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Morgan I Soffler,1,2 Margaret M Hayes,2–4 C Christopher Smith3–5 1Harvard Combined Pulmonary and Critical Care Fellowship at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 3Internal Medicine Residency Program, Beth Israel Deaconess Medical Center, Boston, MA, USA; 4Shapiro Institute for Education and Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; 5Division of General Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA Abstract: Simulation is a popular and effective training modality in medical education across a variety of domains. Central venous catheterization (CVC) is commonly undertaken by trainees, and carries significant risk for patient harm when carried out incorrectly. Multiple studies have evaluated the efficacy of simulation-based training programs, in comparison with traditional training modalities, on learner and patient outcomes. In this review, we discuss relevant adult learning principles that support simulation-based CVC training, review the literature on simulation-based CVC training, and highlight the use of simulation-based CVC training programs at various institutions. Keywords: simulation, central venous catheterization, assessment, competency, central line insertion

Activating mutations in FLT3 occur in ~30% of adult acute myeloid leukemia, primarily consisting of internal tandem duplication (ITD) mutations (~25%) and point mutations in the tyrosine kinase domain (~5%), commonly at the activation loop residue D835. Secondary kinase domain mutations in FLT3-ITD, particularly at the D835 residue are frequently associated with acquired clinical resistance to effective FLT3 tyrosine kinase inhibitors (TKIs). Molecular docking studies have suggested that D835 mutations primarily confer resistance by stabilizing an active Asp-Phe-Gly in ('DFG-in') kinase conformation unfavorable to the binding of type II FLT3 TKIs, which target a 'DFG-out' inactive conformation. We profiled the activity of active type II FLT3 TKIs against D835 kinase domain mutants that have been clinically detected to date. We found that type II inhibitors (quizartinib, sorafenib, ponatinib and PLX3397) retain activity against specific D835 substitutions. Modeling studies suggest that bulky hydrophobic substitutions (D835Y/V/I/F) at this residue are particularly resistant, whereas mutations that preserve interactions between D835 and S838 are relatively sensitive (D835E/N). All mutants retain sensitivity to the type I inhibitor crenolanib. These results suggest that patients with relatively sensitive D835 mutations should be included in clinical trials of type II FLT3 TKIs.

© 2015 Macmillan Publishers Limited Activating mutations in FLT3 occur in ~30% of adult acute myeloid leukemia, primarily consisting of internal tandem duplication (ITD) mutations (~25%) and point mutations in the tyrosine kinase domain (~5%), commonly at

Social physique anxiety (SPA) is the anxiety that people feel when their physique or body is evaluated by others. This research explored the relationships among SPA, type of sport participation, and body size in female athletes. It was hypothesized that elite women athletes would have lower levels of SPA than nonelite athletes and that lightweight women athletes would have lower levels of SPA than heavyweight athletes. In Study 1, one hundred four women rowers participating in the World Indoor Rowing Championships completed the Social Physique Anxiety Scale (SPAS; Hart et al., 1989) and a demographic questionnaire. With regard to SPA for female rowers, there were no significant differences involving elite status and weight class. In Study 2, one hundred thirteen women swimmers of various competitive levels (NCAA Division I, NCAA Division III, recreational) completed the SPAS and a demographic questionnaire. ANOVA indicated that NCAA Division I swimmers had lower SPA than recreational swimmers and that lightweight swimmers had lower SPA than heavyweight swimmers. The role of specific sport demands as they relate to SPA were discussed. [ABSTRACT FROM AUTHOR]

Background: Acute unreconstructible 3- or 4-part proximal humerus fractures can be treated with hemiarthroplasty or reverse polarity shoulder arthroplasty. Randomized trials using implants from multiple different companies or uncemented implants have found superior results with reverse polarity arthroplasty., Hypothesis: We tested the hypothesis that cemented reverse polarity arthroplasty produces a superior outcome compared to cemented hemiarthroplasty using one implant system in patients aged 65 years and over at 12 months follow-up as measured with the Constant Score., Methods: A prospective patient and assessor blinded multicenter randomized controlled trial was conducted of shoulder hemiarthroplasty or reverse polarity arthroplasty in patients aged 65 years and older with acute 3- and 4-part proximal humerus fracture not amenable to osteosynthesis. The primary outcome was the Constant Score at 12 months with total follow-up to 24 months. Block randomization by site was undertaken using random number generation and sealed envelopes. Power analysis indicated that 17 patients were required in each arm to achieve 80% power with an alpha-value of 5%. Secondary outcome measures were the difference in the mean Constant Score, Quick Disabilities of the Arm Shoulder and Hand Questionnaire (QuickDASH), Oxford Shoulder Score, American Shoulder and Elbow Surgeons Score, and EQ5D-5L up to 2 years; differences in complication rate at 1 and 2 years; differences in revision and implant failure at 1 and 2 years., Results: Eighteen patients were randomized to hemiarthroplasty and 18 to reverse polarity arthroplasty across 4 sites. The primary outcome as measured by the Constant Score at 12 months was better in the reverse polarity shoulder arthroplasty group (mean 51.1, s.d. 14.9) compared to the hemiarthroplasty group (mean 35.0, s.d. 13.5) (P = .004). No significant difference was reported at 24 months but this may be due to high rates of attrition (22%). The mean EQ-5D-5 L patient rated health status score was significantly higher in the reverse polarity shoulder arthroplasty group compared to the hemiarthroplasty group at 12 months. One hemiarthroplasty was revised due to implant uncoupling and one reverse polarity shoulder replacement was revised due to instability. No other complications were recorded., Discussion: Treatment of unreconstructible 3- or 4-part proximal humerus fractures with reverse polarity shoulder arthroplasty results in a superior outcome compared to shoulder hemiarthroplasty at 12 months measured with the Constant Score with no increased risk of failure up to 24 months in patients age 65 years and over. High attrition rates are observed in this older population due to cognitive decline and death from other causes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies., (© 2023. The Author(s).)

Abstract: Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A "mutation score" was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points ("Beat-AML intermediate") vs 1+ points ("Beat-AML adverse"). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined "Beat-AML favorable-risk" group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making., (© 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.)

Background: Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). This post hoc analysis reports efficacy and safety by baseline corticosteroid use in the ELEVATE UC clinical programme., Methods: Patients with UC received etrasimod 2 mg or placebo for up to 52 weeks. Corticosteroid use was permitted; tapering was recommended from Week 12. Efficacy was assessed at Weeks 12 and 52 in ELEVATE UC 52, and Week 12 in ELEVATE UC 12, in patients in the corticosteroid (CS) and no-CS subgroups. CS-free efficacy at Week 52 was assessed in patients with baseline CS use., Results: In ELEVATE UC 52 and ELEVATE UC 12, 93/289 (32.2%) and 65/238 (27.3%) patients receiving etrasimod and 42/144 (29.2%) and 34/116 (29.3%) patients receiving placebo, respectively, had concomitant CS use at baseline. In the CS and no-CS subgroups, higher proportions of patients who received etrasimod vs placebo achieved clinical remission (p < 0.05) in ELEVATE UC 52 at Weeks 12 (CS: 32.3% vs 16.7%; no-CS: 26.0% vs 4.9%) and 52 (CS: 31.2% vs 9.5%; no-CS: 33.2% vs 6.9%). In the CS subgroup, significantly more patients receiving etrasimod than placebo achieved CS-free clinical remission at Week 52 (31.2% vs 7.1%). No increases in infection rates were observed with baseline CS use. Safety was comparable between subgroups., Conclusions: Etrasimod demonstrated efficacy in inducing and maintaining remission in both subgroups. CSfree remission was achieved in the CS subgroup. Safety was consistent, with no increase in infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification., (© 2024. The Author(s).)

Phosphatidylethanol (PEth) is an alcohol derivative that has been employed as a blood-based biomarker for regular alcohol use. This study investigates the utility of phosphatidylethanol (PEth) as a biomarker for assessing alcohol consumption in post-mortem brain tissue. Using samples from the New South Wales Brain Tissue Resource Centre, we analysed PEth(16:0/18:1) levels in the cerebellum and meninges of individuals with varying histories of alcohol use, including those diagnosed with alcohol use disorder (AUD) and controls. Our findings demonstrate a significant correlation between PEth levels and blood alcohol content (BAC) at the time of death, supporting the biomarker's sensitivity to recent alcohol intake. Furthermore, this study explores the potential of PEth levels in differentiating AUD cases from controls, taking into consideration the complexities of diagnosing AUD post-mortem. The study also examined the relationship between PEth levels and liver pathology, identifying a link with the severity of liver damage. These results underscore the value of PEth as a reliable indicator of alcohol consumption and its potential contributions to post-mortem diagnostics and consequently, research into alcohol-related brain damage., Competing Interests: Declaration of competing interest The Authors report no known competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This series of FactFinders presents a brief summary of the evidence and outlines recommendations to minimize risks associated with cervical epidural injections. Evidence in support of the following facts is presented. Minimizing Risks with Cervical Interlaminar Epidural Steroid Injections - 1) CILESIs should be performed at C6-C7 or below, with C7-T1 as the preferred access point due to the more generous dorsal epidural space at this level compared to the more cephalad interlaminar segments. This reduces the risk of the minor complication of dural puncture and the major complication of spinal cord injury due to inadvertent needle placement. 2) LF gaps are most prevalent in the midline cervical spine. This can result in diminished tactile feedback with loss of resistance (LOR), increasing the risk for inadvertent dural puncture or spinal cord injury. Based on current evidence, needle placement in the paramedian portion of the interlaminar space is safest to avoid LF gaps. 3) An optimal AP trajectory view and the physician's ability to discern engagement in the LF and subsequent LOR are crucial. Confirmation of minimal needle insertion depth relative to the ventral margin of the lamina with either a lateral or contralateral oblique (CLO) safety view is critical to minimize the risk of inadvertently inserting the needle too ventral. 4) There have been closed claims and case reports of patients who have suffered catastrophic neurologic injuries while receiving CILESIs under deep sedation. If sedation is administered, the least amount necessary should be utilized to ensure the patient can provide verbal feedback during the procedure. 5) CILESIs are an elective procedure; therefore, necessity and likelihood of benefit must be foremost considerations. Current guidelines recommend holding ACAP therapy before CILESIs due to the potentially catastrophic complications associated with epidural hematoma (EH) formation. However, there is also a risk of severe systemic complications with ceasing ACAP in specific clinical scenarios. The treating physician is obligated to determine if the procedure is indicated and can ultimately decide to delay the intervention or not perform the procedure if the benefit does not outweigh the risks. Minimizing Risks with Cervical Transforaminal Epidural Steroid Injections - the Role of Preprocedural Review of Advanced Imaging -- Variations in vascular anatomy may warrant a modified approach to CTFESI. Preprocedural review of cross-sectional imaging can provide critical information for safe injection angle planning specific to individual patients and may help to decrease the risk of unintended vascular events with potentially catastrophic outcomes. Safety of Multi-level or Bilateral Fluoroscopically-Guided Cervical Transforaminal Epidural Steroid Injections -- Safe performance of a CTFESI procedure requires the ability to detect inadvertent arterial injection. Contrast medium placed into the epidural space and/or along the exiting spinal nerves during an initial CTFESI may obscure the detection of inadvertent cannulation of a radiculomedullary artery by a subsequent CTFESI. While no available literature directly addresses the potential risk that exists with a multi-level or bilateral CTFESI, caution is still warranted., Competing Interests: 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., (© 2024 The Author(s).)

Background: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear., Methods: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance., Results: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively., Conclusion: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors., (© 2024 Wiley Periodicals LLC.)

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

The increased muscular force output required for some behaviors is achieved via amplification of motoneuron output via cholinergic C-bouton synapses. Work in neonatal mouse motoneurons suggested that modulation of currents mediated by post-synaptically clustered K V 2.1 channels is crucial to C-bouton amplification. By focusing on more mature motoneurons, we show that conditional knockout of K V 2.1 channels minimally affects either excitability or response to exogenously applied muscarine. Similarly, unlike in neonatal motoneurons or cortical pyramidal neurons, pharmacological blockade of K V 2 currents has minimal effect on mature motoneuron firing in vitro . Furthermore, in vivo amplification of electromyography activity and high-force task performance was unchanged following K V 2.1 knockout. Finally, we show that K V 2.2 is also expressed by spinal motoneurons, colocalizing with K V 2.1 opposite C-boutons. We suggest that the primary function of K V 2 proteins in motoneurons is non-conducting and that K V 2.2 can function in this role in the absence of K V 2.1., Competing Interests: R.M.B. is a co-founder, board member, and consultant to Sania Therapeutics, Inc, an early stage gene therapy company, and CCS in now working for Sania. The work presented here is from the Brownstone UCL lab and has no financial implications for Sania., (© 2024 The Author(s).)

The New South Wales Brain Tissue Resource Centre is a human brain bank that provides top-quality brain tissue for cutting-edge neuroscience research spanning various conditions from alcohol use disorder to neurodegenerative diseases. However, the conventional practice of preserving brain tissue in formalin poses challenges for immunofluorescent staining primarily due to the formalin's tendency, over time, to create cross-links between antigens, which can obscure epitopes of interest. In addition, researchers can encounter issues such as spectral bleeding, limitations in using multiple colors, autofluorescence, and cross-reactivity when working with long-term formalin-fixed brain tissue. The purpose of the study was to test chromogen-based double immunolabeling to negate the issues with immunofluorescent staining. Colocalization of antigens was explored using chromogens 3-amino-9-ethylcarbazole (AEC) and 3,3,-diaminobenzidine in a sequential staining procedure where the AEC signal was eliminated by alcohol treatment. Combinations of 2 or 3 primary antibodies from the same or different species were trialed successfully with this protocol. The colocalization of antigens was also demonstrated with pseudocoloring that mimicked immunofluorescence staining. This staining technique increases the utility of archival formalin-fixed tissue samples., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This series of FactFinders presents a brief summary of the evidence and outlines recommendations to improve our understanding and management of potential procedure-related complications. Evidence in support of the following facts is presented. (1) Epidural Steroid injections for Radicular Pain Due to Spinal Stenosis Caused by Lipomatosis -- There is low-level evidence of an association between epidural steroid injections (ESIs) and the development and/or worsening of spinal epidural lipomatosis (SEL). However, there is insufficient evidence to establish whether ESIs independently result in an increase in spinal stenosis with neurological compromise in individuals with pre-existing SEL . (2) Steroid Exposure Postpartum -- There is no absolute contraindication to steroid injections based on postpartum or lactating status, but there may be disruption of both maternal and breastfed child hypothalamic-pituitary-adrenal (HPA) axis response to steroid administration. For the duration of breastfeeding, milk production may be affected after steroid exposure, and withholding breast milk produced for several hours after exposure minimizes infant exposure., Competing Interests: 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., (© 2024 International Pain and Spine Intervention Society.)