bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Suicidal Behaviors in American Indian and Alaska Native Peoples: A Systematic Review
Authors: Fetter Anna Kawennison , Wiglesworth Andrea , Rey LittleDove F. , Azarani Michael , Chicken Micah L. Prairie , Young Amanda R. , Riegelman Amy , Gone Joseph P.
Published: December 2022

American Indian/Alaska Natives (AI/ANs) experience disproportionate rates of suicide, but current strategies for suicide prevention have not reduced these health disparities. Therefore, to gain insight into factors that may affect risk trajectories for suicide attempts (SAs) among AI/ANs, we conducted a systematic review of the literature. Forty-five articles met inclusion criteria for the final corpus. Results demonstrate that substance use, depression/hopelessness, childhood maltreatment, violent victimization, and friend/family-member death by suicide serve as robust predictors for SAs. For AI/AN youths specifically, risk-taking behaviors, family conflict, and school environment were associated with SAs. Notable differences in risk factors were identified across age, sex, and region. Limitations of this body of evidence are described, including heterogeneity in study design, measurement, and sampling. Predicated on these findings and limitations, we suggest four key strategies to advance the study of risk factors for AI/AN communities to prevent AI/AN suicide.
Correlation of Tibial Torsion With Lower Limb Alignment and Femoral Anteversion in Patients With Patellar Instability
Authors: Qiao Yi , Xu Junjie , Zhang Xiuyuan , Ye Zipeng , Wu Chenliang , Xu Caiqi , Zhao Song , Zhao Jinzhong
Published: December 2022

Background:

Alignment and rotation of the lower extremities have been suggested to be predisposing pathologic factors for patellar instability.

Purpose:

To elucidate the relationship between the lower limb alignment and lower extremity rotation in patients with patellar instability.

Study Design:

Cross-sectional study; Level of evidence, 3.

Methods:

Included were 83 patients with patellar instability. Computed tomography scans and standing full-leg radiographs were used to measure the tibial tuberosity–trochlear groove (TT-TG) distance, mechanical femorotibial angle (mFTA), mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), femoral torsion, and tibial torsion of the different segments. The relationships between femoral torsion, tibial torsion of the different segments, and the mFTA, mLDFA, and mMPTA were evaluated. The levels of tibial torsion and femoral torsion in patients with varus, normal, or valgus alignment were compared with 1-way analysis of variance and chi-square test.

Results:

The total tibial torsion was significantly associated with total femoral anteversion ( r = 0.329; P = .002) and mFTA ( r = –0.304; P = .005). There were no significant correlations between mFTA and TT-TG distance or femoral anteversion. Compared with patients with valgus malalignment, patients with varus malalignment tended to have higher tibial torsion.

Conclusion:

Tibial torsion was associated with leg axis alignment and femoral anteversion in patients with patellar instability. Patients with patellar instability, especially those with concurrent leg axis deformities, should undergo further radiological imaging so that tibial torsion can be assessed and a diagnosis of torsion deformity made early in the treatment pathway and the proper surgical plan formulated.
Selsurtite, (H3O)12Na3(Ca3Mn3)(Na2Fe)Zr3□Si[Si24O69(OH)3](OH)Cl⋅H2O, a new eudialyte-group mineral from the Lovozero alkaline massif, Kola Peninsula, Russia
Authors: Chukanov Nikita V. , Aksenov Sergey M. , Kazheva Olga N. , Pekov Igor V. , Varlamov Dmitry A. , Vigasina Marina F. , Belakovskiy Dmitry I. , Vozchikova Svetlana A. , Britvin Sergey N.
Published: December 2022

The new eudialyte-group mineral selsurtite, ideally (H3O)12Na3(Ca3Mn3)(Na2Fe)Zr3□Si[Si24O69(OH)3](OH)Cl⋅H2O, was discovered in metasomatic peralkaline rock from the Flora mountain, northern spur of the Selsurt mountain, Lovozero alkaline massif, Kola Peninsula, Russia. The associated minerals are aegirine, albite and orthoclase, as well as accessory lorenzenite, calciomurmanite, natrolite, lamprophyllite and sergevanite. Selsurtite occurs as brownish-red to reddish-orange, equant or flattened on (0001) crystals up to 2 mm across and elongate crystals up to 3 cm long. The main crystal forms are {0001}, {11$\bar{2}$0}, and {10$\bar{1}$1}. Selsurtite is brittle, with the Mohs’ hardness of 5. No cleavage is observed. Parting is distinct on (001). D(meas) = 2.73(2) and D(calc) = 2.722 g⋅cm–3. Selsurtite is optically uniaxial (–), with ω = 1.598(2) and ɛ = 1.595(2). The chemical composition is (wt.%, electron microprobe): Na2O 6.48, K2O 0.27, MgO 0.10, CaO 6.83, MnO 4.73, FeO 1.18, SrO 1.88, La2O3 0.57, Ce2O3 1.07, Pr2O3 0.20, Nd2O3 0.44, Al2O3 0.29, SiO2 50.81, ZrO2 13.50, HfO2 0.45, TiO2 0.61, Nb2О5 1.10, Cl 1.01, SO3 0.29, H2O 8.10, –O≡Cl –0.23, total 99.68. The empirical formula is H25.94Na6.03K0.16Mg0.07Ca3.51Sr0.52Ce0.19La0.10Nd0.08Pr0.03Mn1.91Fe0.47Ti0.22Zr3.16Hf0.06Nb0.24Si24.40Al0.16S0.10Cl0.82O79.13. The crystal structure was determined using single-crystal X-ray diffraction data and refined to R = 0.0484. Selsurtite is trigonal, space group R3, with a = 14.1475(7) Å, c = 30.3609(12) Å, V = 5262.65(7) Å3 and Z = 3. Infrared and Raman spectra show that hydronium cations are involved in very strong hydrogen bonds and form Zundel- and Eigen-like complexes. The strongest lines of the powder X-ray diffraction pattern [d, Å (I, %)(hkl)] are: 11.38 (56)(101), 7.08 (59)(110), 5.69 (36)(202), 4.318 (72)(205), 3.793 (36)(303), 3.544 (72)(027, 220, 009), 2.970 (100)(315) and 2.844 (100)(404). The mineral is named after the discovery locality.
How I Prevent Viral Reactivation in High-risk Patients
Authors: Dadwal Sanjeet Singh , Papanicolaou Genovefa , Boeckh Michael
Published: December 2022

Preventing viral infections at an early stage is a key strategy of successfully improving transplant outcomes. Preemptive therapy and prophylaxis using antiviral agents have been used successfully to prevent clinically significant viral infections in hematopoietic cell transplant (HCT) recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors as well as the introduction of novel antiviral agents and advances in immunotherapies. High quality evidence exists for the effective prevention for herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) infection and disease. Fewer data are available on the effective prevention of human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), Adenovirus (ADV) and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity, and cases that feature differences in approaches, reflecting distinct HCT practices such as ex-vivo T cell depletion.
Evidence of in vivo exogen protein uptake by red blood cells: a putative therapeutic concept
Authors: Hertz Laura , Flormann Daniel , Birnbaumer Lutz , Wagner Christian , Laschke Matthias W. , Kaestner Lars
Published: December 2022

For some molecular players in red blood cells (RBCs), the functional indications and molecular evidence are discrepant. One such protein is transient receptor potential channel of canonical subfamily, member 6 (TRPC6). Transcriptome analysis of reticulocytes revealed the presence of TRPC6 in mouse RBCs and its absence in human RBCs. We transfused TRPC6 knockout RBCs into wild-type mice and performed functional tests. We observed the “rescue” of TRPC6 within 10 days; however, the “rescue” was slower in splenectomized mice. The latter finding led us to mimic the mechanical challenge with the cantilever of an atomic force microscope and simultaneously carry out imaging by confocal (3D) microscopy. We observed the strong interaction of RBCs with the opposed surface at around 200 pN and the formation of tethers. The results of both the transfusion experiments and the atomic force spectroscopy suggest mechanically stimulated protein transfer to RBCs as a protein source in the absence of the translational machinery. This protein transfer mechanism has the potential to be utilized in therapeutic contexts, especially for hereditary diseases involving RBCs, such as hereditary xerocytosis or Gárdos channelopathy.
Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII
Authors: Zhang Yuan , Liu Zhigang , Zhang Bin
Published: December 2022

Mutations in lectin, mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency protein 2 (MCFD2) cause the combined deficiency of factor V (FV) and FVIII (F5F8D). LMAN1 and MCFD2 form a protein complex that transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi. Although both proteins are required for the cargo receptor function, little is known about the specific roles of LMAN1 and MCFD2 in transporting FV/FVIII. We used different LMAN1 and MCFD2 deficient cell lines to investigate the LMAN1/MCFD2-dependent FV/FVIII secretion pathway. LMAN1 deficiency led to more profound decreases in FV/FVIII secretion in HEK293T and HepG2 cells than in HCT116 cells, suggesting that regulation of cargo transport by the LMAN1/MCFD2 pathway varies in different cell types. Using these cell lines, we developed functional assays to accurately assess the pathogenicity of recently reported potential LMAN1 and MCFD2 missense mutations. LMAN1 with mutations abolishing carbohydrate binding can still partially rescue FV/FVIII secretion, suggesting that N-glycan binding is not essential for FV/FVIII transport. Surprisingly, overexpression of either wild-type or mutant MCFD2 is sufficient to rescue FV/FVIII secretion defects in LMAN1 deficient cells. These results suggest that cargo binding and transport are carried out by MCFD2 and that LMAN1 primarily serves as a shuttling carrier of MCFD2. Finally, overexpression of both LMAN1 and MCFD2 does not further increase FV/FVIII secretion, suggesting that the amount of the LMAN1-MCFD2 receptor complex is not a rate-limiting factor in ER-Golgi transport of FV/FVIII. This study provides new insight into the molecular mechanism of F5F8D and the intracellular trafficking of FV and FVIII.
Sequencing therapy in relapsed DLBCL
Authors: Flowers Christopher R. , Odejide Oreofe O.
Published: December 2022

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy worldwide, comprising approximately 30% of all lymphomas. Currently, 50% to 60% of patients diagnosed with DLBCL are alive at 5 years and cured with modern therapy, but about 10% to 15% of patients are refractory to first-line therapy, and an additional 20% to 30% relapse following a complete response. Patients who have relapses beyond 2 years may experience more favorable outcomes and have forms of DLBCL that can be distinguished biologically. Patients who experience early relapse or who have primary refractory disease (less than a complete response or relapse within 3 to 6 months of initial therapy) have worse outcomes. For decades, the standard of care treatment strategy for fit patients with relapsed DLBCL has been salvage therapy with non–cross-resistant combination chemoimmunotherapy regimens followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) as stem cell rescue for patients with chemosensitive disease. Recent data suggest that certain patients may benefit from chimeric antigen receptor T-cell therapy (CAR T) in the second-line setting. Additional novel therapies exist for patients who are ineligible, who are unable to access these therapies, or who fail ASCT and/or CAR T. Despite the advent of new therapies for DLBCL and improved outcomes, DLBCL remains a life-threatening illness. Thus, it is essential for clinicians to engage in serious illness conversations with their patients. Goals-of-care communication can be improved through skills-based training and has been demonstrated to have an impact on patient experiences.
New approaches to tackle cytopenic myelofibrosis
Authors: Reynolds Samuel B. , Pettit Kristen
Published: December 2022

Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation. Despite sharing this pathogenic feature, MF disease behavior can vary widely. MF can generally be categorized into 2 distinct subgroups based on clinical phenotype: proliferative MF and cytopenic (myelodepletive) MF. Compared to proliferative phenotypes, cytopenic MF is characterized by lower blood counts (specifically anemia and thrombocytopenia), more frequent additional somatic mutations outside the Jak/STAT pathway, and a worse prognosis. Cytopenic MF presents unique therapeutic challenges. The first approved Jak inhibitors, ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF. Supportive care measures that aim to improve anemia or thrombocytopenia are often ineffective. Fortunately, new treatment strategies for cytopenic MF are on the horizon. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 109/L. Several other Jak inhibitors are in development to extend therapeutic benefits to those with either anemia or thrombocytopenia. While many other novel non–Jak inhibitor therapies are in development for MF, most carry a risk of hematologic toxicities and often exclude patients with baseline thrombocytopenia. As a result, significant unmet needs remain for cytopenic MF. Here, we discuss clinical implications of the cytopenic MF phenotype and present existing and future strategies to tackle this challenging disease.
Allogeneic transplantation for advanced acute leukemia
Authors: Weisdorf Daniel
Published: December 2022

Outcomes of allogeneic hematopoietic cell transplantation (HCT) for patients with advanced acute leukemia and myelodysplastic syndromes (MDS) remain uncertain. All published series include the important and often not stated selection bias that influences outcome. Performance status, patient age, prompt donor availability, risk phenotype of the leukemia, and tumor burden all influence the decision-making process about HCT with active disease. In addition, patients with MDS do not achieve a true pre-HCT complete remission, and thus much less stringent measures are used to indicate suitability for allografting in that disease. Post-HCT maintenance or investigational approaches for tumor depletion may improve the outcomes.
Transplant in AML with measurable residual disease: proceed or defer?
Authors: Craddock Charles
Published: December 2022

Allogeneic stem cell transplantation plays a central role in the management of fit adults with high-risk acute myeloid leukemia (AML) in first complete morphologic remission (CR1). Advances in both donor selection and transplant technology have both dramatically increased accessibility of transplant and led to significant reductions in transplant-related mortality over the past 2 decades. There has, however, been no concomitant reduction in the risk of disease relapse, which remains the major cause of transplant failure. Pivotal to the design of innovative strategies with the potential to reduce relapse risk is accurate identification of patients at the highest risk of disease recurrence. Multiple retrospective studies have identified an increased risk of disease relapse in patients allografted for AML in CR1 with evidence of pretransplant measurable residual disease (MRD). The prognostic significance of pretransplant MRD has been confirmed recently in prospective analyses. The optimal management of patients with evidence of pretransplant MRD remains a matter of conjecture with regard to 2 key issues. First, should the presence of pretransplant MRD delay a decision to proceed to transplant, allowing time for delivery of additional MRD-directed therapy prior to transplant? Second, to what extent can the intensity of the conditioning regimen or the magnitude of the graft-vs-leukemia effect be manipulated to improve the outcome of such patients?
The first relapse in multiple myeloma: how to pick the next best thing
Authors: Devarakonda Srinivas , Sharma Nidhi , Efebera Yvonne
Published: December 2022

The choice of treatment for patients with multiple myeloma (MM) at first relapse/progression is based on many factors: (1) treatment-related factors, which include the regimen used during first induction, the quality and duration of first response achieved, toxicities from the first treatment, whether the patient underwent autologous stem cell transplant, and whether the patient was on maintenance at the time of relapse/progression; (2) disease-related factors, including disease presentation and pace of progression; and (3) patient-related factors, including functional age and performance status. The learning objectives are to present the treatment options for patients with MM upon their first relapse and to learn about various strategies for selecting an optimal treatment regimen.
The evolution of targeted therapy in pediatric AML: gemtuzumab ozogamicin, FLT3/IDH/BCL2 inhibitors, and other therapies
Authors: Pommert Lauren , Tarlock Katherine
Published: December 2022

Despite the maximum intensification of chemotherapy and the increased use of hematopoietic stem cell transplantation (HCT) in pediatric patients with acute myeloid leukemia (AML), nearly 40% of patients still experience relapse, and cure in this setting remains a significant challenge. Recent improvements in AML characterization, including advances in flow cytometry and comprehensive genomic sequencing, have led to a better understanding of AML biology and the identification of multiple potential therapeutic targets. Novel agents targeting genomic lesions, cell surface antigens, and other mechanisms that permit oncogenesis or immune escape are being incorporated into current treatment strategies or are under investigation in efforts to improve outcomes and decrease the toxicities and late effects associated with traditional intensive chemotherapeutic and HCT treatment. However, multiple challenges still exist, including the biologic and immunophenotypic heterogeneity of childhood AML, the differences in underlying biology as compared to adult AML, and the significant potential for on-target/off-tumor toxicity associated with therapies directed at targets common to myeloid cells, both leukemic and normal. This article reviews the current landscape of genomic and cell surface targets for children with AML with a focus on the currently available targeted therapeutic agents, those in active clinical investigation, and those still in development.
Divergent paths: management of early relapsed follicular lymphoma
Authors: Takiar Radhika , Karimi Yasmin , Phillips Tycel J.
Published: December 2022

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades—most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.
Coming soon to a pharmacy near you? FXI and FXII inhibitors to prevent or treat thromboembolism
Authors: Cohen Omri , Ageno Walter
Published: December 2022

Anticoagulants have been in use for nearly a century for the treatment and prevention of venous and arterial thromboembolic disorders. The most dreaded complication of anticoagulant treatment is the occurrence of bleeding, which may be serious and even life-threatening. All available anticoagulants, which target either multiple coagulation factors or individual components of the tissue factor (TF) factor VIIa or the common pathways, have the potential to affect hemostasis and thus to increase bleeding risk in treated patients. While direct oral anticoagulants introduced an improvement in care for eligible patients in terms of safety, efficacy, and convenience of treatment, there remain unmet clinical needs for patients requiring anticoagulant drugs. Anticoagulant therapy is sometimes avoided for fear of hemorrhagic complications, and other patients are undertreated due to comorbidities and the perception of increased bleeding risk.

Evidence suggests that the contact pathway of coagulation has a limited role in initiating physiologic in vivo coagulation and that it contributes to thrombosis more than it does to hemostasis. Because inhibition of the contact pathway is less likely to promote bleeding, it is an attractive target for the development of anticoagulants with improved safety.

Preclinical and early clinical data indicate that novel agents that selectively target factor XI or factor XII can reduce venous and arterial thrombosis without an increase in bleeding complications.
Special considerations in GI bleeding in VWD patients
Authors: Chornenki Nicholas L.J. , Ocran Edwin , James Paula D.
Published: December 2022

Gastrointestinal (GI) bleeding is an important cause of morbidity and mortality in von Willebrand disease (VWD). It has been noted that GI bleeding caused by angiodysplasia is overrepresented in VWD patients compared to other causes. The bleeding from angiodysplasia is notoriously difficult to treat; recurrences and rebleeds are common. A growing body of basic science evidence demonstrates that von Willebrand factor negatively regulates angiogenesis through multiple pathways. VWD is clinically highly associated with angiodysplasia. The predisposition to angiodysplasia likely accounts for many of the clinical difficulties related to managing GI bleeding in VWD patients. Diagnosis and treatment are challenging with the current tools available, and much further research is needed to further optimize care for these patients with regard to acute treatment, prophylaxis, and adjunctive therapies. In this review we provide an overview of the available literature on GI bleeding in VWD and explore the molecular underpinnings of angiodysplasia-related GI bleeding. Considerations for diagnostic effectiveness are discussed, as well as the natural history and recurrence of these lesions and which therapeutic options are available for acute and prophylactic management.
Leukemogenesis in infants and young children with trisomy 21
Authors: Roberts Irene
Published: December 2022

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21–associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.
Cellular therapy for multiple myeloma: what's now and what's next
Authors: Rodriguez-Otero Paula , San-Miguel Jesús F.
Published: December 2022

Despite significant improvement in the treatment of multiple myeloma (MM), a cure remains elusive, and patients failing proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies remain a challenge due to a lack of standard of care treatment and a dismal survival rate. The development of T-cell redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, have transformed the outcome of triple-class exposed relapsed and refractory MM (RRMM). B-cell maturation antigen (BCMA) has proven to be an important target in MM, and BCMA-directed CAR T cells have shown unprecedented efficacy with a prolonged duration of response in a population with advanced RRMM, leading to the approval of 2 different BCMA CAR T-cell products. Still, and in contrast to prior experience in the field of CD19-directed CARs, no plateau has been seen in the survival curves, and relapses continue to occur. Therefore, further improvement is needed. Early use in the course of the disease as well as of next- generation CARs may further augment the efficacy of these therapies. In this review we address current state-of-the-art approved BCMA-directed CAR T-cell therapy in RRMM, as well as potential future developments focused on optimizing patient care and novel CAR designs.
Germline risk factors for second malignant neoplasms after treatment for pediatric hematologic malignancies
Authors: Bhatia Smita
Published: December 2022

Survivors of childhood hematologic malignancies are at a substantially higher risk of developing subsequent neoplasms (SNs) when compared with the general population. SNs commonly observed in this population include basal cell carcinoma, brain tumors, thyroid cancer, breast cancer, bone tumors, and sarcoma. Radiation is the primary therapeutic exposure associated with the development of these SNs. There is emerging evidence of an association between chemotherapeutic exposures (alkylating agents/anthracyclines) and the development of SNs. Despite a strong dose-dependent association between therapeutic exposures and SN risk, there is significant interindividual variability in the risk for SNs for any given dose of therapeutic exposure. This interindividual variability in risk suggests the role of genetic susceptibility. This article describes the clinical and molecular epidemiology of SNs commonly observed in survivors of childhood hematologic malignancies and also highlights some of the work focusing on the development of risk prediction models to facilitate targeted interventions.
Evaluating patients with autoimmune hemolytic anemia in the transfusion service and immunohematology reference laboratory: pretransfusion testing challenges and best transfusion-management strategies
Authors: Johnson Susan T. , Puca Kathleen E.
Published: December 2022

The serologic evaluation of autoimmune hemolytic anemia (AIHA) confirms the clinical diagnosis, helps distinguish the type of AIHA, and identifies whether any underlying alloantibodies are present that might complicate the selection of the safest blood for any needed transfusion. The spectrum of testing is generally dependent on the amount and class (immunoglobulin G or M) of autoantibody as well as the resources and methodologies where testing is performed. The approach may range from routine pretransfusion testing, including the direct antiglobulin test, to advanced techniques such as adsorptions, elution, and red cell genotyping. When transfusion is needed, the selection of the optimal unit of red blood cells is based on urgency and whether time allows for the completion of sophisticated serologic and molecular testing methods. From the start of when AIHA is suspected until the completion of testing, communication among the clinical team and medical laboratory scientists in the transfusion service and immunohematology reference laboratory is critical as testing can take several hours and the need for transfusion may be urgent. The frequent exchange of information including the patient's transfusion history and clinical status, the progress of testing, and any available results is invaluable for timely diagnosis, ongoing management of the patient, and the safety of transfusion if required before testing is complete.
Mitigating the risk of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory-based therapy
Authors: Covut Fahrettin , Sanfilippo Kristen M.
Published: December 2022

Patients with multiple myeloma (MM) have up to a 20-fold increased risk of venous thromboembolism (VTE) compared with the general population, with most events occurring within the first 6 months of diagnosis. Treatment with immunomodulatory drugs (IMiDs) is a strong risk factor for VTE in MM. In a meta-analysis of 2 large, randomized trials comparing anticoagulant thromboprophylaxis vs placebo in ambulatory patients with cancer at high risk of VTE based on a validated risk score, the risk of VTE decreased without increasing the risk of major bleeding. However, few patients with MM participated in these trials (1.1%). Initial guidance for risk-stratifying patients with MM resulted in persistent rates of VTE >10% and highlighted the need for improved VTE risk stratification in patients with MM. Three validated risk scores are now available to quantify risk of VTE in patients with MM: SAVED, IMPEDE VTE, and PRISM scores. Using best available data, thromboprophylaxis should be strongly considered in patients with MM assessed as high risk for VTE, especially newly diagnosed patients receiving IMiD-based combination therapies. However, prospective studies are needed to further validate available models and identify the optimal thromboprophylactic agent for each VTE risk category.
The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study
Authors: Jalnapurkar Isha , Frazier Jean A. , Roth Mark , Cochran David M. , Foley Ann , Merk Taylor , Venuti Lauren , Ronco Lucienne , Raines Shane , Cadavid Diego
Published: December 2022

Background

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP.

Methods

Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules.

Results

There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants and lowest in the FXS boys. Measurement of FMR1 mRNA and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab.

Conclusion

Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP in longitudinal studies.
Comparison of apical and basolateral Cu treatment for iron-related gene regulation during deferoxamine induced iron deficiency
Authors: Evcan Ezgi , Gulec Sukru
Published: December 2022

Background

Intestinal copper transporter (Atp7a) mutant-brindled mice with systemic Cu deficiency had elevated Cu levels in enterocyte cells without any perturbation of iron-regulating genes, suggesting that blood Cu level might be important for intestinal iron homeostasis during iron deficiency (ID). We hypothesized that the blood Cu level and polarization (apical and basolateral) of enterocyte cells might be important regulators for the compensatory response on the regulation of genes in enterocyte cells during iron deficiency.

Methods

We grew Caco-2 cells on a bicameral cell culture plate to mimic the human intestine system and on a regular tissue culture plate. Iron deficiency was induced by deferoxamine (DFO). The cells were treated with Cu and Cu with Fe following mRNA expressions of DMT1, FPN, TFR, and ANKRD37 were analyzed.

Results

Our main finding was that basolateral treatment of Cu significantly reduced mRNA expressions of iron-regulated genes, including DMT1, FPN, TFR, and ANKRD37, compared to DFO-treated and DFO with apical Cu-treated groups in both bicameral and regular tissue culture plates.

Conclusions

Cu level in the basolateral side of Caco-2 cells significantly influenced the intracellular gene regulation in DFO-induced iron-deficient condition, and polarization of the cells might be important factor gene regulation in enterocyte cells.
Drug response prediction using graph representation learning and Laplacian feature selection
Authors: Xie Minzhu , Lei Xiaowen , Zhong Jianchen , Ouyang Jianxing , Li Guijing
Published: December 2022

Background

Knowing the responses of a patient to drugs is essential to make personalized medicine practical. Since the current clinical drug response experiments are time-consuming and expensive, utilizing human genomic information and drug molecular characteristics to predict drug responses is of urgent importance. Although a variety of computational drug response prediction methods have been proposed, their effectiveness is still not satisfying.

Results

In this study, we propose a method called LGRDRP (Learning Graph Representation for Drug Response Prediction) to predict cell line-drug responses. At first, LGRDRP constructs a heterogeneous network integrating multiple kinds of information: cell line miRNA expression profiles, drug chemical structure similarity, gene-gene interaction, cell line-gene interaction and known cell line-drug responses. Then, for each cell line, learning graph representation and Laplacian feature selection are combined to obtain network topology features related to the cell line. The learning graph representation method learns network topology structure features, and the Laplacian feature selection method further selects out some most important ones from them. Finally, LGRDRP trains an SVM model to predict drug responses based on the selected features of the known cell line-drug responses. Our five-fold cross-validation results show that LGRDRP is significantly superior to the art-of-the-state methods in the measures of the average area under the receiver operating characteristics curve, the average area under the precision-recall curve and the recall rate of top-k predicted sensitive cell lines.

Conclusions

Our results demonstrated that the usage of multiple types of information about cell lines and drugs, the learning graph representation method, and the Laplacian feature selection is useful to the improvement of performance in predicting drug responses. We believe that such an approach would be easily extended to similar problems such as miRNA-disease relationship inference.
Relationship between red blood cell distribution width-to-albumin ratio and outcome of septic patients with atrial fibrillation: a retrospective cohort study
Authors: Gu You-lan , Yang Duo , Huang Zhi-bin , Chen Yan , Dai Zai-shen
Published: December 2022

Background

This retrospective cohort study aimed to investigate the association between red blood cell distribution width-to-albumin ratio (RAR) and in-hospital mortality in patients with sepsis and atrial fibrillation (AF).

Methods

Data were obtained from the Medical Information Mart for the Intensive Care Database IV database version 1.0. Multivariate Cox regression models, curve-fitting, and Kaplan–Meier analyses were performed to determine the correlation between RAR and in-hospital mortality in patients with sepsis and AF.

Results

This study included 3042 patients with sepsis and AF. Confounding variables were adjusted for in the Multivariable Cox regression analysis models. RAR was independently associated with in-hospital mortality (hazard ratio 1.06; 95% confidence interval 1.03–1.08; p < 0.001). A linear relationship was found between the RAR and in-hospital mortality in patients with sepsis and AF.

Conclusion

Elevated RAR levels are associated with increased in-hospital mortality in patients with sepsis and AF. Further research is required to confirm this association.
Examining the predictors of healthcare facility choice for outpatient care among older adults in India using Andersen’s revised healthcare utilization framework model
Authors: Rahaman Margubur , Chouhan Pradip , Roy Avijit , Rana Md. Juel , Das Kailash Chandra
Published: December 2022

Background

In India, the demand for outpatient care is substantially higher than inpatient care among older adults. Therefore, the current study examines the level, patterns, and factors associated with outpatient care use.

Methods

The present research used data from the first wave of the Longitudinal Ageing Study in India (LASI, 2017–18). A total of 34,588 older adults (45 years and above) who accessed outpatient healthcare services in one year prior to the survey were included in this study. A bivariate chi-square test was applied to present the percentage distribution of types of outpatient healthcare utilization by background characteristics and healthcare responsiveness. Multinomial logistic regression analyses were employed to explore the interplay of outpatient healthcare utilization and allied predisposing, enabling, and need factors.

Results

About 63.7% of total older adults used a private facility, followed by 22.8% used a public facility, and 13.5% used other facilities. Years of schooling, household wealth status, place of residence, self-rated health, and health insurance were all found to be significant determinants of public or private facility use. In contrast, respondents' sex was found to be a significant determinant of private healthcare use only. The study finds that there was inadequate healthcare reaction to public health facilities.

Conclusion

The current study revealed that the use of private facility for outpatient care is noticeably high in India. Older adults' educational attainments, health insurance coverage, and household level economic background were found to be significant factors in healthcare choice. The current study emphasizes the need to strengthen public healthcare services for outpatient care.
Impact of body mass index on in-hospital mortality in older patients hospitalized for bacterial pneumonia with non-dialysis-dependent chronic kidney disease
Authors: Okada Akira , Yamaguchi Satoko , Jo Taisuke , Yokota Isao , Ono Sachiko , Ikeda Kurakawa Kayo , Nangaku Masaomi , Yamauchi Toshimasa , Kadowaki Takashi
Published: December 2022

Background

Low body mass index (BMI) in older individuals with decreased kidney function is important because of its association with poor prognosis and frailty. Herein, we aimed to clarify the association between BMI and in-hospital mortality among older patients with non-dialysis-dependent chronic kidney disease (CKD) stratified by kidney function.

Methods

Using data from the Medical Vision Database, this multicentre cohort study included people aged ≥ 60 years with an estimated glomerular filtration rate of < 60 ml/min/1.73 m2 but without dialysis dependency, hospitalised for bacterial pneumonia during 2014–2019. We compared the risk of in-hospital death between patients with BMI categories based on the quartiles (low, medium–low, medium–high, and high) setting medium–high BMI as a reference. We further assessed the association with BMI using a cubic spline, setting BMI as a nonlinear continuous variable and a BMI of 22 kg/m2 as a reference. We also evaluated the association between BMI and kidney function using a generalised additive model adjusted for interaction terms between nonlinear continuous BMI and kidney function.

Results

We obtained data for 3,952 patients, with 350 (8.9%) in-hospital deaths. When compared with medium–high BMI, low BMI was associated with an increased risk of death and longer hospital stay, whereas the other two categories were comparable. Models using a cubic spline showing an association between BMI and in-hospital death showed an L-shaped curve; BMI < 22.0 kg/m2 was associated with an increased risk for mortality, and at a BMI of 18.5 kg/m2, the odds ratio was 1.43 with a 95% confidence interval of 1.26–1.61 when compared with a BMI of 22.0 kg/m2. Analysis of the interactive effects of kidney function using the generalised additive model showed that a protective association of high BMI tapered along with decreased kidney function.

Conclusions

This cohort study suggests not only that lower BMI and low kidney function are associated with in-hospital mortality independently but also that the protective effects of high BMI weaken as kidney function decreases via the analysis of the interaction terms. This study highlights the necessity for the prevention of underweight and demonstrates the interaction between BMI and kidney function in older patients with non-dialysis-dependent CKD.
Composite hemangioendothelioma in the cervical spine with kaposiform hemangioendothelioma features in an elderly patient: a case report
Authors: Nakamura Shunsuke , Uehara Masashi , Kobayashi Shota , Hasegawa Hiromasa , Tanaka Atsushi , Takahashi Jun
Published: December 2022

Background

Composite hemangioendothelioma (CHE) is an intermediate group of tumors with features between hemangioma and angiosarcoma both histologically and biologically. CHE is predominant in young and middle-aged adults, but very infrequently affects the spine. We describe the case of primary CHE in the cervical spine exhibiting kaposiform hemangioendothelioma (KHE)-like components that was associated with cervical myelopathy with vertebral body destruction in an elderly woman. We retrospectively reviewed the case of a primary cervical spinal tumor, diagnosed as CHE with KHE-like components in pathological findings, associated with cervical myelopathy and cervical vertebral body destruction.

Case presentation

An 80-year-old woman presented with progressive cervical myelopathy caused by a cervical spine tumor. Preoperative cervical MRI revealed a neoplastic lesion invading the cervical spine that strongly compressed the spinal cord, causing right upper-limb paralysis. We performed partial tumor resection along with posterior decompression and fixation. Postoperatively, pathological findings showed that the tumor was CHE with KHE-like features. Following radiotherapy, no recurrences have been observed in 21 months.

Conclusions

This is the first report of CHE with features of KHE in the spine of an elderly patient. Posterior decompression and fusion of the cervical spine and subsequent radiotherapy resulted in a good outcome.
Biofilm infection of a central venous port-catheter caused by Mycobacterium avium complex in an immunocompetent child with cystic fibrosis
Authors: Kavvalou Alexandra , Stehling Florian , Tschiedel Eva , Kehrmann Jan , Walkenfort Bernd , Hasenberg Mike , Olivier Margarete , Steindor Mathis
Published: December 2022

Background

Mycobacterium (M.) chimaera is a non-tuberculous mycobacterium (NTM) that belongs to M. avium complex (MAC). In patients with cystic fibrosis (CF), MAC can cause bronchopulmonary infections that can be prolonged and difficult to treat. MAC infections of sites other than the lungs or central catheters are rare and almost exclusively associated with immunodeficiency.

Case presentation

We present a case of an 8-year-old CF patient (delF508 homozygous) with recurrent pulmonary exacerbations, gradual clinical deterioration, B-symptoms (fever, fatigue, weight loss, night sweat), elevated transaminases and intermittent detection of M. chimaera in the sputum without radiological signs of NTM-associated lung disease with a central venous port-catheter. Next-generation sequencing (NGS) revealed M. chimaera port infection that was also confirmed by mycobacterial culture. The patient recovered within 4 weeks after removal of the catheter and initiation of MAC targeted antimicrobial therapy. Electron microscopy of the catheter illustrated the presence of mycobacteria in a biofilm.

Conclusions

MAC central venous catheter infection needs to be considered in immunocompetent people. NGS is a valuable tool for rapid identification of rare infections. MAC capability of biofilm formation renders catheter removal the central therapeutic intervention for the clearance of the infection.
A rare case of proliferative glomerulonephritis with monoclonal IgG2 kappa deposit: a case report
Authors: Ito Daisuke , Shiozaki Yuriko , Shimizu Yoshitaka , Suzuki Yumiko , Takeda Asami , Misaki Taro
Published: December 2022

Background

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare monoclonal gammopathy of renal significance with dense deposits of monoclonal immunoglobulin.

Case presentation

We report a 78-year-old Japanese male patient with mild proteinuria and lower extremity edema. Monoclonal immunoglobulin could not be identified in his serum or urine. Although his bone marrow biopsy was negative, renal biopsy found features of membranoproliferative glomerulonephritis (MPGN) with deposition of monoclonal IgG2 kappa. Electron microscopy examination revealed non-organized electron-dense deposits in the subepithelial, and subendothelial mesangial regions. Steroid monotherapy was performed after diagnosis of PGNMID but complete remission was not achieved.

Conclusion

PGNMID with IgG3 kappa deposits is the most common in cases with the histological feature of MPGN. There are few cases of PGNMID with IgG2 kappa deposits exhibiting MPGN. This report describes a very rare case of PGNMID with the histological feature of MPGN.