bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical hemolytic uremic syndrome: diagnosis, management, and discontinuation of therapy
Authors: Java Anuja
Published: December 2024

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy typically characterized by anemia, thrombocytopenia, and end-organ injury. aHUS occurs due to endothelial injury resulting from overactivation of the alternative pathway of the complement system. The etiology of the dysregulated complement system is either a genetic mutation in 1 or more complement proteins or an acquired deficiency due to autoantibodies. Over the past decade, advancements in our understanding of the role of complement in the pathophysiology of aHUS as well as the availability of anticomplement drugs has been a game-changer for our patients. These drugs have revolutionized the clinical course, outcome, and prognosis of this disease. Therefore, all patients in whom aHUS is suspected should undergo testing for complement genetic variants and autoantibodies. In approximately 30% to 40% of patients, a genetic variant of uncertain significance (VUS) may be identified. Such patients should undergo further testing to define the significance of the VUS. A combination of antigenic, functional, and biomarker analyses can assist in establishing the significance of the variants and thereby define the etiology in most patients. These analyses will also help to determine the duration of treatment based on the individual's genetic alteration. This review aims to shed light on the diagnosis and management of aHUS and discusses how to stratify patients to determine who can safely discontinue anticomplement therapy.
To consolidate or not to consolidate: the role of autologous stem cell transplantation in MCL
Authors: Silkenstedt E. , Dreyling M.
Published: December 2024

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions. However, ASCT is also hampered by acute and delayed toxicity. Thus, alternative first-line treatment strategies without ASCT but including novel agents are under investigation. With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care. Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined. In addition, it remains unclear how effective Bruton's tyrosine kinase inhibitor (BTKi) therapy will be in the relapsed setting for patients who received BTKi as part of first-line therapy. It also remains unclear whether the TRIANGLE data can be extrapolated to other BTKi, which is particularly relevant considering it is no longer FDA approved for MCL. Until then, individual patient characteristics and preferences, disease biology, and estimation of risk of toxicity needs to be taken into account when deciding about the addition of ASCT to an ibrutinib-containing induction therapy. For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.
Trousseau syndrome: management of refractory VTE
Authors: Zwicker Jeffrey I.
Published: December 2024

Managing recurrent and refractory venous thromboembolism (VTE) in patients with cancer presents unique challenges. This review outlines the complexities and therapeutic strategies for recurrent VTE in cancer patients, which includes distinguishing thrombus acuity, differentiating between tumor and bland thrombi, and evaluating potential contributing factors including anticoagulant adherence, extrinsic tumor compression, drug interactions, and anticoagulant-specific considerations such as heparin-induced thrombocytopenia or antithrombin deficiency. Different anticoagulation strategies are discussed, including the administration of escalated-dose low molecular weight heparin (LMWH) as well as the indications and rationale for switching between direct oral anticoagulants or LMWH.
Transplant options and outcomes for TP53 myeloid disease
Authors: Fernández Hugo F. , Mishra Asmita
Published: December 2024

TP53-mutated myeloid disease is a constellation of abnormalities seen in both de novo and therapy-related acute myeloid leukemia and myelodysplastic syndrome. Historically, this group of disorders has had a poor prognosis. Newer treatment combinations allow patients to be treated with less toxicity. If response to induction therapy is achieved, fit and willing patients should be considered for allogeneic hematopoietic cell transplantation (HCT). The addition of allogeneic HCT to the treatment approach has modestly improved outcomes compared to chemotherapy alone, more so for those patients with disease control. Tailoring the conditioning regimen and maintenance therapy may improve outcomes in TP53 myeloid patients. In addition to chemotherapy, disease-modulating and immunological treatments continue to be studied to further improve outcomes.
Challenges in hospice and end-of-life care in the transfusion-dependent patient
Authors: Rodenbach Rachel , Caprio Thomas , Loh Kah Poh
Published: December 2024

Despite promising advances leading to improved survival, many patients with hematologic malignancies end up dying from their underlying disease. Their end-of-life (EOL) care experience is often marked by worsening symptoms, late conversations about patient values, increased healthcare utilization, and infrequent involvement of palliative care and hospice services. There are several challenges to the delivery of high-quality EOL care that span across disease, patient, clinician, and system levels. These barriers include an unpredictable prognosis, the patient's prognostic misunderstandings and preference to focus on the immediate future, and the oncologist's hesitancy to initiate EOL conversations. Additionally, many patients with hematologic malignancies have increasing transfusion requirements at the end of life. The hospice model often does not support ongoing blood transfusions for patients, creating an additional and substantial hurdle to hospice utilization. Ultimately, patients who are transfusion-dependent and elect to enroll in hospice do so often within a limited time frame to benefit from hospice services. Strategies to overcome challenges in EOL care include encouraging repeated patient-clinician conversations that set expectations and incorporate the patient's goals and preferences and promoting multidisciplinary team collaboration in patient care. Ultimately, policy-level changes are required to improve EOL care for patients who are transfusion-dependent. Many research efforts to improve the care of patients with hematologic malignancies at the end of life are underway, including studies directed toward patients dependent on transfusions.
Practical guide to the diagnosis and management of heparin-induced thrombocytopenia
Authors: May Jori , Cuker Adam
Published: December 2024

Heparin-induced thrombocytopenia (HIT) is an immune reaction to heparin associated with thrombocytopenia, thrombotic risk, and a high risk of morbidity and mortality. Given the frequent use of heparin and the common occurrence of thrombocytopenia in hospitalized patients, the diagnosis and management of HIT is a recurrent challenge in everyday inpatient care. This article presents practical guidance and tools to support the individual clinician providing evidence-based care to patients with suspected or confirmed HIT. The optimal diagnostic evaluation requires the stepwise use of risk-stratification tools and laboratory assays. Management requires the selection and use of nonheparin anticoagulation in these complex patients with both increased thrombotic risk and possible concurrent increased bleeding risk due to thrombocytopenia. Each step in the diagnostic and management process has important nuances and complexities, many of which vary based on patient characteristics and institutional resources. Given the many challenges of HIT care, truly practical management is best achieved when tools are implemented to support the delivery of consistent, high quality, and cost-effective care across health systems.
Iron overload in acquired sideroblastic anemias and MDS: pathophysiology and role of chelation and luspatercept
Authors: Gattermann Norbert
Published: December 2024

Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload.
Has PD-1 blockade changed the standard of care for cHL?
Authors: Kuczmarski Thomas M. , Lynch Ryan C.
Published: December 2024

The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.
Molecular profiling in MPN: who should have it and why?
Authors: Chee Ashlyn , Mead Adam J.
Published: December 2024

Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that result from somatic mutations in hematopoietic stem cells, causing constitutive activation of JAK-STAT signaling pathways with consequent overproduction of 1 or more myeloid lineages. The initiating event in MPN pathogenesis is a genetic mutation, and consequently molecular profiling is central to the diagnosis, risk stratification, and, increasingly, monitoring of therapy response in persons with MPN. In this review we summarize current approaches to molecular profiling of classical MPNs (essential thrombocythemia, polycythemia vera, and myelofibrosis), using illustrative clinical case histories to demonstrate how genetic analysis is already fully integrated into MPN diagnostic classification and prognostic risk stratification. Molecular profiling can also be used in MPN to measure response to therapy both in clinical trials and increasingly in routine clinical practice. Taking a forward look, we discuss how molecular profiling in MPN might be used in the future to select specific molecularly targeted therapies and the role of additional genetic methodologies beyond mutation analysis.
Pregnancy: MPN management before, during, and after pregnancy
Authors: How Joan , Hobbs Gabriela
Published: December 2024

The aging obstetric population, combined with more frequent myeloproliferative neoplasm (MPN) diagnoses in younger patients, will result in hematologic providers increasingly caring for MPN patients in pregnancy. There are special considerations that pertain to management of pregnancy in MPN patients. This includes increased risks of thrombosis and hemorrhage as well as pregnancy complications that are likely related to placental dysfunction associated with an MPN diagnosis, including preeclampsia, preterm delivery, and intrauterine growth restriction. Complicating these outcomes is the uncertainty of the safety of many commonly used drugs in MPNs in pregnancy and breastfeeding. Given the overall low incidence of pregnancy in MPNs, many guidelines are based on expert opinions and extrapolation from other high-risk pregnancy populations. In this case-based review, we summarize the literature on MPN pregnancy outcomes and synthesize recommendations to provide guidance on the antepartum and postpartum management of MPN patients. Special attention is also made to issues relevant to preconception, including fertility and the use of assisted reproductive technology.
What is the ideal approach—doublet, triplet, or quadruplet(s)?
Authors: Kumar Shaji K.
Published: December 2024

Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.
EBV and post-transplant lymphoproliferative disorder: a complex relationship
Authors: El-Mallawany Nader Kim , Rouce Rayne H.
Published: December 2024

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous category of disease entities occurring in the context of iatrogenic immune suppression. Epstein-Barr virus (EBV)–driven B-cell lymphoproliferation represents the prototype of quintessential PTLD, which includes a range of histologies named nondestructive, polymorphic, and monomorphic EBV+ diffuse large B-cell lymphoma (DLBCL) PTLD. While EBV is associated with the majority of PTLD cases, other drivers of lymphoid neoplasia and lymphoma transformation can occur—with or without EBV as a codriver—thus underlining its vast heterogeneity. In this review, we discuss the evolution in contemporary PTLD nomenclature and its emphasis on more precise subcategorization, with a focus on solid organ transplants in children, adolescents, and young adults. We highlight the fact that patients with quintessential EBV-associated PTLD—including those with monomorphic DLBCL—can be cured with low-intensity therapeutic approaches such as reduction in immune suppression, surgical resection, rituximab monotherapy, or rituximab plus low-dose chemotherapy. There is, though, a subset of patients (approximately 30%-40%) with quintessential PTLD that remains refractory to lower-intensity approaches, for whom intensive, lymphoma-specific chemotherapy regimens are required. Other forms of monomorphic PTLD, which are as diverse as the spectrum of defined lymphoma entities that also occur in immunocompetent patients, are rarely cured with lower-intensity therapies and appear to be better categorized as posttransplant lymphomas. These distinct scenarios represent the variations in lymphoid pathology that make up a conceptual framework for PTLD consisting of lymphoid hyperplasia, neoplasia, and malignancy. This framework serves as the basis to inform risk stratification and determination of evidence-based treatment strategies.
Beyond IV push: alternative methods for management of acute pain in SCD
Authors: Azul Melissa , Brandow Amanda M.
Published: December 2024

Acute pain in sickle cell disease (SCD) involves multiple, complex downstream effects of vaso-occlusion, ischemia, and inflammation, ultimately resulting in severe and sudden pain. Historically, opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) have been the cornerstone of treatment for acute SCD pain. However, given the evolving understanding of the complexity of pain pathways in SCD and the desire to avoid NSAID and opioid-induced side effects, a multimodal approach is needed to effectively treat acute SCD pain. In this article we review recent research supporting the utilization of nonopioid pharmacologic interventions and nonpharmacologic interventions while also describing the research questions that remain surrounding their use and efficacy and effectiveness in the management of acute SCD pain. Furthermore, we review care delivery processes shown to improve acute SCD pain outcomes and highlight areas where more work is needed. Through this comprehensive approach, alternative mechanistic pathways may be addressed, leading to improved SCD pain outcomes.
Novel clinical care models for patients with sickle cell disease
Authors: Bartolucci Pablo
Published: December 2024

This educational program outlines the importance of evolving clinical care models in response to increased life expectancy and variability in individual patient experiences, particularly in the context of sickle cell disease (SCD). It emphasizes the need for personalized and adaptive care models, in which the patient should play a central role, and the need for collaborative networks of physicians and caregivers, taking into account the multisystemic nature of the disease. The proposal also discusses the role of personalized medicine and technological advances, highlighting the need for a shared medical record; the balance between rare center expertise and widespread dissemination of knowledge; and the challenges in high- and low-income countries. It emphasizes the need to move toward personalized medicine, given the significant interindividual variability in both follow-up and treatment, and the introduction of more appropriate biomarkers and predictive algorithms to aid decision-making. The proposal includes real-world examples of successful adaptation in clinical care models. It concludes with a summary of the importance and benefits of evolving clinical care models and a future outlook on the evolution of clinical care in response to demographic changes. These proposals are intended to provide a comprehensive overview of the current state and future directions of clinical care models for SCD.
Biology of post-transplant relapse: actionable features
Authors: Orofino Giorgio , Vago Luca
Published: December 2024

In patients receiving allogeneic hematopoietic cell transplantation to cure acute myeloid leukemia (AML), recurrence of the underlying disease, or relapse, represents a crucial unanswered issue and prominent cause of mortality. Still, over recent years, advancements in omic technologies have allowed us to gain new insights into the dynamic changes occurring in cancer and the host over the course of treatments, providing a novel evolutionary perspective on the issue of disease relapse. In this review, we summarize current knowledge on the molecular features of relapsing AML, with a specific focus on changes in the mutational asset of the disease and in the interplay between the tumor and the donor-derived immune system. In particular, we discuss how this information can be translated into relevant indications for monitoring transplanted patients and selecting the most appropriate therapeutic options to prevent and treat relapse.
Maintenance strategies for relapse prevention and treatment
Authors: Geramita Emily , Hou Jing-Zhou , Shlomchik Warren D. , Ito Sawa
Published: December 2024

Posttransplant relapse is the most significant challenge in allogeneic stem cell transplantation (alloSCT). Posttransplant interventions, in conjunction with optimal conditioning regimens and donor selection, are increasingly supported by evidence for their potential to prolong patient survival by promoting antileukemia or graft-versus-leukemia effects. Our review begins by highlighting the current evidence supporting maintenance therapy for relapse prevention in acute myeloid leukemia and acute lymphocytic leukemia. This includes a broad spectrum of strategies, such as targeted therapies, hypomethylating agents, venetoclax, and immunotherapies. We then shift our focus to the role of disease monitoring after alloSCT, emphasizing the potential importance of early detection of measurable residual disease and a drop in donor chimerism. We also provide an overview of salvage therapies for overt relapse, including targeted therapies, chemotherapies, immunotherapies, donor lymphocyte infusion, and selected agents under investigation in ongoing clinical trials. Finally, we review the evidence for a second alloSCT (HSCT2) and discuss factors that impact donor selection for HSCT2.
Hormone-related thrombosis: duration of anticoagulation, risk of recurrence, and the role of hypercoagulability testing
Authors: Scheres Luuk J. J. , Middeldorp Saskia
Published: December 2024

Hormone-related venous thromboembolism (VTE) is common and entails scenarios in which VTE occurs during exposure to exogenous or endogenous female sex hormones, typically estrogen and progestogen. For the management of hormone-related VTE, it is important to realize that many patients use these hormones for a vital purpose often strongly related to the patient's well-being and quality of life. In this review we discuss clinical cases of VTE related to hormonal contraceptive use and pregnancy to illustrate key considerations for clinical practice. We cover practice points for primary VTE treatment and detail the evidence on the risk of recurrent VTE and bleeding in this population. The potential value of thrombophilia testing is described, including “who, why, when, what, and how.” We also discuss key aspects of shared decision-making for anticoagulant duration, including a reduced-dose anticoagulant strategy in hormone-related VTE.
Targeted medical therapies for vascular anomalies
Authors: Borst Alexandra
Published: December 2024

The last 2 decades of genetic discovery in the field of vascular anomalies have brought targeted medical therapies to the forefront of care patients with vascular anomalies and have broadened the role of hematologists/oncologists in this field. Many vascular anomalies have now been identified to be driven by somatic gain-of-function variants in the PI3K/AKT/ mTOR and Ras/MAPK intracellular signaling pathways. This has led to the introduction of various antiangiogenic agents that inhibit these pathways. Knowledge of the indications for and the safe administration of these agents in patients with vascular anomalies is now a crucial part of training for hematologists/oncologists.
In pursuit of a functional cure for follicular lymphoma
Authors: Trotman Judith , Falconer Janlyn
Published: December 2024

We are now a quarter of a century after the transformative impact of rituximab in improving overall survival for patients with follicular lymphoma. With a burgeoning array of effective immunochemotherapy approaches, we can now frame many patients' expectations of longevity and a “functional cure,” with survival estimates for many newly diagnosed patients comparable to age- and gender-matched populations. We highlight not just heterogeneity in disease but also in patients, which influences therapeutic decision-making in an immunochemotherapy era where progression-free survival advances are associated with efficacy-toxicity trade-offs, and no clear overall survival advantage is associated with any specific regimen. We provide the metrics that assist, prognostication both at diagnosis and after initial therapy, but we also highlight the limited long-term follow-up in institutional, population, and clinical trial data sets to inform our survival estimates. Nonetheless, the data are sufficient to empower us to reframe more optimistic conversations with our patients and the lymphoma community, discussions that engender hope and planning for a life lived long, and well, after therapy for follicular lymphoma.
T-cell–based therapies for treating relapsed or refractory mantle cell lymphoma
Authors: Epstein-Peterson Zachary D. , Palomba M. Lia
Published: December 2024

While targeted therapies such as Bruton's tyrosine kinase and BCL2 inhibitors have fundamentally changed the treatment of mantle cell lymphoma (MCL), not all patients respond to these therapies, and responses are finite and can be fleeting, especially with high-risk MCL. As patients progress through successive therapies, the clinical course is characterized by shortening response times,1 frequent disease acceleration, and limited survival outcomes. Recently, the sensitivity of MCL to novel immune-based therapies is being realized with favorable results, as chimeric antigen receptor–modified T cells and bispecific T-cell–engaging antibodies are being investigated and implemented into practice for patients. However, critical issues remain to understand the role of these agents in routine practice. In this review, we discuss the current landscape regarding these agents, examine our approach to incorporating them into practice, and consider unanswered questions that we must ultimately address to improve outcomes for patients.
Management of anticoagulation in patients with brain metastasis
Authors: Hamulyák Eva. N. , Yust-Katz Shlomit , Leader Avi
Published: December 2024

Venous thromboembolism (VTE) is a prevalent and serious complication among cancer patients, necessitating therapeutic anticoagulation for many individuals with brain metastases. Simultaneously, patients with brain metastases, particularly those with high-risk primary tumors, have an increased risk of intracranial hemorrhage (ICH). Managing anticoagulation in these patients presents a dual challenge: preventing thromboembolism while avoiding hemorrhagic events. Here, we present our approach to anticoagulation for acute VTE in patients with brain metastases, based on the available evidence. We review potential risk factors for anticoagulation-associated ICH in this population and discuss strategies for managing acute VTE in patients with and without ICH.
Givosiran: a targeted treatment for acute intermittent porphyria
Authors: Dickey Amy K. , Leaf Rebecca K.
Published: December 2024

The acute hepatic porphyrias (AHPs) are a family of rare genetic diseases associated with attacks of abdominal pain, vomiting, weakness, neuropathy, and other neurovisceral symptoms. Pathogenic variants in 1 of 4 enzymes of heme synthesis are necessary for the development of AHP, and the onset of acute attacks also requires the induction of δ-aminolevulinic acid synthase 1 (ALAS1), the first and rate-limiting step of heme synthesis in the liver. Givosiran is an RNA interference medication that inhibits hepatic ALAS1 and was designed to treat AHP. In 2019 the US Food and Drug Administration approved givosiran for AHP based on positive results from a phase 3 clinical trial of 94 patients with AHP who demonstrated a marked improvement in AHP attacks and a substantial decrease in δ-aminolevulinic acid and porphobilinogen, the primary disease markers of AHP. A long-term follow-up study demonstrated continued improvement in AHP attack rates, biochemical measures of disease, and quality of life. Real-world studies have also confirmed these results. Common side effects include injection site reactions, hyperhomocysteinemia, and abnormalities of liver and renal biochemistries. This article reviews the studies that led to givosiran approval, discusses real-world clinical data, and highlights remaining questions in the treatment of AHP.
Porphyria cutanea tarda: a unique iron-related disorder
Authors: Leaf Rebecca K. , Dickey Amy K.
Published: December 2024

The porphyrias are a group of disorders of heme biosynthesis, each characterized by an enzymatic defect in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT) arises due to the inhibition of uroporphyrinogen decarboxylase (UROD) in the presence of hepatic iron and oxidative stress. Most patients with PCT have evidence of siderosis on liver biopsy, and the disease resolves with iron depletion. PCT manifests as skin fragility, blistering cutaneous lesions on sun-exposed areas, dark urine, and elevated plasma and urine porphyrins. Factors contributing to the development of PCT include alcohol use, hepatitis C virus infection, human immunodeficiency virus, estrogen use, UROD pathogenic variants, and hereditary hemochromatosis. Treatment includes therapeutic phlebotomy to decrease total body iron levels and low-dose hydroxychloroquine, which reduces hepatic porphyrin content. The following review explores the biology of PCT, the critical role of iron in disease pathogenesis, and our approach to the management of these patients.
DOACs: role of anti-Xa and drug level monitoring
Authors: Mithoowani Siraj , Siegal Deborah
Published: December 2024

Direct oral anticoagulants (DOACs) do not require routine monitoring of anticoagulant effect, but measuring DOAC activity may be desirable in specific circumstances to detect whether clinically significant DOAC levels are present (eg, prior to urgent surgery) or to assess whether drug levels are excessively high or excessively low in at-risk patients (eg, after malabsorptive gastrointestinal surgery). Routine coagulation tests, including the international normalized ratio (INR) or activated partial thromboplastin time (aPTT), cannot accurately quantify drug levels but may provide a qualitative assessment of DOAC activity when considering the estimated time to drug clearance based on timing of last drug ingestion and renal and hepatic function. Drug-specific chromogenic and clot-based assays can quantify drug levels but they are not universally available and do not have established therapeutic ranges. In this review, we discuss our approach to measuring DOAC drug levels, including patient selection, interpretation of coagulation testing, and how measurement may inform clinical decision-making in specific scenarios.
Effects of a SWELE program for improving mental wellbeing in children and adolescents with special educational needs: protocol of a quasi-experimental study
Authors: Lee Regina Lai Tong , Chan Sally Wai Chi , Chong Yuen Yu , Chau Steven Wai Ho , Choi Kai Chow , Chien Wai Tong
Published: December 2024

Background

Unstructured play has also been found effective on promoting positive emotions and emotional competence among children and adolescents with special educational needs (SEN). Unstructured Outdoor Play coupled with Mindfulness-based Interventions via ‘Supporting Wellness in E-Child Learning Environments’ (SWELE) program can foster the mental health and wellbeing of children and adolescents with SEN. Currently there is a lack of the unstructured play with mindfulness-based interventions in the special schools in Hong Kong. Thus, aim of the SWELE program is to examine the effects of unstructured play with mindfulness-based interventions—(SWELE) program combining unstructured outdoor play activities with mindfulness-based interventions to promote mental wellbeing among SEN children and adolescents.

Methods

This 16-week SWELE program focuses on combining unstructured outdoor play activities with mindfulness-based interventions to promote mental wellbeing among children and adolescents with SEN. Training workshops for schoolteachers, school principals, parents and student mental health ambassadors in each special school together with a 16-week SWELE program and each last 45–60 min. Unstructured play allows students the freedom to explore, create and discover without predetermined rules or guidelines. Outdoor unstructured play activities include naturally run, jump and move on a playground, riding a bike, climbing trees, playing tag, playing with blocks, colour, water play, and boxes. A convergent parallel mixed-methods design both with a quantitative measure using a single group pre- and post-tests quasi-experiment behavioural observational method to preliminarily evaluate the impact of SWELE Program on SEN children’s and adolescents’ mental wellbeing; and with a qualitative design to conduct eight focus group discussions including schoolteachers, school principals, parents, SEN students, school nurses from six selected special groups and to explore their perceptions and experiences after participated the SWELE program.

Discussion

The purpose of this protocol is to examine the effects of a 16-week SWELE program on the mood, anxiety level, social skills and playfulness behaviours among children and adolescents with SEN in the special schools in Hong Kong. From the evaluation and observation, the pre-set aim and objectives on the improvement of mental wellbeing in children and adolescents with SEN can be confirmed.

Trial registration

ClinicalTrial.gov, NCT06112483. Registered on 31 October 2023.
Technology frustration in healthcare – does it matter in staff ratings of stress, emotional exhaustion, and satisfaction with care? A cross-sectional correlational study using the job demands-resources theory
Authors: Wirkkala Maarit , Wijk Katarina , Larsson Agneta C. , Engström Maria
Published: December 2024

Background

Health information technology has developed into a cornerstone of modern healthcare. It has changed workflows and enhanced communication, efficiency, and patient safety. However, technological development has progressed faster than research on its potential effects on care quality and the healthcare work environment. Using the Job Demand-Resources theory, this study investigated the associations between "frustration with technology" and three outcomes: stress, emotional exhaustion, and staff satisfaction with care, holding job resources and the demand workload constant.

Method

A cross-sectional correlational study was conducted between January and April 2022. Healthcare staff from different professions (e.g., physicians, registered nurses, physiotherapists, licensed practical nurses) and workplaces (n = 417, response rate 31%) answered a survey regarding job demands and resources in the workplace, frustration with technology, stress, emotional exhaustion, and satisfaction with care. Data were analyzed with Spearman’s rank correlation coefficient, the Mann–Whitney U test, and the Kruskal–Wallis test, and multiple variables, one for each outcome, were tested with Generalized Estimated Equations models in SPSS.

Results

The bivariate correlation analyses confirmed statistically significant associations between all the independent variables and the outcomes, except for the independent variable high workload. A high workload was associated with stress and emotional exhaustion but not with staff satisfaction with care. In the three GEE models, one for each outcome, higher stress was statistically significantly associated with more frustration with technology and lower scores for the variables participation in decision-making, sense of community at work, and higher workload. Higher emotional exhaustion was associated with more frustration with technology, higher workload, a lower teamwork climate, and lower growth opportunities. Lower staff satisfaction with care was associated with lower scores for the variable participation in decision-making.

Conclusions

Taking other variables into account, technology frustration matters in staff ratings of stress and emotional exhaustion, but not with the satisfaction of given care. Future studies should aim to further investigate what causes technology frustration and how to mitigate it.
Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases
Authors: Wang Ling , Zhang Xiaoyan , Yang Ziyi , Wang Binquan , Gong Hongyang , Zhang Ke , Lin Yi , Sun Mingkuan
Published: December 2024

Extracellular vesicles (EVs) are membrane vesicles originating from different cells within the brain. The pathophysiological role of EVs in neurodegenerative diseases is progressively acknowledged. This field has advanced from basic biological research to essential clinical significance. The capacity to selectively enrich specific subsets of EVs from biofluids via distinctive surface markers has opened new avenues for molecular understandings across various tissues and organs, notably in the brain. In recent years, brain-derived EVs have been extensively investigated as biomarkers, therapeutic targets, and drug-delivery vehicles for neurodegenerative diseases. This review provides a brief overview of the characteristics and physiological functions of the various classes of EVs, focusing on the biological mechanisms by which various types of brain-derived EVs mediate the occurrence and development of neurodegenerative diseases. Concurrently, novel therapeutic approaches and challenges for the use of EVs as delivery vehicles are delineated.
The State and the Family: Privatizing Care and Welfare in Contemporary Sweden
Authors: Gotby Alva
Published: December 2024

This essay starts from a theoretical perspective developed by Marxist feminists, who have argued that the family has a central role in capitalist societies. Families provide much of the care that people need to maintain their own capacity to work, and they also function as the most important institution for rearing children. We can also apply this perspective to the welfare state and look at how the family and the state interact to ensure a particular type of reproduction. Exploring the welfare state as one way of sustaining a capitalist economy, this essay seeks to unpack some assumptions about Swedish society. It looks at missed opportunities to more radically transform the institution of the family in the earlier periods of Swedish social democracy, and how that laid the groundwork for increasingly privatized forms of care provision in contemporary Sweden. Arguing that the Swedish family continued to be based on white and heterosexual norms that hindered attempts to create greater gender equality, the essay looks at more progressive alternatives to the family form.
Elemental stoichiometry and insect chill tolerance: evolved and plastic changes in organismal Na+ and K+ content in Drosophila
Authors: Chalmer Sarah C. , Rudman Seth M. , Andersen Mads K. , Schmidt Paul , MacMillan Heath A.
Published: December 2024

Acclimation and evolutionary adaptation can produce phenotypic changes that allow organisms to cope with challenges. Determining the relative contributions and the underlying mechanisms driving phenotypic shifts from acclimation and adaptation is of central importance to understanding animal responses to change. Rates of evolution have traditionally been considered slow relative to ecological processes that shape biodiversity. Many organisms nonetheless show patterns of genetic variation that suggest that adaptation may act sufficiently fast to allow continuous change in phenotypes in response to environmental change (called ‘adaptive tracking’). In Drosophila, both plastic and evolved differences in chill tolerance are associated with ionoregulation. Here, we combine an acclimation experiment, field collections along a well-characterized latitudinal cline, and a replicated field experiment to assess the concordance in the direction, magnitude, and potential mechanisms of acclimation and adaptation on chill coma recovery and elemental (Na and K) stoichiometry in both sexes of Drosophila melanogaster. Acclimation strongly shaped chill coma recovery, spatial adaptation produced comparatively modest effects, and temporal adaptation had no significant effect. Leveraging knowledge on the mechanisms underlying variation in chill tolerance traits, we find that relationships between elemental stoichiometry and chill coma recovery in the context of acclimation may differ from those that are associated with spatial adaptive change.
Extracellular vesicles and nanoparticles at a glance
Authors: Jeppesen Dennis K. , Zhang Qin , Coffey Robert J.
Published: December 2024

Cells can communicate with neighboring and more distant cells by secretion of extracellular vesicles (EVs). EVs are lipid bilayer membrane-bound structures that can be packaged with proteins, nucleic acids and lipids that mediate cell–cell signaling. EVs are increasingly recognized to play numerous important roles in both normal physiological processes and pathological conditions. Steady progress in the field has uncovered a great diversity and heterogeneity of distinct vesicle types that appear to be secreted from most, if not all, cell types. Recently, it has become apparent that cells also release non-vesicular extracellular nanoparticles (NVEPs), including the newly discovered exomeres and supermeres. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of the diversity of EVs and nanoparticles that are released from cells into the extracellular space, highlighting recent advances in the field.
An MST-based assay reveals new binding preferences of IFIT1 for canonically and noncanonically capped RNAs
Authors: Spiewla Tomasz , Grab Katarzyna , Depaix Anais , Ziemkiewicz Kamil , Warminski Marcin , Jemielity Jacek , Kowalska Joanna
Published: December 2024

IFITs (interferon-induced proteins with tetratricopeptide repeats) are components of the innate immune response that bind to viral and cellular RNA targets to inhibit translation and replication. The RNA target recognition is guided by molecular patterns, particularly at the RNA 5′ ends. IFIT1 preferably binds RNAs modified with the m7G cap-0 structure, while RNAs with cap-1 structure are recognized with lower affinity. Less is known about the propensity of IFIT1 to recognize noncanonical RNA 5′ ends, including hypermethylated and noncanonical RNA caps. Further insights into the structure-function relationship for IFIT1–RNA interactions are needed but require robust analytical methods. Here, we report a biophysical assay for quick, direct, in-solution affinity assessment of differently capped RNAs with IFIT1. The procedure, which relies on measuring microscale thermophoresis of fluorescently labeled protein as a function of increasing ligand concentration, is applicable to RNAs of various lengths and sequences without the need for their labeling or affinity tagging. Using the assay, we examined 13 canonically and noncanonically 5′-capped RNAs, revealing new binding preferences of IFIT1. The 5′ terminal m6A mark in the m7G cap had a protective function against IFIT1, which was additive with the effect observed for the 2′-Oposition (m6Amcap-1). In contrast, an increased affinity for IFIT1 was observed for several noncanonical caps, including trimethylguanosine, unmethylated (G), and flavin-adenine dinucleotide caps. The results suggest new potential cellular targets of IFIT1 and may contribute to broadening the knowledge of the innate immune response mechanisms and the more effective design of chemically modified mRNAs.
Dijital Diplomaside Büyük Dil Modelleri: Fırsatlar ve Riskler
Authors: Akıllı Erman , Şimşek Murat
Published: December 2024

Bu makale, Büyük Dil Modellerinin (BDM) dijital diplomasi üzerindeki etkilerini ve uluslararası ilişkilerdeki rolünü incelemektedir. BDM’ler, dil bariyerlerini aşarak, gerçek zamanlı çeviri ile karşılıklı anlayışı artırma ve diplomatik iletişimleri otomatikleştirme yoluyla diplomatik süreçleri iyileştirme potansiyeline sahiptir. Ancak, yanıltıcı bilgi yayılma (halüsinasyon) riski ve veri güvenliği önlemleri gereksinimi gibi önemli zorluklar da beraberinde getirmektedir. BDM’lerin potansiyelini diplomaside tam olarak kullanabilmek ve bu riskleri azaltmak için uluslararası standartlar ve etik kuralların inşa edilmesi şarttır.
A compilation of histidine kinase genes in Enterobacter hormaechei strain HCF3 isolated from the North West Province of South Africa
Authors: Udeh Ebere Loveyn , Otun Sarah Oluwatobi , Makhetha Lerato Lisbeth Njaki , Ntushelo Khayalethu
Published: December 2024

This study investigates the histidine kinase (HK) gene repertoire of Enterobacter hormaechei strain HCF3, isolated from fresh cow dung in Mogosane Village, Northwest Province, South Africa. Histidine kinases are critical components of bacterial two-component signal transduction systems, enabling bacteria to sense and adapt to diverse environmental conditions. Given the growing concern over antimicrobial resistance (AMR) associated with E. hormaechei, this research elucidates the genetic components that facilitate its environmental adaptability. After isolating the strain, genomic sequencing using Illumina technology, resulting in high-quality sequence data, was conducted. The assembled genome was meticulously annotated and deposited in the National Center for Biotechnology Information (NCBI) under BioProject number PRJNA991313, with additional accession numbers for raw reads (JAUOLV000000000.1) and BioSample (SAMN36292742). Histidine kinase genes were identified based on conserved domains, particularly HisKA and HATPase. This led to compiling a comprehensive HK gene catalogue with locus tags, protein accession numbers, and functional annotations. To validate the HK gene set of E. hormaechei HCF3, we conducted a rigorous comparative analysis with other strains. This revealed that strain HCF1 contains 21 histidine kinase genes, HCF2 has 25, while HCF4 has 19. These findings underscore the diversity and conservation of HK genes across different Enterobacter species, providing a new perspective on their evolutionary significance. The assembled dataset provides valuable insights into the signalling pathways of E. hormaechei, highlighting the potential roles of HKs in environmental sensing, adaptation, and pathogenicity. Furthermore, this research lays the groundwork for future studies on the applications of these genes in agriculture and biotechnology, offering new avenues for understanding and managing E. hormaechei in various ecological contexts.