Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression.

Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we define the early subpopulation of pre-HE cells based on both surface markers and transcriptomes. We identify the transcription factor Meis1 as an essential regulator of hemogenic cell specification in the embryo prior to Runx1 expression. Meis1 is expressed at the earliest stages of EHT and distinguishes pre-HE cells primed towards the hemogenic trajectory from the arterial endothelial cells that continue towards a vascular fate. Endothelial-specific deletion of Meis1 impairs the formation of functional Runx1-expressing HE which significantly impedes the emergence of pre-HSPC via EHT. Our findings implicate Meis1 in a critical fate-determining step for establishing EHT potential in endothelial cells.

High-risk criteria for the physiologically difficult paediatric airway: A multicenter, observational study to generate validity evidence.

BACKGROUND: Single-center studies have identified risk factors for peri-intubation cardiac arrest in the emergency department (ED). The study objective was to generate validity evidence from a more diverse, multicenter cohort of patients. METHODS: We completed a retrospective cohort study of 1200 paediatric patients who underwent tracheal intubation in eight academic paediatric EDs (150 per ED). The exposure variables were 6 previously studied high-risk criteria for peri-intubation arrest: (1) persistent hypoxemia despite supplemental oxygen, (2) persistent hypotension, (3) concern for cardiac dysfunction, (4) post-return of spontaneous circulation (ROSC), (5) severe metabolic acidosis (pH < 7.1), and (6) status asthmaticus. The primary outcome was peri-intubation cardiac arrest. Secondary outcomes included extracorporeal membrane oxygenation (ECMO) cannulation and in-hospital mortality. We compared all outcomes between patients that met one or more versus no high-risk criteria, using generalized linear mixed models. RESULTS: Of the 1,200 paediatric patients, 332 (27.7%) met at least one of 6 high-risk criteria. Of these, 29 (8.7%) suffered peri-intubation arrest compared to zero arrests in patients meeting none of the criteria. On adjusted analysis, meeting at least one high-risk criterion was associated with all 3 outcomes - peri-intubation arrest (AOR 75.7, 95% CI 9.7-592.6), ECMO (AOR 7.1, 95% CI 2.3-22.3) and mortality (AOR 3.4, 95% 1.9-6.2). Four of 6 criteria were independently associated with peri-intubation arrest: persistent hypoxemia despite supplemental oxygen, persistent hypotension, concern for cardiac dysfunction, and post-ROSC. CONCLUSIONS: In a multicenter study, we confirmed that meeting at least one high-risk criterion was associated with paediatric peri-intubation cardiac arrest and patient mortality.

The Hong Kong consensus statements on unresectable hepatocellular carcinoma: narrative review and update for 2021.

Background and Objective: Hong Kong, like many parts of Asia, faces a high burden of hepatocellular carcinoma (HCC) caused by high endemic rates of hepatitis B virus infection. Hong Kong clinicians have developed a high level of expertise in HCC treatment across surgical, transarterial, ablative, radiotherapeutic and systemic modalities. This publication summarizes the latest evidence-based recommendations on how these modalities should be used. Methods: In two meetings held in 2020, a multidisciplinary panel of surgeons, oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC, with an emphasis on treatment of HCC not amenable to surgical resection. Close attention was paid to new evidence published since the previous version of these statements in 2018. Key Content and Findings: The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable HCC. Since the previous version of these statements, considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new evidence. Conclusions: Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for resection. In particular, there is a need for more evidence to aid physicians in the selection of second-line systemic therapies, as currently most data are limited to patients with disease progression on first-line sorafenib.

Calculated decisions: Pediatric NIHSS Stroke Scale (PedNIHSS).

This supplement reviews the evidence and applications for Pediatric NIH Stroke Scale, which quantifies stroke severity using a child-specific version of the National Institutes of Health Stroke Score.

Elucidating the importance and regulation of key enhancers for human MEIS1 expression.

Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.

Total Isolated Monocular Vision Loss in a Patient Who Suffered Closed Head Injury.

BACKGROUND: Head injuries are an important cause of morbidity and mortality in children and young adults. There are multiple sight-threatening complications of head injury, even in closed head injury without visible violation of the globe or orbits. One such entity is traumatic optic neuropathy. CASE REPORT: Herein we describe a case of traumatic optic neuropathy in an otherwise healthy teenage patient who suffered total monocular vision loss after a fall and without any other injuries on examination. Unfortunately, the prognosis for this condition is relatively poor in terms of visual recovery. Though much research has been conducted attempting to treat this condition, to date there have been no studies showing a clear benefit of medical or surgical intervention. Why Should an Emergency Physician Be Aware of This? Although there is no proven treatment for traumatic optic neuropathy, emergency physicians may encounter this in their practice while caring for both pediatric and adult patients presenting with head injury. Having more background knowledge on this condition will enhance emergency physicians' ability to consult with subspecialist providers as well as to educate patients and their families on their condition and prognosis.

Calculated decisions: Modified Mallampati classification.

The Modified Mallampati Classification stratifies predicted difficulty of endotracheal intubation based on anatomic features.

Calculated decisions: Jones criteria for acute rheumatic fever diagnosis

The Jones criteria are use to diagnose acute rheumatic fever based on major and minor criteria.

Calculated decisions: Pediatric appendicitis risk calculator (pARC)

The pediatric appendicitis risk calculator quantifies appendicitis risk in pediatric patients with abdominal pain, possibly better than the pediatric appendicitis score.

Calculated Decisions: PECARN Rule for Low-Risk Febrile Infants

The PECARN rule for low-risk febrile infants predicts the risk for urinary tract infection, bacteremia, or bacterial meningitis in febrile infants aged ≤ 60 days.

Gestalt similarity groupings are not constructed in parallel.

Our visual system organizes spatially distinct areas with similar features into perceptual groups. To better understand the underlying mechanism of grouping, one route is to study its capacity and temporal progression. Intuitively, that capacity seems unlimited, and the temporal progression feels immediate. In contrast, here we show that in a visual search task that requires similarity grouping, search performance is consistent with serial processing of those groups. This was true across several experiments, for seeking a single ungrouped pair among grouped pairs, vice versa, and for displays with tiny spacings between the grouped items. In a control condition that ruled out display complexity confounds, when the small inter-object spacing was removed so that that pairs touched, removing the need to group by similarity, search became parallel. Why is similarity grouping so slow to develop? We argue that similarity grouping is 'just' feature selection - seeing a red, bright, or square group is global selection of those features. This account predicts serial processing of one feature group at a time, and makes new falsifiable predictions about how properties of feature-based selection should be reflected in similarity grouping.

Lack of utility of measuring serum bilirubin concentration in distinguishing perforation status of pediatric appendicitis.

BACKGROUND: Pediatric appendicitis is a common, potentially serious condition. Determining perforation status is crucial to planning effective management. PURPOSE: Determine the efficacy of serum total bilirubin concentration [STBC] in distinguishing perforation status in children with appendicitis. METHODS: Retrospective review of 257 cases of appendicitis who received abdominal CT scan and measurement of STBC. RESULTS: There were 109 with perforation vs 148 without perforation. Although elevated STBC was significantly more common in those with [36%] vs without perforation [22%], the mean difference in elevated values between groups [0.1mg/dL] was clinically insignificant. Higher degrees of hyperbilirubinemia [>2mg/dL] were rarely encountered [5%]. Predictive values for elevated STBC in distinguishing perforation outcome were imprecise [sensitivity 38.5%, specificity 78.4%, PPV 56.8%, NPV 63.4%]. ROC curve analysis of multiple clinical and other laboratory factors for predicting perforation status was unenhanced by adding the STBC variable. Specific analysis of those with perforated appendicitis and percutaneously-drained intra-abdominal abscess which was culture-positive for Escherichia coli showed an identical rate of STBC elevation compared to all with perforation. CONCLUSIONS: The routine measurement of STBC does not accurately distinguish perforation status in children with appendicitis, nor discern infecting organism in those with perforation and intra-abdominal abscess.