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One cannot successfully employ point-of-care ultrasound (POCUS) without a process to provide support and guidance. POCUS administration is a multifaceted topic that demands the utmost attention from those responsible for program implementation and long-term execution. This article delves into POCUS administration and is meant to serve as a guide for the practitioner seeking to start, maintain, or augment their POCUS program., Competing Interests: Disclosure C. Thom—Financial disclosures: Consulting: None and for research/grants: Rivanna Medical. J. Nomura—Financial disclosures: Consulting: Phillips, Caption AI; and for research/grants: Bayer, Germany, Bristol-Myers Squibb, United States., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Trisomy 21 (T21), or Down syndrome (DS), is associated with baseline macrocytic erythrocytosis, thrombocytopenia, and neutrophilia, as well as transient abnormal myelopoiesis (TAM) and myeloid leukemia of DS (ML-DS). TAM and ML-DS blasts both arise from an aberrant megakaryocyte-erythroid progenitor and exclusively express GATA1s, the truncated isoform of GATA1 , while germline GATA1s mutations in a non-T21 context lead to congenital cytopenia(s) without a leukemic predisposition. This suggests that T21 and GATA1s both perturb hematopoiesis in multipotent progenitors, but studying their individual effects is challenging due to limited access to relevant human progenitor populations. To dissect individual developmental impacts, we used single-cell RNA-sequencing to interrogate hematopoietic progenitor cells (HPCs) from isogenic human induced pluripotent stem cells differing only by chromosome 21 and/or GATA1 status. The transcriptomes of these HPCs revealed significant heterogeneity and lineage skew dictated by T21 and/or GATA1s. T21 and GATA1s each disrupted temporal regulation of lineage-specific transcriptional programs and specifically perturbed cell cycle genes. Trajectory inference revealed that GATA1s nearly eliminated erythropoiesis, slowed MK maturation, and promoted myelopoiesis in the euploid context, while in T21 cells, GATA1s competed with the enhanced erythropoiesis and impaired megakaryopoiesis driven by T21 to promote production of immature erythrocytes, MKs, and myeloid cells. The use of isogenic cells revealed distinct transcriptional programs that can be attributed specifically to T21 and GATA1s, and how they independently and synergistically result in HPC proliferation at the expense of maturation, consistent with a pro-leukemic phenotype.

Neonatal and adult megakaryocytes differ in proliferative capacity and ploidy levels, and neonatal and adult platelets differ in function, gene expression, and protein content. The mechanisms underlying these differences are incompletely understood. CDK8 and CDK19 are transcriptional kinases part of the CDK-mediator complex, which regulates gene transcription in a cell-specific manner. We discovered that cortistatin A, a potent highly selective inhibitor of CDK8/CDK19, significantly reduced cell expansion and increased ploidy in cord blood-derived megakaryocytes. These phenotypic changes were associated with gene expression changes that partially overlapped developmentally regulated genes. These findings might have relevance for the management of developmental megakaryocyte disorders., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Abdominal pain and vomiting are frequent complaints for pediatric patients presenting to the Emergency Department (ED). When a diagnosis such as chronic abdominal pain, cyclic vomiting, or abdominal migraine has previously been made, it can lead to diagnostic momentum and confirmation bias on behalf of the treating physician. Dietl's crisis is a commonly missed diagnosis in the pediatric population that presents with intermittent episodes of pain and vomiting. It can be readily diagnosed at the bedside by the emergency physician (EP) through the employment of point of care ultrasound (POCUS)., Case Series: We present two cases of pediatric patients with episodic abdominal pain and vomiting who were previously diagnosed with cyclic vomiting syndrome. In both cases, pediatric gastroenterology evaluations had occurred with negative diagnostic testing having been performed. Both patients also presented to their primary pediatrician and the ED multiple times with each encounter resulting in treatment of symptoms and discharge. Each patient eventually presented to the ED when an EP was present who performed a renal POCUS. In each patient, the POCUS revealed severe unilateral hydronephrosis. Subsequent workup confirmed the diagnosis of Dietl's crisis as the etiology of symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In pediatric patients, EPs should be wary of the diagnosis of cyclic vomiting syndrome until ureteral obstruction has been ruled out. A bedside POCUS can rapidly establish this diagnosis and potentially preclude recurrent health care visits, unnecessary diagnostic testing, and permanent loss of renal function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tropomyosins coat actin filaments to impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. TPM1 has been shown to regulate blood cell formation in vitro, but it remains unclear how or when TPM1 affects hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, we found that TPM1 knockout augmented developmental cell state transitions and key signaling pathways, including tumor necrosis factor alpha (TNF-α) signaling, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses revealed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced HE formation during embryogenesis, without increasing the number of hematopoietic stem cells. These findings illuminate novel effects of TPM1 on developmental hematopoiesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10-4), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10-4), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10-3) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10-2) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10-2). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shivakumar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Biliary ultrasound is often utilized in the evaluation of abdominal pain in the Emergency Department (ED). Common bile duct (CBD) identification is traditionally a standard component of the biliary ultrasound examination but can be challenging to perform for the novice sonographer. Previous work has demonstrated that CBD dilatation is rare in cases of cholecystitis with normal liver function tests (LFTs). We sought to assess the frequency of CBD dilatation in the subset of ED patients undergoing hepatobiliary ultrasound who have normal LFTs and an absence of gallstones or biliary sludge on ultrasound. We also performed an assessment of changes in CBD diameter by age and cholecystectomy status., Methods: This was a retrospective chart review at a single academic ED. Patients were enrolled in the study if they underwent a radiology performed (RP) hepatobiliary ultrasound within the 2 year study period. Records were reviewed for the presence of gallstones or sludge, CBD diameter, age, clinical indication for the ultrasound, and LFTs. Descriptive analyses were performed, and interobserver agreement among data abstractors was assessed by K analysis for the presence of CBD dilatation. The Mann-Whitney test was utilized to assess statistical significance in the comparison of differences between CBD diameters amongst age groups., Results: Of 1929 RP hepatobiliary ultrasounds performed in the study period, 312 were excluded and 1617 met inclusion criteria. Amongst these, there were 506 patients who had normal LFTs and an ultrasound with no stones or sludge. Ten patients within this group had a dilated CBD > 7 mm (1.98%, 95% CI of 1.08% to 3.6%). We also noted a statistically significant increase in CBD size in the older age cohort and in those individuals with a history of cholecystectomy., Conclusion: CBD dilation in ED patients who present with normal LFTs and an absence of gallstones and biliary sludge is rare. Physicians should be reassured that the routine identification of the CBD on ultrasound in this setting is of low yield and need not be pursued., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Thom et al.)

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by cardiovascular, anthropometric, lung function, and lifestyle-related risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures., Competing Interests: D.H., E.S., K.L., T.L.A., C.S.T., and B.F.V. have no conflicting interest to report. S.M.D receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Hui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Transvaginal (TVUS) and transabdominal ultrasound (TAUS) are both utilized in the evaluation of early pregnancy patients. While many practitioners using point of care ultrasound (POCUS) will generally not pursue TVUS in cases where an intrauterine pregnancy (IUP) is visualized on TAUS, this may not be true in Radiology performed ultrasound., Objectives: To evaluate for differences in transvaginal ultrasound (TVUS) utilization between Radiology performed (RP) ultrasound and point of care ultrasound (POCUS) by Emergency Department (ED) physicians in early pregnancy patients. Secondarily, to assess length of stay (LOS) differences and the impact of specialized emergency ultrasound training on TVUS utilization., Methods: This was a retrospective study at a single academic ED. Study population was all ED patients who underwent first trimester ultrasound during the one year period of March 1, 2021 to February 28, 2022. Variables evaluated were chief complaint, gestational age, LOS, TAUS and TVUS utilization, ultrasound findings, and ultrasound specialty training of the ED physician., Results: There were 133 cases of POCUS ultrasound and 254 cases of RP ultrasound. All cases had TAUS imaging performed. Median LOS for patients when POCUS was utilized was 207 min (IQR 151-294) and 258 min (IQR 208-328) for those only using RP ultrasound, p ≤ 0.001. In the POCUS cohort, 38% (95% CI 30%-46%) received TVUS, while 94% received TVUS in the RP cohort (95% CI 90%-96%), p ≤ 0.001. Patients seen by ED faculty with ultrasound specialty training had TVUS 53% of the time (95% CI 41%-65%), while those seen by other ED faculty had TVUS 79% (95% CI 74%-83%) of the time, p = 0.035., Conclusion: POCUS in early pregnancy is associated with a significant reduction in TVUS usage. We suspect that POCUS users elect not to pursue TVUS after an IUP is identified on TAUS, while technicians perform protocol-based TVUS irrespective of TAUS findings. Patients seen by ultrasound trained ED physicians are less likely to receive TVUS., Competing Interests: Declaration of competing interest The authors and co-authors have no financial disclosures to declare. None of the submitted work utilized generative AI in any form., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions., Objectives: This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets., Methods: We isolated resting umbilical cord blood-derived platelets from healthy full-term neonates (n = 8) and resting blood platelets from healthy adults (n = 6) and compared protein and phosphoprotein contents using data-independent acquisition mass spectrometry., Results: We identified 4770 platelet proteins with high confidence across all samples. Adult and neonatal platelets were clustered separately by principal component analysis. Adult platelets were significantly enriched in immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched in ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched in phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched in phosphorylated proteins involved in insulin growth factor signaling., Conclusion: Using label-free data-independent acquisition mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation between neonatal and adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Abstract: During development, erythroid cells are produced through at least 2 distinct hematopoietic waves (primitive and definitive), generating erythroblasts with different functional characteristics. Human induced pluripotent stem cells (iPSCs) can be used as a model platform to study the development of red blood cells (RBCs) with many of the differentiation protocols after the primitive wave of hematopoiesis. Recent advances have established that definitive hematopoietic progenitors can be generated from iPSCs, creating a unique situation for comparing primitive and definitive erythrocytes derived from cell sources of identical genetic background. We generated iPSCs from healthy fetal liver (FL) cells and produced isogenic primitive or definitive RBCs which were compared directly to the FL-derived RBCs. Functional assays confirmed differences between the 2 programs, with primitive RBCs showing a reduced proliferation potential, larger cell size, lack of Duffy RBC antigen expression, and higher expression of embryonic globins. Transcriptome profiling by scRNA-seq demonstrated high similarity between FL- and iPSC-derived definitive RBCs along with very different gene expression and regulatory network patterns for primitive RBCs. In addition, iPSC lines harboring a known pathogenic mutation in the erythroid master regulator KLF1 demonstrated phenotypic changes specific to definitive RBCs. Our studies provide new insights into differences between primitive and definitive erythropoiesis and highlight the importance of ontology when using iPSCs to model genetic hematologic diseases. Beyond disease modeling, the similarity between FL- and iPSC-derived definitive RBCs expands potential applications of definitive RBCs for diagnostic and transfusion products., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Induced pluripotent stem cell (iPSC)-based models are excellent platforms to understand blood development, and iPSC-derived blood cells have translational utility as clinical testing reagents and transfusable cell therapeutics. The advent and expansion of multiomics analysis, including but not limited to single nucleus RNA sequencing (snRNAseq) and Assay for Transposase-Accessible Chromatin sequencing (snATACseq), offers the potential to revolutionize our understanding of cell development. This includes developmental biology using in vitro hematopoietic models. However, it can be technically challenging to isolate intact nuclei from cultured or primary cells. Different cell types often require tailored nuclear preparations depending on cellular rigidity and content. These technical difficulties can limit data quality and act as a barrier to investigators interested in pursuing multiomics studies. Specimen cryopreservation is often necessary due to limitations with cell collection and/or processing, and frozen samples can present additional technical challenges for intact nuclear isolation. In this manuscript, we provide a detailed method to isolate high-quality nuclei from iPSC-derived cells at different stages of in vitro hematopoietic development for use in single-nucleus multiomics workflows. We have focused the method development on the isolation of nuclei from iPSC-derived adherent stromal/endothelial cells and non-adherent hematopoietic progenitor cells, as these represent very different cell types with regard to structural and cellular identity. The described troubleshooting steps limited nuclear clumping and debris, allowing the recovery of nuclei in sufficient quantity and quality for downstream analyses. Similar methods may be adapted to isolate nuclei from other cryopreserved cell types.

The CHOPWT17_TPM1KOc28 iPSC line was generated to interrogate the functions of Tropomyosin 1 (TPM1) in primary human cell development. This line was reprogrammed from a previously published wild type control iPSC line., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Rapid diagnostic tools available to the emergency physician caring for cardiac arrest patients are limited. Focused ultrasound (US), and in particular, focused echocardiography, is a useful tool in the evaluation of patients in cardiac arrest. It can help identify possible causes of cardiac arrest like tamponade and pulmonary embolism, which can guide therapy. US can also yield prognostic information, with lack of cardiac activity being highly specific for failure to achieve return of spontaneous circulation. US may also be used to aid in procedural guidance. Recently, focused transesophageal echocardiography has been used in the emergency department setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Ultrasonography has an important role in the evaluation of Emergency Department (ED) patients presenting with early pregnancy complaints. Both transabdominal (TAUS) and transvaginal ultrasound (TVUS) can be utilized. While TVUS generally allows for greater detail, it is unclear how much added benefit exists in performing TVUS once an intrauterine pregnancy (IUP) has been identified on TAUS., Methods: This was a retrospective study utilizing Radiology Department ultrasound examinations obtained in first trimester pregnancy ED patients during a consecutive four month period in 2019. Studies wherein both TAUS and TVUS were both performed were included. Two ED physicians with specialized training in point of care ultrasound reviewed only the TAUS images from these studies. Their findings were compared to the Radiologist interpretation, which was inclusive of both TAUS and TVUS components of the study., Results: 108 studies met inclusion criteria. Amongst these, 82 had IUP's identified on the radiologist report. 69 studies had an IUP identified by ED physician review of the TAUS images, with 1 false positive. Each case of intrauterine fetal demise (IUFD) was identified on ED physician review of TAUS. Two ectopic pregnancies were present, neither of which was mistaken for IUP on ED physician TAUS review. There were 15 studies with subchorionic hemorrhage and 3 studies with an ovarian cyst noted on the radiologist report., Conclusion: Following the identification of an IUP on TAUS, the added diagnostic value of TVUS amongst this cohort of ED patients was low. Given the added time and cost of TVUS, selective instead of routine usage should be encouraged., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Thom et al.)

Introduction: Neuropathy of the lateral femoral cutaneous nerve, also known as meralgia paresthetica, causes pain and paresthesia to the anterolateral thigh. It commonly results from nerve irritation from extrinsic compression; however, it may occur spontaneously. Symptoms from this condition can be debilitating, and the pain may be ascribed to other conditions leading to delays in diagnosis. Peripheral nerve blockade can be useful both diagnostically and therapeutically for meralgia paresthetica., Case Report: Two female patients in their sixties presented to the emergency department for chronic, atraumatic, left upper thigh pain. In both cases the patients had hyperalgesia and paresthesia to the anterolateral, upper thigh. The emergency physician performed an ultrasound-guided nerve block of the lateral femoral cutaneous nerve for each patient, which resulted in temporary, complete resolution of their pain., Conclusion: Meralgia paresthetica is an uncommon but painful condition that can elude diagnosis. Physical exam findings such as allodynia and hyperalgesia of the anterolateral thigh in the absence of back pain is suggestive of the diagnosis. Utrasound-guided nerve blockade can be helpful to the emergency physician to confirm the diagnosis and provide non-opioid pain relief to the patient.

Background: Ultrasound has been used previously in fracture identification, analgesia delivery, and fracture reduction for patients in the emergency department. It has not been previously described as a tool for the guidance of closed fracture reduction in fifth metacarpal neck fractures ("boxer's fractures")., Case Report: A 28-year-old man presented with hand pain and swelling after punching a wall. Point-of-care ultrasound revealed a significantly angulated fifth metacarpal fracture, which was confirmed with a subsequent hand x-ray study. After an ultrasound-guided ulnar nerve block, closed reduction was performed. Ultrasound was used to assess reduction and ensure improvement in bony angulation during the closed reduction attempts. Post-reduction x-ray study confirmed improved angulation and adequate alignment. Why Should an Emergency Physician Be Aware of This? Point-of-care ultrasound has previously had efficacy in fracture diagnosis and anesthesia delivery for fifth metacarpal fractures. Ultrasound can also be used at the bedside to assist in the determination of adequate fracture reduction when performing closed reduction of a boxer's fracture., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Distal forearm fractures are a commonly encountered injury in the emergency department (ED), accounting for 500,000 to 1.5 million visits and 17% of ED fractures. The evaluation and management of these fractures frequently employs x-ray studies, conscious sedation, closed reduction, and splinting. Point-of-care ultrasound (POCUS) can offer significant benefit in the diagnosis and management of these common injuries., Objective of the Review: To review the clinical utility of POCUS in the diagnosis of distal forearm fractures, as well as to demonstrate the performance of ultrasound-guided analgesia delivery and ultrasound-guided reduction technique., Discussion: The initial evaluation of forearm injuries frequently includes x-ray studies. However, multiple studies have shown ultrasound to be sensitive and specific for distal radius fractures, with the added value of detecting soft tissue injuries missed by conventional radiography. POCUS may also facilitate analgesia through the use of ultrasound-guided hematoma blocks, which removes the need for conscious sedation prior to manipulation. Finally, POCUS can be used after manipulation to assess cortical realignment of the bone fragments and spare the patient multiple reduction attempts and repeat radiographs., Conclusion: Distal forearm fractures are common, and the emergency physician should be adept with the evaluation and management of these injuries. POCUS can be a reliable modality in the detection of these fractures and can be used to facilitate analgesia and augment success of reduction attempts. These techniques may decrease length of stay, improve patient pain, and decrease reduction attempts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction It is commonly taught that positioning the patient in the left lateral decubitus (LLD) position will improve transthoracic echocardiography (TTE) image quality. Despite this, no previous studies have been performed that study this practice. Our goal was to quantify the difference in image quality of TTE views between the supine and LLD positions.  Methods This was a prospective study in a single academic Emergency Department (ED) of a convenience sample of 30 patients. Three separate ED physicians performed TTE views in both the supine and LLD position on each patient. The order of position was randomized. Images were then reviewed on a previously validated TTE image quality scale by two blinded ED physicians with specialized training in ultrasound. The scale used a 0 to 5 (highest quality) metric for quality assessment. Interpretability of right ventricular and left ventricular function was also assessed. Results The mean image quality for the supine position was 2.85 (standard deviation {SD} 1.1) and 3.05 (SD 1.2) for the LLD position (p=0.044). In the subset of parasternal and apical windows, the mean quality for the supine position was 2.87 (SD 1.1) and 3.23 (SD 1.1) for the LLD position (p=0.003). The number of studies in which right ventricular function was interpretable was significantly higher in the LLD position (62% versus 42%, p=0.044). Conclusions There was a statistically significant increase in image quality when TTE was performed in the LLD position as compared to supine. This was especially pronounced in the apical four and parasternal windows., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ottenhoff et al.)

Pediatric extreme thrombocytosis (EXT, platelet count > 1000 x 10 3 /µL) is rare. In a single center retrospective analysis of hospitalized children with EXT, infants with congenital diaphragmatic hernia (CDH) were overrepresented. In general pediatric patients, EXT is usually secondary to infection or inflammation, but most of the 14 CDH patients with EXT had no identifiable inciting factor. Instead, there was evidence that splenic dysfunction and bone marrow hyperactivity underlied EXT in CDH patients. None were associated with bleeding or thrombosis. Our findings identify mechanisms underlying EXT, and aid clinical interpretation and management of EXT in the pediatric population.

Background: The majority of Genome Wide Associate Study (GWAS) loci fall in the non-coding genome, making causal variants difficult to identify and study. We hypothesized that the regulatory features underlying causal variants are biologically specific, identifiable from data, and that the regulatory architecture that influences one trait is distinct compared to biologically unrelated traits., Results: To better characterize and identify these variants, we used publicly available GWAS loci and genomic annotations to build 17 Trait Specific Annotation Based Locus (TSABL) predictors to identify differences between GWAS loci associated with different phenotypic trait groups. We used a penalized binomial logistic regression model to select trait relevant annotations and tested all models on a holdout set of loci not used for training in any trait. We were able to successfully build models for autoimmune, electrocardiogram, lipid, platelet, red blood cell, and white blood cell trait groups. We used these models both to prioritize variants in existing loci and to identify new genomic regions of interest., Conclusions: We found that TSABL models identified biologically relevant regulatory features, and anticipate their future use to enhance the design and interpretation of genetic studies., (© 2022. The Author(s).)

Background: Intramuscular (i.m.) injections are a commonly utilized route for medication delivery. Intramuscular-associated soft tissue infections are rare and can include pyomyositis and i.m. abscess. Intramuscular testosterone injections have not been previously implicated in causing pyomyositis. Point-of-care ultrasound is an important bedside tool that can identify pyomyositis and differentiate this infection from more common entities such as cellulitis., Case Reports: We present two cases of i.m. testosterone-associated pyomyositis. In both cases, the physical examination features were consistent with simple cellulitis. However, point-of-care ultrasound evaluation revealed changes consistent with pyomyositis in each case. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although uncommon, i.m. injections such as testosterone carry a risk of soft tissue infection. As demonstrated in the above cases, ultrasound can be helpful in making the differentiation between simple cellulitis and pyomyositis. The emergency physician should be cognizant of this complication of therapeutic i.m. injections, as well as the diagnostic efficacy of point-of-care ultrasound in evaluating the extent and location of the soft tissue infection., (Copyright © 2021. Published by Elsevier Inc.)

Body mass index (BMI), hyperlipidemia, and truncal adipose distribution concordantly elevate cardiovascular disease risks, but have unknown genetic effects on blood trait variation. Using Mendelian randomization, we define unexpectedly opposing roles for increased BMI and truncal adipose distribution on blood traits. Elevated genetically determined BMI and lipid levels decreased hemoglobin and hematocrit levels, consistent with clinical observations associating obesity and anemia. We found that lipid-related effects were confined to erythroid traits. In contrast, BMI affected multiple blood lineages, indicating broad effects on hematopoiesis. Increased truncal adipose distribution opposed BMI effects, increasing hemoglobin and blood cell counts across lineages. Conditional analyses indicated genes, pathways, and cell types responsible for these effects, including Leptin Receptor and other blood cell-extrinsic factors in adipocytes and endothelium that regulate hematopoietic stem and progenitor cell biology. Our findings identify novel roles for obesity on hematopoiesis, including a previously underappreciated role for genetically determined adipose distribution in determining blood cell formation and function., Competing Interests: CT, MW, SC, BV No competing interests declared, (© 2022, Thom et al.)

Introduction: Abdominal compartment syndrome (ACS) is a rare condition in which increased intra-abdominal pressure causes multiorgan dysfunction through decreased perfusion. Causes of this condition are variable, and early recognition is critical for favorable patient outcomes. Measurement of bladder pressure is recommended for diagnosis., Case Report: A 64-year-old female on clozapine with a two-year history of chronic constipation presented to the emergency department in extremis with a protuberant abdomen. After resuscitative measures, computed tomography showed a dilated, stool-filled colon with a decompressed inferior vena cava and decreased perfusion. She died despite surgical decompression., Conclusion: Severe constipation is a rare cause of ACS, and there is a lack of evidence-based guidelines. Options for bedside decompression are limited. To reduce morbidity and mortality in this population, early recognition of ACS is imperative. Initial interventions should support hemodynamics and respiration. Definitive management is surgical decompression.

We describe a high-temperature, uniaxial creep apparatus designed to investigate nonlinear attenuation of materials over a wide range of temperatures (25-1300 °C) using forced oscillations combined with a bias stress. This apparatus is primarily designed for investigation of minerals and rocks with high melting temperatures. An oscillatory compressional stress is used to determine attenuation and Young's modulus at frequencies of 10 -1 -10 2  Hz and high stress amplitudes (>0.1 MPa). Large bias stresses are applied in addition to the oscillatory stresses such that attenuation tests are conducted simultaneously with the ongoing creep. The complex compliance of the apparatus was characterized by conducting calibration tests on orientated crystals of sapphire. The real part of the apparatus compliance exhibits a dependence on sample length and frequency, whereas the imaginary part is only dependent on frequency. The complex compliance is not dependent on the oscillation amplitude or the bias stress. We assess the accuracy and precision of this calibration by comparing measurements of the attenuation and Young's modulus of aluminum and acrylic to previously published values. We outline a set of criteria defining the conditions over which this apparatus can precisely determine the attenuation and Young's modulus of a sample based on the sample length and expected values of attenuation and Young's modulus.

Background: Joint arthrocentesis is a commonly performed procedure by the emergency physician (EP). Point of care ultrasound (POCUS) has demonstrated promise in identifying joint effusions and guiding arthrocentesis procedures. EP-performed talonavicular joint arthrocentesis has not been previously described in the literature. We present a case in which an isolated talonavicular joint effusion was identified and then subsequently aspirated using POCUS., Case Report: A 65-year-old man presented with atraumatic right ankle pain. On arrival, he was noted to have diffuse warmth and edema around the ankle and midfoot. POCUS was performed to evaluate for an ankle joint effusion, which was not present. The ultrasound was then moved distally, where a talonavicular joint effusion was noted. Inflammatory markers were found to be elevated. A magnetic resonance imaging scan revealed an isolated talonavicular joint effusion without additional acute findings. POCUS was then used to perform an arthrocentesis, which revealed monosodium urate crystals consistent with an initial episode of gouty arthritis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: POCUS provides the EP with an efficient tool to diagnose joint effusions and guide arthrocentesis procedures. The foot is composed of several small joints where ultrasound can be particularly helpful. Similar to the ankle joint, these joints can be afflicted with pyogenic infections and crystalline arthropathies. To our knowledge, we present the first report of EP-performed talonavicular arthrocentesis guided by POCUS. The approach to this joint and technique for arthrocentesis are presented., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mutations in the calcium channel gene Transient Receptor Potential cation channel subfamily V member 4 ( TRPV4 ) cause autosomal dominant skeletal dysplasia, with phenotypes ranging from mild to perinatal lethality. A recent report detailed enhanced proplatelet formation and increased murine platelet count in the context of TRPV4 activation. No prior reports have described platelet count abnormalities in human TRPV4 disease. Here, we report a case of prolonged thrombocytosis in the context of TRPV4 -associated metatropic dysplasia that was lethal in the infantile period.

Background: Extreme thrombocytosis (EXT, platelet count > 1000 × 10 3 /μL) is an uncommon but potentially clinically significant finding. Primary EXT in the setting of myeloproliferative disorders is linked to thrombotic and/or bleeding complications more frequently than secondary EXT, which typically occurs in reaction to infection, inflammation, or iron deficiency. However, comorbidities have been reported in adults with secondary EXT. Clinical implications of EXT in children are not well defined, as prior studies targeted small and/or specialized pediatric populations., Objectives: Our objectives were to determine etiologies and sequelae of EXT in a hospitalized general pediatric patient population., Patients and Methods: We retrospectively analyzed EXT cases from a single-center pediatric cohort of ~80 000 patients over 8 years., Results: Virtually all cases (99.8%) were secondary in nature, and most were multifactorial. Many cases of EXT occurred in children under 2 years old (47%) and/or during critical illness (55%). No thrombotic or bleeding events directly resulted from EXT, confirming a paucity of clinical complications associated with EXT in pediatric patients. There were indications that neonatal hematopoiesis and individual genetic variation influenced some cases, in addition to certain diagnoses (eg, sickle cell anemia) and clinical contexts (eg, asplenia)., Conclusion: Our findings confirm that thrombotic events related to EXT are rare in pediatric patients, which can inform the use of empiric anti-platelet therapy., (© 2020 International Society on Thrombosis and Haemostasis.)

Objective: Children's hospitals frequently care for infants with various life-threatening airway anomalies. Management of these infants can be challenging given unique airway anatomy and potential malformations. Airway emergency management must be immediate and precise, often demanding specialized equipment and/or expertise. We developed a Neonatal-Infant Emergency Airway Program to improve medical responses, communication, equipment usage and outcomes for all infants requiring emergent airway interventions in our neonatal and infant intensive care unit (NICU)., Patients and Methods: All patients admitted to our quaternary NICU from 2008 to 2019 were included in this study. Our program consisted of a multidisciplinary airway response team, pager system, and emergency equipment cart. Respiratory therapists present at each emergency event recorded specialist response times, equipment utilization, and outcomes. A multidisciplinary oversite committee reviewed each incident., Results: Since 2008, there were 159 airway emergency events in our NICU (~12 per year). Mean specialist response times decreased from 5.9 ± 4.9 min (2008-2012, mean ± SD) to 4.3 ± 2.2 min (2016-2019, p = 0.12), and the number of incidents with response times >5 min decreased from 28.8 ± 17.8% (2008-2012) to 9.3 ± 11.4% (2016-2019, p = 0.04 by linear regression). As our program became more standardized, we noted better equipment availability and subspecialist communication. Few emergency situations (n = 9, 6%) required operating room management. There were 3 patient deaths (2%)., Conclusions: Our airway safety program, including readily available specialists and equipment, facilitated effective resolution of airway emergencies in our NICU and multidisciplinary involvement enabled rapid and effective changes in response to COVID-19 regulations. A similar program could be implemented in other centers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR 1.21, 95% CI: 1.15-1.27, P = 1 × 10-12) and coronary artery disease (CAD; OR 1.21, 95% CI: 1.16-1.26, P = 2 × 10-20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54-0.98 kg/m2, P = 1.8 × 10-11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01-1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08-1.17, P = 3 × 10-8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12-1.37, P = 2 × 10-5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89-1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity., (© The Author(s) 2020. Published by Oxford University Press.)

Background: The evaluation of septic hip arthritis often incorporates the utilization of hip ultrasonography to determine the presence of a hip joint effusion, as well as to guide arthrocentesis. Point-of-care (POC) hip ultrasound has previously been demonstrated to be accurate when performed by the emergency physician. Time to diagnosis and subsequent intervention in septic arthritis (SA) is critical to favorable outcomes., Methods: Retrospective single-center study of all emergency department (ED) patients who had a POC or radiology hip ultrasound or arthrocentesis as part of their ED evaluation for SA in a 3-year period. We investigated the difference in time to obtain hip ultrasonography results and the time to arthrocentesis between radiology and emergency physician-performed studies in cases of suspected septic hip arthritis., Results: Seventy-four patients met inclusion criteria. The median time to hip ultrasound completion was 68 (interquartile range [IQR], 38.8-132) minutes in the emergency physician-performed ultrasound group versus 208.5 (IQR, 163.8-301.3) minutes for the radiology group ( P  < 0.001). A total of 17 patients had a hip arthrocentesis performed. Time to arthrocentesis was 211 (IQR 141.3-321.5) minutes in the emergency physician-performed arthrocentesis group and 602 (IQR 500-692) minutes in the radiology arthrocentesis ( P  < 0.001)., Conclusion: There was a statistically shorter time to ultrasound result and arthrocentesis when POC hip ultrasound was utilized by the emergency physician. Given that unfavorable outcomes in SA are associated with delay in treatment, further study is warranted to determine if emergency physician-performed hip ultrasound and arthrocentesis could lead to improved patient-centered clinical end points., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Background: Genetic associations link hematopoietic traits and disease end-points, but most causal variants and genes underlying these relationships are unknown. Here, we used genetic colocalization to nominate loci and genes related to shared genetic signal for hematopoietic, cardiovascular, autoimmune, neuropsychiatric, and cancer phenotypes., Methods: Our aim was to identify colocalization sites for human traits among established genome-wide significant loci. Using genome-wide association study (GWAS) summary statistics, we determined loci where multiple traits colocalized at a false discovery rate < 5%. We then identified quantitative trait loci among colocalization sites to highlight related genes. In addition, we used Mendelian randomization analysis to further investigate certain trait relationships genome-wide., Results: Our findings recapitulated developmental hematopoietic lineage relationships, identified loci that linked traits with causal genetic relationships, and revealed novel trait associations. Out of 2706 loci with genome-wide significant signal for at least 1 blood trait, we identified 1779 unique sites (66%) with shared genetic signal for 2+ hematologic traits. We could assign some sites to specific developmental cell types during hematopoiesis based on affected traits, including those likely to impact hematopoietic progenitor cells and/or megakaryocyte-erythroid progenitor cells. Through an expanded analysis of 70 human traits, we defined 2+ colocalizing traits at 2123 loci from an analysis of 9852 sites (22%) containing genome-wide significant signal for at least 1 GWAS trait. In addition to variants and genes underlying shared genetic signal between blood traits and disease phenotypes that had been previously related through Mendelian randomization studies, we defined loci and related genes underlying shared signal between eosinophil percentage and eczema. We also identified colocalizing signals in a number of clinically relevant coding mutations, including sites linking PTPN22 with Crohn's disease, NIPA with coronary artery disease and platelet trait variation, and the hemochromatosis gene HFE with altered lipid levels. Finally, we anticipate potential off-target effects on blood traits related novel therapeutic targets, including TRAIL., Conclusions: Our findings provide a road map for gene validation experiments and novel therapeutics related to hematopoietic development, and offer a rationale for pleiotropic interactions between hematopoietic loci and disease end-points.

Background: Identifying causal variants and genes from human genetic studies of hematopoietic traits is important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modeling using available genome-wide association datasets for platelet and red blood cell traits., Results: Our model identified a joint collection of genomic features enriched at established trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte and erythroid cell yields., Conclusions: Our findings may help explain human genetic associations and identify a novel genetic strategy to enhance in vitro hematopoiesis. A similar trait-specific gene prioritization strategy could be employed to help streamline functional validation experiments for virtually any human trait.

Human induced pluripotent stem cell (iPSC)-based model systems can be used to produce blood cells for the study of both hematologic and non-hematologic disorders. This commentary discusses recent advances that have utilized iPSC-derived red blood cells, megakaryocytes, myeloid cells, and lymphoid cells to model hematopoietic disorders. In addition, we review recent studies that have defined how microglial cells differentiated from iPSC-derived monocytes impact neurodegenerative disease. Related translational insights highlight the utility of iPSC models for studying pathologic anemia, bleeding, thrombosis, autoimmunity, immunodeficiency, blood cancers, and neurodegenerative disease such as Alzheimer's., Competing Interests: Conflicts of Interest The authors declare no relevant conflicts of interest.

Background: Traumatic arthrotomy of the knee (TAK) involves the violation of the knee capsule. TAK differs from simple lacerations because it requires operative management to prevent resultant septic arthritis. The diagnostic test of choice in the emergency department is the saline load test (SLT). SLT sensitivity ranges from 34% to 99%, depending on volume used. Computed tomography (CT) is a possible alternative, using intra-articular air as a diagnostic marker. Ultrasound can identify air in various tissues, given its highly echogenic nature., Objective: We sought to determine the sensitivity and specificity of ultrasound for detecting intra-articular air in cadaveric knee joints., Methods: Soft embalmed cadavers were utilized. The knees were block randomized to having 1 mL of air injected into the joint or sham skin injection. Two blinded, expert operators scanned the knees with a high-frequency linear transducer. The sensitivity and specificity were calculated., Results: Twenty knees were included. Knees that had any prior dissection were excluded from analysis. Ten knees were randomized for air injection. The pooled sensitivity was 0.65 (95% confidence interval [CI] 0.41-0.85) with a specificity of 0.75 (95% CI 0.48-0.93). Mean time taken was 143 s., Conclusions: Ultrasound may have utility in evaluation of TAK. There were limitations. Some knees had effusions with echogenic material present, which could have led to false-positive results. It is also unknown how much air is typical of TAK. One milliliter was used based on previous work with CT. The use of ultrasound for diagnosis of TAK warrants further study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In β-thalassemia, accumulated free α-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51-like kinase 1 ( Ulk1 ) gene in β-thalassemic mice reduces autophagic clearance of α-globin in red blood cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy-related 5 ( Atg5 ) gene has relatively minor effects. Systemic treatment with the mTORC1 inhibitor rapamycin reduces α-globin precipitates and lessens pathologies in β-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from CD34 + cells of β-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating β-thalassemia., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Renal colic is a frequently encountered diagnosis among emergency department patients. Point-of-care (POC) ultrasound has taken on an increasingly important role in the diagnostic strategy of this disease, as it has been shown to be an effective modality for diagnosis and for guiding management. The primary pathology that the emergency physician will evaluate for in cases of suspected renal colic is hydronephrosis, which is a dilatation of the renal pelvis and calyces resulting from a distal obstruction such as a ureteral stone. However, other significant findings can be seen, one of which is the extravasation of urine around the kidney secondary to a forniceal, or calyceal, rupture., Case Series: We present three cases of unanticipated perinephric fluid collections identified initially on POC ultrasound in cases of suspected simple renal colic. Concomitant hydronephrosis was also seen in each of these cases. Why Should an Emergency Physician Be Aware of This? While the utilization of POC ultrasound in cases of suspected renal colic increases, we should be prepared to encounter and identify perinephric fluid collections in our evaluations. Although the ideal management of these cases is not completely defined from the current literature, we benefit from knowing how to identify these on POC ultrasound, understanding the underlying pathophysiology, and appreciating the possibility of complications that may arise., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology. We studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to: (1) examine the performance of the exome test for IPD genes, (2) determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, (3) to evaluate the frequency of variants of uncertain significance identified, and (4) to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis. We established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. In conclusion, ES has the potential to molecularly diagnose causes of IPD, and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned., (© 2017 Wiley Periodicals, Inc.)