bluuebunny/crossref_metadata_2025 huggingface dataset:
RON Kinase Inhibition Reduces Renal Endothelial Injury in Sickle Cell Disease Mice
Authors: Jerebtsova Marina , Khaibullina Alfia , Adjei Elena Afia , Afangbedji Nowah Kokou Apeadoufia , Ivanov Andrey , Kumari Namita , Quezado Zena , Nekhai Sergei
Published: April 2021

BACKGROUND: Patients with Sickle Cell Disease (SCD) have an approximately three-fold higher risk of developing chronic kidney disease (CKD) than the general population. Endothelial dysfunction and inflammation which are induced by hemolysis and lead to vasculopathy are major mechanisms in the development of CKD. Red blood cells (RBCs) hemolysis inside the renal tissue stimulates macrophages infiltration. Endocytosis of RBC hemolysis products by infiltrating macrophages activates to MT-SP1 protease which cleaves and activates non-active circulating Macrophage Stimulating Protein 1 (MSP1). MSP1 binds to and activates cell surface receptor tyrosine kinase, recepteur d'origine nantais (RON).

OBJECTIVES: To determine the role of RON in the development of renal endothelial injury.

METHODS: Human renal glomerular endothelial cells (HGEC) and a mouse model of SCD (Townes) were used. The animal protocol was approved by the Institutional Animal Care and Use Committee at the Children's National Health System. The SCD mice express human Hgb S and Hgb F. Control mice express human Hgb A1. Two-month-old mice were injected with 10 mg/kg of body weight of RONi (BSM-777607, Santa Cruz Scientific), an inhibitor of RON, subcutaneously daily for 14 consecutive days. Kidneys were collected, and paraffin-embedded sections were used for H&E and PAS staining, and immunostaining.

RESULTS: Treatment of cultured human renal glomerular endothelial cells (HGEC) with MSP1 activated RON receptor and induced downstream signaling evidenced by increased phosphorylation of ERK and AKT kinases. RONi significantly reduced ERK and AKT phosphorylation. MSP1 treatment also increased motility of HGEC, and expression of F-actin and von Willebrand Factor (vWF). Renal disease in SCD mice was characterized by glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury demonstrated by H&E and PAS staining, and ICAM, vWF and CD34 immunostaining. We observed accumulation of MSP1 in the glomerular capillaries of SCD mice. Treatment of mice with RONi significantly reduced glomerular hypertrophy, capillary dilation and congestion, and also reduced endothelial injury (Figure 1).

CONCLUSIONS: Renal glomerular accumulation of MSP1 and RON kinase activation contribute to the induction of renal endothelial injury in SCD mice. Inhibition of RON kinase activation significantly reduced endothelial injury and development of kidney disease.

ACKNOWLEDGMENTS: This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH.

Disclosures

No relevant conflicts of interest to declare.
Valine as a Key Metabolic Regulator of Hematopoietic Stem Cell Maintenance
Authors: Nakauchi Hiromitsu
Published: April 2021

Hematopoietic stem cells (HSCs) are maintained by a specialized bone marrow microenvironment (niche) and are largely quiescent during the steady-state conditions1. However, upon stimulation or transplantation, HSCs can expand and differentiate into any mature hematopoietic cell type. This ability of donor HSCs to reform a recipient's hematopoietic system is key to the success of HSC transplantation (HSCT). For donor HSCs to engraft, the recipient bone marrow niche must first be emptied via myeloablative irradiation or chemotherapy. However, myeloablative conditioning can cause severe complications and even mortality. As an alternative, we have recently developed a metabolic conditioning approach for HSCT. By screening the amino acid requirements of HSCs, we identified the essential amino acid valine as indispensable for the expansion and maintenance of HSCs2. Both mouse and human HSCs failed to expand when cultured in valine-restricted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within one week. Dietary valine restriction thereby emptied the mouse bone marrow niche and just a two-week diet afforded long-term donor-HSC engraftment without chemoirradiative myeloablation. We conclude that valine plays a critical role in HSC maintenance and suggest dietary valine restriction as a conditioning regimen that may reduce iatrogenic complications in HSCT. These findings, and recent efforts to optimize this metabolic conditioning approach through mechanistic understanding of the HSC valine dependency, will be presented. Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000;192:1273-1280.Taya Y, Ota Y, Wilkinson AC, et al. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation. Science. 354:1152-1155.

Disclosures

Nakauchi: ReproCELL Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Megakaryon Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; iBUKI Corp: Equity Ownership; iCELL Inc: Equity Ownership; Advanced Immunothearpy Inc: Equity Ownership.
GATA2 in Bone Marrow Failure
Authors: Holland Steven M.
Published: April 2021

The syndrome now known as GATA2 haploinsufficiency had been published at least since the 1970s under different clinical guises. With the identification of the gene in 2011, GATA2 deficiency became the overarching diagnosis for a complex syndrome with acoustic, cutaneous, lymphatic, pulmonary, leukemic, hematologic and infectious manifestations. Arising in both spontaneous and autosomal dominant patterns, the genetics made it recognizable and diagnosable even before symptoms arose. Over the last several years it has become clear that GATA2 is a major contributor to: pediatric and adolescent MDS, AML in younger adults, some cases of ALL, severe genital HPV infection, disseminated mycobacterial infections, pulmonary alveolar proteinosis, pulmonary hypertension and is associated with a variety of solid tumors. Mutations with more profound effects on GATA2 expression (nonsense and deletions) appear to have a more severe phenotype than do intronic mutations that alter transcript level but not transcript integrity. These latter intronic mutations may be associated with later onset of disease and more variable penetrance. Elucidating the gene targets on which GATA2 works and which partners it engages will lead to important observations in the molecular genetics of hematopoietic control.

This variability of penetrance and expression is most apparent with the intronic mutations, in which whole generations may be relatively protected, presumably from genes in trans to GATA2 . An active search is on for these genes that appear to regulate GATA2 . One of the consequences of the variable penetrance of GATA2 deficiency is that it may be discordant within a family, allowing a false sense of security about use of a clinically well relative for bone marrow transplant donation. Hematopoietic stem cell transplantation is highly effective for cure of GATA2 deficiency. We have now done almost 40 transplants in GATA2 deficiency with high survival rates using related haploidentical donors, as well as with fully matched donors. The effects of transplantation are profound both in terms of hematopoietic and somatic results, including resolution of most HPV lesions, resolution of pulmonary alveolar proteinosis and resolution of pulmonary hypertension, when present. We have now encountered several cases of transplant from unexpectedly affected donors into a known GATA2, all of which have had poor outcomes. These cases reinforce the critical need for molecular confirmation of the GATA2 status of any related donor, regardless of lack of symptoms.

GATA2 deficiency is recently recognized but successful treatments have emerged alongside the science. Efforts to understand and allow for manipulation of GATA2 expression are underway.

Disclosures

No relevant conflicts of interest to declare.
Role of Platelets in Adaptive Changes to Anti-Angiogenesis Therapy
Authors: Sood Anil
Published: April 2021

While anti-angiogenesis therapies have shown remarkable activity in ovarian and other cancers, adaptive resistance can develop within weeks to months. Moreover, concerns have been raised about the potential for more aggressive tumor growth following withdrawal of anti-angiogenesis drugs. Here, we will discuss the role of platelets, specifically platelet extravasation into the tumor microenvironment in stimulating tumor growth. Among the various factors regulating this process, focal adhesion kinase (FAK) expression in platelets plays an important role in their migration into the tumor microenvironment. Mice with FAK-deficient platelets do not exhibit rebound tumor growth following exposure to anti-angiogenesis drugs. Combination therapy with a FAK inhibitor and anti-angiogenic agents reduced tumor growth and inhibited the negative effects following withdrawal of anti-angiogenic therapy. These biological findings, other emerging mechanisms and clinical implications will be discussed.

Disclosures

No relevant conflicts of interest to declare.
Genetic Disorders of Immune Tolerance: The Flip Side of Immune Deficiency Where Autoimmunity Trumps Infection
Authors: Torgerson Troy R.
Published: April 2021

Primary Immune Regulatory Disorders (PIRD) are group of congenital Immunodeficiencies that present primarily with autoimmunity and less frequently with infections. The paradigm for these disorders is the syndrome of Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX), a disorder caused by a lack of functional regulatory T cells due defects in the lineage-specifying transcription factor, FOXP3. We have collected and evaluated a large cohort of patients with clinical manifestations suggestive of IPEX and have found FOXP3 mutations in more than 90 patients. This has informed our further investigation into the structure and function of the FOXP3 transcription factor. In patients that have IPEX-like clinical features but lack FOXP3 mutations, we have identified defects in several other genes now associated with an IPEX-like clinical phenotype, including germline STAT1 and STAT3 gain-of-function (GOF) mutations, CTLA4 haploinsufficiency, LRBA deficiency and others. We have shown that within this cohort, all have IPEX-like clinical features but there are some clinical and laboratory features that can help with differentiating between the different genetic syndromes. To determine the best approach to treatment of these disorders, we have also collected data on the international experience with bone marrow transplant for some of these disorders including IPEX, CTLA4 haploinsufficiency, STAT1-GOF, and STAT3-GOF disease. We have demonstrated that bone marrow transplant can be curative for each of these disorders but that patients with autosomal dominant gain-of-function mutations in STAT1 and STAT3 may pose unique challenges for transplant that will be discussed. These data will be presented along with preliminary data suggesting non-transplant approaches to management using targeted therapies.

Disclosures

Torgerson: CSL Behring: Consultancy, Research Funding; Shire Bioopharmaceuticals: Consultancy, Research Funding; UCB Biopharma: Consultancy; ADMA Biosciences: Consultancy.
Novel Glycan Dependent Platelet Clearance Mechanisms
Authors: Hoffmeister Karin M.
Published: April 2021

Platelet numbers are intricately regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. The growth factor thrombopoietin (TPO) promotes platelet biogenesis by controlling megakaryocyte maturation and differentiation. Recently, we identified a feedback mechanism by which clearance of aged, desialylated platelets stimulates TPO synthesis by hepatocytes in mice. The Ashwell-Morell receptor (AMR) of hepatocytes, originally termed the hepatic asialoglycoprotein receptor, was the first cellular receptor to be identified and isolated and the first lectin (carbohydrate-binding) to be detected in mammals. Our work showed that the AMR recognizes and removes senescent, sialic acid-depleted platelets (desialylated) under steady state conditions. Desialylated platelets and the AMR are the physiological ligand-receptor pair regulating hepatic TPO mRNA production. The AMR-mediated removal of desialylated platelets regulates hepatic TPO synthesis by recruiting JAK2 and STAT3 to increase thrombopoiesis. Recent genetics studies have revealed that AMR haplodeficiency provides protection from atherosclerosis by regulating plasma glycolipids and platelets. The potential interactions of AMR with LDL receptor may regulate the rate of LDL uptake and as a result may lower plasma non-HDL cholesterol. Taken together, the AMR appears to be a multifaceted receptor, specializing in the clearance of desialylated platelets and plasma glycolipids. Thus, platelet clearance, its biogenesis via TPO, and vascular integrity appear to be regulated by intricately interwoven mechanisms dependent on the AMR.

Disclosures

Hoffmeister: Amgen: Consultancy.
Splenic Mechanisms of Thrombocytopenia
Authors: Semple John W.
Published: April 2021

The spleen is the largest secondary lymphoid organ in the body and contains up to 25 percent of the body's lymphocyte populations. It is not only responsible for initiating immune responses against a multitude of infectious antigens within its white pulp, it also has the exquisite ability to filter the blood and remove, for example, senescent erythrocytes and platelets. This natural process is carried out within the red pulp of the spleen which is composed monocyte-rich connective tissue cords of Billroth intertwined with sinus cavities lined by parallel-oriented endothelial cells that have interendothelial slits which allow for the mechanical sorting of "old" cells. This occurs because of the inability of the senescent cells to properly migrate through the endothelial fenestrae into the venous circulation allowing them to be identified by cells of the reticuloendothelial system (RES) and quickly destroyed by phagocytosis. This process also allows for the efficient recycling of iron from destroyed erythrocyte hemoglobin molecules. There are a wide variety of clinical conditions that can significantly alter the ability of the RES to destroy blood cells including hereditary blood cell defects, inflammation, cancer and abnormal immune responses. This lecture will focus on the central role that the spleen plays in not only generating immune responses against platelets but also in primarily causing the destruction of both senescent and antibody-opsonized platelets leading to thrombocytopenia. It will discuss the soluble and cellular mechanisms of splenic sequestration, destruction and the ability of the spleen to modulate anti-platelet immunity. Mechanisms involving complement activation, Fc Receptor-mediated phagocytosis, antibody dependent cellular cytotoxicity and platelet self-destruction will be addressed. It will compare the spleen's platelet destructive capabilities with other organs, particularly the liver and will detail how immune responses generated in the white pulp can modulate platelet destructive processes in the red pulp.

Disclosures

Semple: Amgen: Consultancy, Honoraria, Speakers Bureau; Rigel: Consultancy, Honoraria; UCB: Consultancy, Honoraria.
Understanding the Transferrin Receptor and Cellular Iron Deficiency Outside the Erythron
Authors: Andrews Nancy C.
Published: April 2021

Our laboratory showed that mouse embryos lacking the classical transferrin receptor, Tfrc, experienced anemia, pericardial effusion and a kinking of the neural tube, but otherwise appeared to be developing normally, suggesting that Tfrc was not needed by most tissues (Levy et al. 1999). Subsequently, we reported that Tfrc was essential for hematopoiesis but seemed to be dispensable in other tissues (Ned et al., 2003). A recent paper showing that a missense mutation in the TFRC internalization motif resulted in immunodeficiency without other clinical manifestations was consistent with this idea (Jabara et al., 2016). Nonetheless, we were not entirely convinced. More than thirty years ago, Larrick and Hyman described a patient with an anti-TFRC autoantibody who suffered from a broader range of clinical problems, suggesting that TFRC might have other roles (Larrick and Hyman, 1984). To help resolve the issue, we developed mice carrying an allele of Tfrc that can be conditionally inactivated, and used Cre/lox-mediated recombination to disrupt that allele in vivo, in several key cell types. We asked two questions: (1) is Tfrc important in those cell types and, if so, (2) what are the cellular consequences of Tfrc loss? We found that some cell types do not need Tfrc but others are highly dependent upon it. Those cell types that depend upon Tfrc generally need it for iron uptake, as expected, with one exception. Tfrc is critically important for normal development of the intestinal epithelium, but our data indicate that its essential role does not involve iron uptake. While surprising in view of our earlier results, the roles of Tfrc that we have unmasked through conditional knockout experiments would not have been apparent prior to the death of global Tfrc knockout embryos in mid-gestation. Nonetheless those roles are important, and our results give insight into why iron deficiency exacerbates heart failure, how muscle iron deficiency leads to disruption of systemic carbon metabolism, and how iron deficiency, rather than iron excess, may play a role in the pathogenesis of neurodegenerative disorders.

Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396-9.

Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood. 2003;102:3711-8.

Jabara HH, Boyden SE, Chou J et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016;48:74-8.

Larrick JW, Hyman ES. Acquired iron-deficiency anemia caused by an antibody against the transferrin receptor. N Engl J Med. 1984;311:214-8.

Disclosures

Andrews: Novartis: Membership on an entity's Board of Directors or advisory committees.
Enforcing Post-Transcriptional Circuitries to Achieve Human Hematopoietic Stem Cell Expansion
Authors: Hope Kristin
Published: April 2021

The balance between hematopoietic stem cell (HSC) differentiation and self-renewal is central to clinical regenerative paradigms. Unravelling the precise molecular mechanisms that govern HSC fate choices will thus have far reaching consequences for the development of effective therapies for hematopoietic and immunological disorders. There is an emerging recognition that beyond transcription, HSC homeostasis is subject to post-transcriptional control by RNA-binding proteins (RBPs) that ensure precise control of gene expression by modulating mRNA splicing, polyadenylation, localization, degradation or translation. RBPs can synchronously regulate the fates of operationally similar RNAs, in what have been termed RNA regulons. We have used a variety of functional approaches, in combination with unbiased genome- and proteome-scale, methods to define the tenets that govern this regulation and to determine key downstream circuitries of stem cell-regulating RBPs whose targeting could provide the basis for novel regenerative treatments. Through loss-of-function efforts, we have identified the RBP, MSI2, as a required factor for human HSC maintenance. By contrast, at supraphysiological levels, MSI2 has a profound positive effect on human HSC self-renewal decisions. Using a combination of global profiling, including mapping MSI2's targets through cross-linking immunoprecipitation (CLIP)-seq, we show that MSI2 achieves its ex vivo self-renewal-promoting effects by directing a co-ordinated post-transcriptional repression of key targets within the aryl hydrocarbon receptor (AHR) pathway. We are currently exploring the "rules" by which MSI2 influences its downstream effects on target RNAs and how it functions, in combination with other protein interactors, to instill a putative RBP regulatory code in HSCs. HSCs exhibit highly unique epigenomes, transcriptomes and proteomes and it is this distinctive molecular landscape that provides the canvas upon which MSI2, and indeed any other HSC-specific RBP exert their post-transcriptional influence over stem cell function. As such, to decipher the bona fide RNA networks that RBPs function upon in HSCs and to understand how they influence this network to enforce self-renewal, we are working towards performing systematic studies of RBP regulons in these cells specifically. In turn these approaches are elucidating a host of RBPs and post-transcriptional control mechanisms previously unappreciated for their role in HSC control. When modulated appropriately, we can successfully tailor these post-transcriptional regulons to enforce desired HSC outputs ex vivo. In summary, approaches to elucidate key HSC-regulatory RBPs and their protein and RNA interactomes provide valuable insights into a layer of HSC control previously not well understood, and one that can be capitalized on to achieve successful HSC expansion.

Disclosures

No relevant conflicts of interest to declare.
IL-17-Driven Immune Signaling in Autoimmunity and Fungal Infections
Authors: Gaffen Sarah
Published: April 2021

Interleukin (IL)-17 is a pro-inflammatory cytokine that is the founding member of a distinct subclass of cytokines (reviewed in Amatya et al., 2017). IL0-17 is produced by conventional Th17 cells as well as a variety of innate immune subtypes (gd-T cells, ILC3 and NKT cells, for example). IL-17 promotes immunity to extracellular microbes, particularly fungi. On the flip side, dysregulation of IL-17 expression or signaling promotes pathology in a variety of autoimmune settings, particularly plaque psoriasis. Consequently, biologic therapies targeting the IL-17/Th17 pathway have been used successfully in the clinic. Understanding how the balance between host defense and autoimmune inflammation is maintained remains a vital issue. Candida albicans is a commensal fungus responsible for opportunistic oropharyngeal candidiasis (OPC, thrush) in settings of immunodeficiency such as HIV/AIDS and chemotherapy. C. albicans also causes systemic and dermal infections. In recent years it has become evident that IL-17 is essential for protective immunity to C. albicans (Conti and Gaffen, 2015). In both mice and humans, T cell deficiencies and more specifically impairments in IL-17 receptor (IL-17R) signaling components (for example, IL-17RA, IL-17RC, Act1) are associated with chronic mucosal candidiasis. However, to date we lack a detailed understanding of the signaling components and effector activities of IL-17 that promote antifungal immunity. The IL-17R complex is ubiquitously expressed, and antifungal signaling by IL-17 has been documented in cells of mesenchymal and epithelial origin but also in hematopoietic cells. This talk will focus on multiple mechanisms by which IL-17 drives immunity to C. albicans, including (i) tissue-specific effects of IL-17 signaling, (ii) sources of IL-17 that drive immunity to mucosal candidiasis, and (iii) fungal-derived factors that drive IL-17 production in vivo in the context of infection.

Amatya N, Garg AV, Gaffen SL. IL-17 signaling: The Yin and the Yang. Trends Immunol. 2017; 38:310-322.

Conti HR, Gaffen SL. IL-17 and Candida albicans infections. J Immunol, 2015; 195:780-788.

Disclosures

Gaffen: Lycera: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Abbvie: Consultancy; UCB Celltech: Consultancy; Genentech: Speakers Bureau; Novartis: Consultancy.
Dissecting Human Antibody Responses: Useful, Basic, and Surprising Findings
Authors: Lanzavecchia Antonio
Published: April 2021

We use cell culture-based high-throughput methods to interrogate human memory B cell and plasma cell repertoires and to isolate antibodies selected on the basis of their neutralizing potency and breadth. Relevant examples are antibodies that neutralize all influenza A viruses or even four paramyxoviruses. By targeting conserved structures, these broadly neutralizing antibodies are less prone to select escape mutants and are promising candidates for prophylaxis and therapy of infections, as well as tools for vaccine design. The value of a target-agnostic approach to vaccine design is illustrated by our discovery of extremely potent antibodies that neutralize human cytomegalovirus, which led to the identification of their viral ligand, a pentameric complex that was then produced and tested as an effective vaccine. By reconstructing the genealogy trees of specific B cell clones, we investigate the role of somatic mutations in affinity maturation and in generation of antibody variants with broader or different specificity. Somatic mutations can also generate autoantibodies, as found in patients with pemphigus and autoimmune pulmonary alveolar proteinosis. Recently, while searching for antibodies that broadly react with malaria variant antigens, we discovered a new mechanism of antibody diversification, which relies on templated insertions of genomic DNA sequences into immunoglobulin genes, followed by somatic mutations.

Disclosures

Lanzavecchia: Humabs SA: Equity Ownership, Research Funding.
DNA Methylation in Cancer and Development: An Evolving Paradigm
Authors: Figueroa Maria E.
Published: April 2021

DNA methylation is an epigenetic mark which, in mammals, occurs primarily on position 5 of cytosines, especially at those found in the context of CpG dinucleotides. This CpG methylation is known to play a major role in gene regulation. Cytosine methylation is regulated by the DNA methyltransferases, responsible for adding the methyl group to unmethylated CpGs, and the TET dioxygenases, involved in the DNA demethylation pathway. Initially, DNA methylation was believed to be important mainly for gene silencing through promoter DNA methylation, especially at CpG-rich promoters containing CpG islands. However, our understanding of the role that DNA methylation plays in gene regulation during normal development and how this process becomes deregulated in cancer, has evolved in recent years. Moreover, the discovery of frequent mutations in DNMT3A and TET2 both in clonal hematopoiesis of indeterminate significance as well as in many hematological malignancies has brought new interest into understanding what role DNA methylation plays in normal HSC function as well as how it contributes to malignant transformation. In this session, we will review the current understanding in the field of DNA methylation and gene regulation, and present data on DNA methylation in normal HSCs as well as the role that this epigenetic mark plays during leukemic transformation in acute myeloid leukemia.

Disclosures

No relevant conflicts of interest to declare.
Effect of intermittent isometric handgrip exercise protocol with short exercise duration on cognitive performance
Authors: Saito Shotaro , Washio Takuro , Watanabe Hironori , Ando Soichi , Ogoh Shigehiko
Published: April 2021

The handgrip exercise, a small muscle exercise, is useful for exercise therapy, particularly in the elderly and bedridden patients. The isometric handgrip (IHG) exercise has been utilized in training programs to reduce resting blood pressure; however, the acute effects of the IHG exercise on cognitive performance are not fully understood. The present study aimed to investigate the effect of an intermittent IHG exercise protocol with short exercise duration, which minimizes the arterial blood pressure response to exercise, on cognitive performance. Twenty-two young healthy subjects performed the intermittent IHG exercise protocol, which consisted of 30-s IHG and 45-s recovery × 16 trials; the exercise intensity of the IHG exercise was 30% of the maximal voluntary contraction. Cognitive performance was evaluated before and after the exercise with the Go/No-Go and memory recognition tasks. Specifically, the reaction time (RT) and performance accuracy were measured. The intermittent IHG exercise protocol did not change the RT or performance accuracy of either the Go/No-Go task (P = 0.222 and P = 0.260, respectively) or the memory recognition task (P = 0.427 and P = 0.245, respectively). These findings suggest that the intermittent IHG exercise protocol with short exercise duration may not provide enough stimulation to improve cognitive performance despite being useful as a safe exercise therapy in the elderly and in patients with cardiovascular disease.
Establishing a consensus for the hallmarks of cancer based on gene ontology and pathway annotations
Authors: Chen Yi , Verbeek Fons. J. , Wolstencroft Katherine
Published: April 2021

Background

The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods for translating these high-level concepts into data-level associations between hallmarks and genes (for high throughput analysis), vary widely between studies. The examination of different strategies to associate and map cancer hallmarks reveals significant differences, but also consensus.

Results

Here we present the results of a comparative analysis of cancer hallmark mapping strategies, based on Gene Ontology and biological pathway annotation, from different studies. By analysing the semantic similarity between annotations, and the resulting gene set overlap, we identify emerging consensus knowledge. In addition, we analyse the differences between hallmark and gene set associations using Weighted Gene Co-expression Network Analysis and enrichment analysis.

Conclusions

Reaching a community-wide consensus on how to identify cancer hallmark activity from research data would enable more systematic data integration and comparison between studies. These results highlight the current state of the consensus and offer a starting point for further convergence. In addition, we show how a lack of consensus can lead to large differences in the biological interpretation of downstream analyses and discuss the challenges of annotating changing and accumulating biological data, using intermediate knowledge resources that are also changing over time.
Simultaneous comparison of depth of sedation performance between SedLine and BIS during general anesthesia using custom passive interface hardware: study protocol for a prospective, non-blinded, non-randomized trial
Authors: Jones James Harvey , Nittur Vinay Ravikumar , Fleming Neal , Applegate Richard L.
Published: April 2021

Background

Intraoperative brain function monitoring with processed electroencephalogram (EEG) indices, such as the bispectral index (BIS) and patient state index (PSI), may improve characterization of the depth of sedation or anesthesia when compared to conventional physiologic monitors, such as heart rate and blood pressure. However, the clinical assessment of anesthetic depth may not always agree with available processed EEG indices. To concurrently compare the performance of BIS and SedLine monitors, we present a data collection system using shared individual generic sensors connected to a custom-built passive interface box.

Methods

This prospective, non-blinded, non-randomized study will enroll 100 adult American Society of Anesthesiologists (ASA) class I-III patients presenting for elective procedures requiring general anesthesia. BIS and SedLine electrodes will be placed preoperatively according to manufacturer recommendations and their respective indices tracked throughout anesthesia induction, maintenance and emergence. The concordance between processed EEG indices and clinical assessments of anesthesia depth will be analyzed with chi-square and kappa statistic.

Discussion

Prior studies comparing brain function monitoring devices have applied both sensors on the forehead of study subjects simultaneously. With limited space and common sensor locations between devices, it is not possible to place both commercial sensor arrays according to the manufacturer’s recommendations, thus compromising the validity of these comparisons. This trial utilizes a custom interface allowing signals from sensors to be shared between BIS and SedLine monitors to provide an accurate comparison. Our results will also characterize the degree of agreement between processed EEG indices and clinical assessments of anesthetic depth as determined by the anesthesiologists’ interpretations of acute changes in blood pressure and heart rate as well as the administration, or change to the continuous delivery, of medications at these timepoints. Patient factors (such as burst suppression state or low power EEG conditions from aging brain), surgical conditions (such as use of electrocautery), artifacts (such as electromyography), and anesthesia medications and doses (such as end-tidal concentration of volatile anesthetic or hypnotic infusion dose) that lead to lack of agreement will be explored as well.

Trial registration

Clinical Trials (ClinicalTrials.gov), NCT03865316. Registered on 4 February 2019 – retrospectively registered. Sponsor: Masimo Corporation.
Effectiveness of P-wave ECG index and left atrial appendage volume in predicting atrial fibrillation recurrence after first radiofrequency catheter ablation
Authors: Li Ruibin , Yang Xiaohong , Jia Min , Wang Dong , Cui Xiaoran , Bai Long , Zhao Lei , Zhang Jidong
Published: April 2021

Background

The primary aim was to observe the predictive value of P-wave ECG index and left atrial appendage volume (LLAV) for atrial fibrillation recurrence after first radiofrequency catheter ablation.

Methods

A total of 196 patients with paroxysmal atrial fibrillation were enrolled. The preoperative LLAV was measured by cardiac enhanced CT. The P-wave ECG index including minimum P-wave duration (P-min), maximum P-wave duration (P-max), mean P-wave duration (mPWD), P-wave dispersion (PWD), P-wave terminal force in lead V1 (PtfV1), PR interval prolongation, and interatrial block (IAB) were analyzed and recorded in 12-lead ECG of sinus rhythm.

Results

According to the follow-up results, the patients were divided into two groups: the non-recurrence group and the recurrence group. P-min, PWD, P-max, PtfV1 ≥ 0.04 mV·s, PR interval prolongation, and the ratio of first and third-degree IAB in the recurrence group were higher than those in the non-recurrence group, with significant statistical differences (P < 0.05). Kaplan–Meier curve analysis was performed on time to atrial fibrillation recurrence after catheter ablation when PtfV1 ≥ 0.04 mv s by comparison between groups (Log Rank test: 2 = 4.739, P < 0.001). Kaplan–Meier curve analysis showed that the survival rate without recurrence of atrial fibrillation after catheter ablation was lower when the LLAV exceeded 8.0 mL (log-rank test P < 0.001).

Conclusion

PWD, P-max, PtfV1, PR interval prolongation, first and third-degree IAB, and LLAV can effectively predict atrial fibrillation recurrence after radiofrequency catheter ablation. The combination might be a valid and alternative independent predictor of recurrence.
Healthcare professional-led interventions on lifestyle modifications for hypertensive patients – a systematic review and meta-analysis
Authors: Treciokiene Indre , Postma Maarten , Nguyen Thang , Fens Tanja , Petkevicius Jurgis , Kubilius Raimondas , Gulbinovic Jolanta , Taxis Katja
Published: April 2021

Background

About 0.9 billion people in the world have hypertension. The mortality due to hypertension increased dramatically over the last decades. Healthcare professionals should support patients with hypertension to modify their lifestyle to decrease blood pressure, but an overview of effective lifestyle interventions is lacking. The aim of this study was to determine whether healthcare professional-led interventions on lifestyle modifications are effective in lowering blood pressure in patients with hypertension.

Methods

A systematic literature review following the PRISMA guidelines was conducted. PubMed, EMBASE and CINAHL databases were searched for randomized control trials (RCTs) of interventions on lifestyle modifications of hypertensive patients which were performed by healthcare professionals (physician, nurse, pharmacist) and which reported blood pressure measurements. Papers were reviewed by two reviewers and analysed using Cochrane software Revman 5.4. In a meta-analysis difference in systolic blood pressure (SBP), diastolic blood pressure (DBP) and the percentage of patients with controlled blood pressure (BP) was analysed.

Results

In total, 34 clinical trials reporting on 22,419 patients (mean age 58.4 years, 49.14% female, 69.9% used antihypertensive medications) were included. The mean difference SBP was − 4.41 mmHg (95% CI, − 5.52to − 3.30) and the mean difference DBP was − 1.66 mmHg (95% CI − 2.44 to − 0.88) in favor of the intervention group vs usual care. Fifty-six percent of patients achieved BP control in the intervention group vs 44% in usual care, OR = 1.87 (95% CI, 1.51 to 2.31).

Conclusion

Healthcare professional-led interventions were effective. Patients achieved almost 5 mmHg decrease of SBP and more patients achieved BP control. The results suggest that efforts are needed for widespread implementation.
Exploring the effect of professional experience on knowledge towards geriatric care among nurses working in adult care units
Authors: Amsalu Erkihun Tadesse , Messele Tesfaye Alemayehu , Adane Metadel
Published: April 2021

Background

The elder population suffered from social, economic, and health (which includes physical) related problems. Thus, these problems are complex and interrelated, thereby requiring specific knowledge and expertise to meet them. However, there were limited researches previously done to explore nurse’s knowledge towards geriatric care. Therefore, this study aimed to assess knowledge towards geriatric care and to examine its predictors in North east Ethiopia. The findings will be helpful to develop strategies that would promote nurses’ knowledge, which in turn improves the quality of patient care and consequently, the health of older people.

Methods

A facility-based cross-sectional study was conducted from March 8 to 28, 2020, among 335 nurses. Simple random sampling technique was employed to select study participants. A structured self-administered questionnaire was used to collect data on knowledge of nurses towards older adult care. A multivariable logistic regression model was applied to identify significant predictors and P-value< 0.05 was used to declare the significance of association.

Results

In the study, a total of 335 nurses participated. About 192(57.3%) of them had poor knowledge towards older adult care. Thus, level of education (AOR = 1.9, 95%CI: 1.1–3.2), year of experience 1–5 year (AOR = 2.7, 95%CI: 1.5–4.9), 5–10 years (AOR = 2.5, 95%CI: 1.4–4.4), and previously living with older adult at home (AOR = 1.6, 95%CI: 1.05–2.7) were significant predictors of knowledge on older adult care.

Conclusions

Our study showed; most of nurses had poor knowledge of the care of elder patients. Level of education, level of experience, and lived with the older adult were factors that contributed for poor knowledge. Thus, professional organizations should focus on changing nursing curricula and providing professional development workshops to improve the knowledge of nurses on geriatric care.
Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19
Authors:   on behalf of the DataLoch COVID-19 Collaboration, Lee Kuan Ken , Doudesis Dimitrios , Ross Daniella A. , Bularga Anda , MacKintosh Claire L. , Koch Oliver , Johannessen Ingolfur , Templeton Kate , Jenks Sara , Chapman Andrew R. , Shah Anoop S. V. , Anand Atul , Perry Meghan R. , Mills Nicholas L.
Published: April 2021

Background

Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain.

Methods

In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results.

Results

We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53–80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1–3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing.

Conclusions

In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.
Respiratory microbes detected in hospitalized adults with acute respiratory infections: associations between influenza A(H1N1)pdm09 virus and intensive care unit admission or fatal outcome in Vietnam (2015–2017)
Authors: Truong Phuong Thai , Saito Shinji , Takayama Ikuyo , Furuya Hiroyuki , Nguyen Binh Gia , Do Thanh Van , Phan Phuong Thu , Do Cuong Duy , Dao Co Xuan , Pham Thach The , Dang Tuan Quoc , Ngo Chau Quy , Le Ngan Thi , Bui Vuong Minh , Le Dung Trung , Vu Van Thi Tuong , Pham Thuy Thi Phuong , Arashiro Takeshi , Kageyama Tsutomu , Nakajima Noriko
Published: April 2021

Background

Acute respiratory tract infection (ARI) is a leading cause of hospitalization, morbidity, and mortality worldwide. Respiratory microbes that were simultaneously detected in the respiratory tracts of hospitalized adult ARI patients were investigated. Associations between influenza A(H1N1)pdm09 virus (H1N1pdm) detection and intensive care unit (ICU) admission or fatal outcome were determined.

Methods

This prospective observational study was conducted between September 2015 and June 2017 at Bach Mai Hospital, Hanoi, Vietnam. Inclusion criteria were hospitalized patients aged ≥15 years; one or more of symptoms including shortness of breath, sore throat, runny nose, headache, and muscle pain/arthralgia in addition to cough and fever > 37.5 °C; and ≤ 10 days from the onset of symptoms. Twenty-two viruses, 11 bacteria, and one fungus in airway specimens were examined using a commercial multiplex real-time PCR assay. Associations between H1N1pdm detection and ICU admission or fatal outcome were investigated by univariate and multivariate logistic regression analyses.

Results

The total of 269 patients (57.6% male; median age, 51 years) included 69 ICU patients. One or more microbes were detected in the airways of 214 patients (79.6%). Single and multiple microbes were detected in 41.3 and 38.3% of patients, respectively. Influenza A(H3N2) virus was the most frequently detected (35 cases; 13.0%), followed by H1N1pdm (29 cases; 10.8%). Hematological disease was associated with ICU admission (p < 0.001) and fatal outcomes (p < 0.001) using the corrected significance level (p = 0.0033). Sex, age, duration from onset to sampling, or number of detected microbes were not significantly associated with ICU admission or fatal outcomes. H1N1pdm detection was associated with ICU admission (odds ratio [OR] 3.911; 95% confidence interval [CI] 1.671–9.154) and fatal outcome (OR 5.496; 95% CI 1.814–16.653) after adjusting for the confounding factors of comorbidities, bacteria/Pneumocystis jirovecii co-detection, and age.

Conclusions

H1N1pdm was associated with severe morbidity and death in adult patients hospitalized with respiratory symptoms. The diagnosis of subtype of influenza virus may be epidemiologically important.
Neonatal systemic juvenile Xanthogranuloma with Hydrops diagnosed by Purpura skin biopsy: a case report and literature review
Authors: Uehara Yohji , Wada Yuka Sano , Iwasaki Yuka , Yoneda Kota , Ikuta Yasuhisa , Amari Shoichiro , Maruyama Hidehiko , Tsukamoto Keiko , Isayama Tetsuya , Sakamoto Kenichi , Shioda Yoko , Miyazaki Osamu , Irie Rie , Yoshioka Takako , Mochimaru Naoko , Yoshida Kazue , Ito Yushi
Published: April 2021

Background

Systemic juvenile xanthogranuloma is a very rare disease typically presents as skin lesions with yellow papules or nodules and is sometimes fatal. We report a case of congenital neonatal systemic juvenile xanthogranuloma with atypical skin appearance that made the diagnosis difficult.

Case presentation

A preterm Japanese female neonate with prenatally diagnosed fetal hydrops in-utero was born with purpuric lesions involving the trunk and face. Since birth, she had hypoxemic respiratory failure, splenomegaly, anemia, thrombocytopenia, coagulopathy, and was transfusion dependent for red blood cells, fresh frozen plasma, and platelets. Multiple cystic lesions in her liver, part of them with vascular, were detected by ultrasound. A liver biopsy was inconclusive. A skin lesion on her face similar to purpura gradually changed to a firm and solid enlarged non-yellow nodule. Technically, the typical finding on skin biopsy would have been histiocytic infiltration (without Touton Giant cells) and immunohistochemistry results which then would be consistent with a diagnosis of systemic juvenile xanthogranuloma, and chemotherapy improved her general condition.

Conclusions

This case report shows that skin biopsies are necessary to detect neonatal systemic juvenile xanthogranuloma when there are organ symptoms and skin eruption, even if the skin lesion does not have a typical appearance of yellow papules or nodules.