Considerable variation in current coronoid height and fracture measurement techniques: a systematic review.

BACKGROUND: Coronoid fractures usually occur in the presence of a significant osseoligamentous injury to the elbow. Fracture size and location correlate with degree of instability and many authors have attempted to analyze the effect of fracture variation on decision making and outcome. There remains no standardized technique for measuring coronoid height or fracture size. The aim of this study was to appraise the literature regarding techniques for coronoid height measurement in order to understand variation. METHODS: Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines were followed. A search was performed to identify studies with either a description of coronoid height, fracture size, or bone loss using the terms (Coronoid) AND (Measurement) OR (Size) OR (Height). Articles were shortlisted by screening for topic relevance based on title, abstract and, if required, full-text review. Exclusion criteria were non-English articles, those on nonhuman species or parts other than the ulna coronoid process, and studies that included patients with pre-existing elbow pathology. Shortlisted articles were grouped based on study type, imaging modality, measurement technique, and measurement parameter as well as its location along the coronoid. RESULTS: Thirty out of the initially identified 494 articles met the inclusion criteria. Twenty-one articles were clinical studies, 8 were cadaveric studies, and 1 combined patients as well as cadavers. A variety of imaging modalities (plain radiographs, 2-dimensional computed tomography [CT], 3-dimensional CT, magnetic resonance imaging or a combination of these) were used with CT scan (either 2-dimensional images or 3-dimensional reconstructions or both) being the most common modality used by 21 studies. Measurement technique also varied from uniplanar linear measurements in 15 studies to multiplanar area and volumetric measurements in 6 studies to techniques describing various angles and indices as an indirect measure of coronoid height in 8 studies. Across the 30 shortlisted studies, 19 different measurement techniques were identified. Fifteen studies measured normal coronoid height while the other 15 measured intact coronoid and/or fracture fragment height. The location of this measurement was also variable between studies with measurements at the apex of the coronoid in 24/30 (80%) of studies. Measurement accuracy was assessed by only 1 study. A total of 12/30 (40%) studies reported on the interobserver and intraobserver reliability of their measurement technique. CONCLUSION: The systemic review demonstrated considerable variability between studies that report coronoid height or fracture size measurements. This variability makes comparison of coronoid height or fracture measurements and recommendations based on these between studies unreliable. There is need for development of a consistent, easy to use, and reproducible technique for coronoid height and bone loss.

Reliability of the CURL classification for proximal ulna fracture-dislocations of the elbow.

Background: Proximal ulna fracture-dislocations are challenging injuries with a myriad of existing classification systems. The Coronoid, proximal Ulna, Radius, and Ligaments classification (CURL) is a simple framework designed to focus attention on the key components affecting outcome and guide surgical management. This study evaluates interobserver and intraobserver reliability of this new classification. Methods: Four observers independently reviewed plain radiographs and computed tomography (CT) scans of patients with proximal ulna fracture-dislocations. Each observer scored the Coronoid (C), proximal Ulna (U), and Radius (R) components for each fracture on 2 occasions. The osseous components were subclassified as 'intact', 'simple', or 'complex'. The Ligament component (L) was not rated as this requires intraoperative classification. Interobserver and intraobserver reliability was calculated using Cohen's weighted kappa coefficients. X-ray and CT were compared for patients with both imaging modalities. The Landis and Koch criteria were used to interpret the strength of the kappa statistics. Results: One hundred seventy seven patients had plain X-rays; 58 patients had both X-ray and CT scans. Overall, in the X-ray only cohort, there was 'almost perfect' interobserver reliability for the radial head (k = 0.94) and coronoid (k = 0.83), and 'substantial' reliability (k = 0.68) for the proximal ulna. For the X-ray and CT cohort, interobserver reliability was 'almost perfect' across both modalities for the radial head (k = 0.88 and k = 0.93, respectively) and 'moderate' for the proximal ulna (k = 0.48 and k = 0.52, respectively). For the coronoid, interobserver reliability for X-ray interpretation was 'substantial' (k = 0.74) and for CT was 'almost perfect' (k = 0.89). Intraobserver reliability was 'almost perfect' for all components, other than CT assessment of the proximal ulna which demonstrated 'substantial' reliability (k = 0.74). Conclusion: The Coronoid, proximal Ulna, Radius, and Ligaments classification demonstrates strong interobserver and intraobserver reliability, supporting use of the classification for proximal ulna fracture-dislocations. CT is recommended for improved characterization of any fracture with a coronoid component.

SARS-CoV-2 infection modifies the transcriptome of the megakaryocytes in the bone marrow.

Megakaryocytes, integral to platelet production, predominantly reside in the bone marrow and undergo regulated fragmentation within sinusoid vessels to release platelets into the bloodstream. Inflammatory states and infections influence megakaryocyte transcription, potentially affecting platelet functionality. Notably, COVID-19 has been associated with altered platelet transcriptomes. In this study, we investigated the hypothesis that SARS-CoV-2 infection could impact the transcriptome of bone marrow megakaryocytes. Utilizing spatial transcriptomics to discriminate subpopulations of megakaryocytes based on proximity to bone marrow sinusoids, we identified approximately 19,000 genes in megakaryocytes. Machine learning techniques revealed that the transcriptome of healthy murine bone marrow megakaryocytes exhibited minimal differences based on proximity to sinusoid vessels. Further, at peak SARS-CoV-2 viremia, when the disease primarily affected the lungs, megakaryocytes were not significantly different from those from healthy mice. Conversely, a significant divergence in the megakaryocyte transcriptome was observed during systemic inflammation, although SARS-CoV-2 RNA was never detected in bone marrow and it was no longer detectable in the lungs. Under these conditions, the megakaryocyte transcriptional landscape was enriched in pathways associated with histone modifications, megakaryocyte differentiation, NETosis, and autoimmunity, which could not be explained by cell proximity to sinusoid vessels. Notably, the type-I interferon signature and calprotectin (S100A8/A9) were not induced in megakaryocytes under any condition. However, inflammatory cytokines induced in the blood and lungs of COVID-19 mice were different from those found in the bone marrow, suggesting a discriminating impact of inflammation on this specific subset of cells. Collectively, our data indicate that a new population of bone marrow megakaryocytes may emerge through COVID-19-related pathogenesis.

Almond can be infected by Plum Pox Virus-D isolate Penn4 and is a transmission-competent host.

While currently eradicated from the U.S., Plum pox virus (PPV) poses an ongoing threat to U.S. stone fruit production. Although almond (Prunus dulcis) is known to be largely resistant to PPV, there is conflicting evidence about its potential to serve as an asymptomatic reservoir host for the virus and thus serve as a potential route of entry. Here, we demonstrate that both Tuono and Texas Mission cultivars can be infected by the U.S. isolate PPV-D Penn4 and that Tuono is a transmission-competent host, capable of serving as a source of inoculum for aphid transmission of the virus. These findings have important implications for efforts to keep PPV out of the U.S. and highlights the need for additional research to test the susceptibility of almond to other PPV-D isolates.

Global phylogenetic analysis of soybean dwarf virus isolates and their associations with aphid vectors and severe disease in soybeans.

Soybean dwarf virus (SbDV) was first described in Japan as an agent of severe soybean disease transmitted by the foxglove aphid, Aulacorthum solani, with separable yellowing (Y) and dwarfing (D) strains. SbDV of both Y and D genotypes were later documented in other countries. For three decades, SbDV isolates were assessed to evaluate risk to U.S. soybean production. U.S. SbDV isolates were transmitted by the pea aphid Acyrthosiphum pisum and showed limited disease in soybeans, suggesting it was not a major threat to U.S. soybean production. Here we report 21 new full-length SbDV genome sequences including those of the originally described Japanese Y and D isolates, isolates from Syria and New Zealand associated with severe disease, and 17 isolates from U.S. field collections. Using these new full-length genomes, a global phylogeny was assembled and used to revisit risk assessment based on sequence similarities, isolate pathogenicity, and vector specificity.

Risk Stratification for Supratherapeutic Peak Anti-Xa Levels in Adult Patients on Therapeutic Enoxaparin.

BACKGROUND: The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy. OBJECTIVE: The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin. METHODS: This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts. RESULTS: A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels. CONCLUSION AND RELEVANCE: Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial.

BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.

Sensitivity and specificity of the posterolateral rotatory drawer test in the diagnosis of lateral collateral ligament insufficiency of the elbow.

BACKGROUND: Numerous clinical tests are described for the diagnosis of chronic lateral collateral ligament (LCL) insufficiency of the elbow; however, none of these tests have been adequately assessed for sensitivity, with at most 8 patients included in previous studies. Furthermore, no test has had specificity assessed. The posterolateral rotatory drawer (PLRD) test is thought to have improved diagnostic accuracy over other tests in the awake patient. The aim of this study is to formally assess this test using reference standards in a large cohort of patients. METHODS: A total of 106 eligible patients were identified for inclusion from a single-surgeon database of operative procedures. Examination under anesthetic (EUA) and arthroscopy were chosen as the reference standards to compare the PLRD test against. Only patients with a clearly documented PLRD test finding performed preoperatively in the clinic, and a clearly documented EUA and/or arthroscopic findings from surgery were included. A total of 102 patients underwent EUA, 74 of whom also underwent arthroscopy. Twenty-eight patients had EUA, and then an open procedure without arthroscopy. Four patients had arthroscopy without a clearly documented EUA. Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated with 95% confidence intervals. RESULTS: Thirty-seven patients had a positive PLRD test, and 69 had a negative test. Compared to the reference standard of EUA (n = 102), the PLRD test had a sensitivity of 97.3% (85.8%-99.9%) and a specificity of 98.5% (91.7%-100%) (PPV = 0.973, NPV = 0.985). Compared to the reference standard of arthroscopy (n = 78), the PLRD test had a sensitivity of 87.5% (61.7%-98.5%) and a specificity of 98.4% (91.3%-100%) (PPV = 0.933, NPV = 0.968). Compared to either reference standard (n = 106), the PLRD test has a sensitivity of 94.7% (82.3%-99.4%) and a specificity of 98.5% (92.1%-100%) (PPV = 0.973, NPV = 0.971). CONCLUSION: The PLRD test demonstrated an overall sensitivity of 94.7% and specificity of 98.5% with high positive and negative predictive values. This test is recommended as the primary diagnostic tool for LCL insufficiency in the awake patient and should be widely incorporated into surgical training.

Spatial transcriptomics of murine bone marrow megakaryocytes at single-cell resolution.

Background: While megakaryocytes are known for making platelets, recent single-cell RNA sequencing data have revealed subpopulations of megakaryocytes with predicted immunoregulatory and bone marrow niche-supporting roles. Although these studies uncovered interesting information regarding the transcriptional variation of megakaryocytes, the generation, localization, and regulation of these subsets have not yet been studied and therefore remain incompletely understood. Considering the complex organization of the bone marrow, we reasoned that the application of spatial transcriptomic approaches could help dissect megakaryocyte heterogeneity within a spatiotemporal context. Objectives: The aim of this study was to combine spatial context and transcriptomics to assess the heterogeneity of murine bone marrow megakaryocytes in situ at a single-cell level. Methods: Bone marrow sections were obtained from femurs of C57BL/6J mice. Using the murine whole transcriptome array on the Nanostring GeoMx digital spatial profiling platform, we profiled 44 individual megakaryocytes (CD41+ by immunofluorescence) in situ throughout the bone marrow, both adjacent and nonadjacent to the endothelium (directly in contact with vascular endothelial-cadherin-positive cells). Results: Principal component analysis revealed no association between transcriptomic profile and adjacency to the vasculature. However, there was a significant effect of proximal vs distal regions of the bone. Two and 3 genes were found overexpressed in the proximal and distal sides, respectively. Of note, proplatelet basic protein and platelet factor 4, 2 genes associated with platelet production, had higher expression in proximal megakaryocytes. Conclusion: This study indicates a possible effect of spatial location on megakaryocyte heterogeneity and substantiate further interest in investigating megakaryocyte subpopulations in the context of their spatial orientation.

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy.

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.

Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report.

We report the first case of bilateral hypoglossal nerve stimulator implantation in a patient with Treacher Collins syndrome and very severe obstructive sleep apnea, who was initially intolerant of continuous positive airway pressure (CPAP) treatment. Novel bilateral hypoglossal nerve stimulation in combination with CPAP allowed near obliteration of snoring, improved sleep quality, and ability to maintain the CPAP mask in position in the setting of craniofacial changes associated with this condition. CITATION: Wong ACL, Jones A, Stone A, MacKay SG. Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report. J Clin Sleep Med. 2023;19(1):197-199.

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow-stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFß stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. SIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics. See related commentary by Derecka and Crispino, p. 263. This article is highlighted in the In This Issue feature, p. 247.

Corrigendum: CD317-Positive Immune Stromal Cells in Human "Mesenchymal Stem Cell" Populations.

[This corrects the article DOI: 10.3389/fimmu.2022.903796.].

CD317-Positive Immune Stromal Cells in Human "Mesenchymal Stem Cell" Populations.

Heterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as "mesenchymal stem cells") clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317pos (29.77 ± 3.00% of the total MSC population), comprising CD317dim (28.10 ± 4.60%) and CD317bright (1.67 ± 0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317pos MSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317neg MSCs had no effect. Only CD317neg MSCs were able to suppress proliferative cycles of activated human T cells in vitro, whilst CD317pos MSCs increased polarization towards pro-inflammatory Th1 cells and CD317neg cell lines did not. Using an in vivo peritonitis model, we found that CD317neg and CD317pos MSCs suppressed leukocyte recruitment but only CD317neg MSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317neg MSC lines, but not CD317pos MSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs.

The pathobiology of platelet and megakaryocyte extracellular vesicles: A (c)lot has changed.

Platelet-derived extracellular vesicles (PEVs) were originally studied for their potential as regulators of coagulation, a function redundant with that of their parent cells. However, as the understanding of the diverse roles of platelets in hemostasis and disease has developed, so has the understanding of PEVs. In addition, the more recent revelation of constitutively released megakaryocyte-derived extracellular vesicles (MKEVs) in circulation provides an interesting counterpoint and avenue for investigation. In this review, we highlight the historical link of PEVs to thrombosis and hemostasis and provide critical updates. We also expand our discussion to encompass the roles that distinguish PEVs and MKEVs from their parent cells. Furthermore, the role of extracellular vesicles in disease pathology, both as biomarkers and as exacerbators, has been of great interest in recent years. We highlight some of the key roles that PEVs and MKEVs play in autoimmune blood cell disorders, liver pathology, and cardiovascular disease. We then look at the future of PEVs and MKEVs as candidates for novel therapeutics.

Anticoagulation Considerations in Liver Disease.

Coagulopathy of liver disease is a complex pathology that may result in thrombosis and/or bleeding complications. Routine laboratory values are not always reflective of the degree of these risks. Additionally, prophylaxis and treatment of venous thromboembolism in patients with cirrhosis require careful evaluation when selecting and monitoring drug therapy for these indications. Therefore, this article aims to provide insight regarding coagulopathy of liver disease, influence on laboratory values, and anticoagulant therapy considerations for critical care nurses assuming care for patients with cirrhosis.

The bone marrow niche from the inside out: how megakaryocytes are shaped by and shape hematopoiesis.

Megakaryocytes (MKs), the largest of the hematopoietic cells, are responsible for producing platelets by extending and depositing long proplatelet extensions into the bloodstream. The traditional view of megakaryopoiesis describes the cellular journey from hematopoietic stem cells (HSCs) along the myeloid branch of hematopoiesis. However, recent studies suggest that MKs can be generated from multiple pathways, some of which do not require transit through multipotent or bipotent MK-erythroid progenitor stages in steady-state and emergency conditions. Growing evidence suggests that these emergency conditions are due to stress-induced molecular changes in the bone marrow (BM) microenvironment, also called the BM niche. These changes can result from insults that affect the BM cellular composition, microenvironment, architecture, or a combination of these factors. In this review, we explore MK development, focusing on recent studies showing that MKs can be generated from multiple divergent pathways. We highlight how the BM niche may encourage and alter these processes using different mechanisms of communication, such as direct cell-to-cell contact, secreted molecules (autocrine and paracrine signaling), and the release of cellular components (eg, extracellular vesicles). We also explore how MKs can actively build and shape the surrounding BM niche.