossistema de inovação do Instituto Hélice (região da Serra doRio Grande do Sul).
Originalidade: o artigo desenvolve um modelo integrado para criação e captura do valor do ecossistema, mostrando como as estratégias do ecossistema, as percepções de valor e o engajamento dos atores definem os mecanismos para criar e capturar valor.
Impactos: o modelo apresentado neste artigo pode ser aplicado nos ecossistemas de inovação para colocar criação e a captura devalor como elementos centrais em seu desenvolvimento.
Palavras-chave: estratégia de inovação, criação de valor, captura de valor, ecossistemas de inovação, engajamento de atores, desenvolvimento do ecossistema.
Desenvolvendo universidades empreendedoras
Authors: Vedana Dario , Andreassi Tales
Published: December 2024

Objetivo: propor um framework para o desenvolvimento de Universidades Empreendedoras (UEs).
Estado da arte: um dos principais conceitos associados à UE é a integração do modelo de stakeholders da Quádrupla Hélice, que enfatiza a colaboração entre empresas, academia, comunidade e governo nos processos de inovação. Embora haja vastas pesquisas sobre empreendedorismo, a literatura não possui um modelo prático e integrado para o desenvolvimento de UEs.
Escopo: foi realizada revisão sistemática de literatura de 83 artigos científicos, a partir das bases de dados Web of Science e EBSCO de modo a construir um framework para o desenvolvimento da UE.
Originalidade: o framework desenvolvido conecta diversos aspectos internos e externos da UE de modo a ampliar o papel das universidades no processo empreendedor.
Impacto: o framework traz um mapa prático aos gestores de universidades, líderes empresariais e líderes de governo e de outras organizações.
Case Report: Case report : Mindfulness training led to catharsis and mindfulness-to-meaning in a patient with social anxiety disorder comorbid with persistent depressive disorder (Dysthymia)
Authors: Kaiya Hisanobu , Hasegawa Asuka , Komatsu Chika , Noda Shota , Minami Fusaka , Goldin Philippe , Hasegawa Yosuke
Published: December 2024

Background The use of mindfulness in the treatment of anxiety and depression is becoming more and more widespread, but there are few reports that it has fundamentally changed patients’ sense of life. Case Presentation This report showed 9 year’s progress of treatment for Social Anxiety Disorder and Persistent Depressive Disorder in a 41-year-old female patient experiencing a long-term painful married life with a reckless husband and controlling mother-in-law. During the past 25 months, she received 180 sessions of mindfulness training, resulting in complete remission of the anxiety and depression symptoms. After the 30th session she experienced an episode of the catharsis during the mindfulness training and experienced what can be called Mindfulness-To-Meaning, which is characterized by durable eudaimonic well-being in the face of adversity. Conclusions The psychological mechanisms that supported arriving at Mindfulness-To-Meaning are delineated as: Heightened (1) awareness which promoted (2) verbalization of the primary theme of suppression, in which the stress was (3) appraised metacognitively. Then (4) decentering permitted integrating this painful theme into a new adaptive self and world view, which resulted in (5) emotional catharsis, or release. Furthermore (6) positive appraisal of this experience enhanced awareness and led to the experience of (7) Mindfulness-To-Meaning.
Hepatic GPx1 and GIT1 expression altered by ethanol exposure during third trimester-equivalent development
Authors: JOTTY-Arroyo KARICK , Díaz--Castillo Albert , Gomez--Estrada Harold , Pineda--Aleman Rafael
Published: December 2024

Background Ethanol (EtOH) exposure throughout gestation and breastfeeding leads to multiple adverse outcomes in the hepatic system. Under oxidative stress, alterations in the liver are related to the inhibition of induced nitric oxide synthase activity in sinusoidal cells as a consequence of low expression of G-protein-coupled receptor (GPCR)-kinase interacting (GIT1). Here, we hypothesized that both glutathione peroxidase 1 (GPx1) and GIT1 could be altered by EtOH exposure during the third trimester of human equivalent development. Methods We exposed rats during the third trimester equivalent [postnatal days (PD) 2-8] to moderate levels of maternal EtOH (20%). GPx1 and GIT1 expression was detected by western blotting, and the antioxidant activity of glutathione peroxidase GPx and the concentration of hepatic carbonyl groups (CG were determined by spectrophotometry. Serum biochemistry parameters such as alanine aminotransferase (ALT), glucose (gluc), cholesterol (chol), and triglycerides (TG) were also measured. Results We found that ethanol decreased both GIT1 and GPx1 selenoprotein expression, affecting GPx antioxidant activity and increasing protein oxidation. Conclusions These results demonstrate for the first time that the GPx antioxidant system altered by EtOH exposure during the third trimester of development is related to a parallel decrease in GIT1 expression [1].