Decision-making in action: How international-level professional football players gain an advantage.

Understanding how both visual and contextual in-game information influences player's attempts to gain an advantage over their opponent is key to understanding skilled decision-making in fast-ball sports. In the present study, we conducted semi-structured interviews with 15 male professional football players to explore their reported behaviours and perspectives on their in-game decision-making and the ways in which they adapt to gain an advantage over their opponent. Professional players who have competed internationally at either Under 17, Under 19, Under 21, or senior level took part in semi-structured interviews.

Strengthening the Chain: A Continuing Medical Education Program for Test Results Follow-up.

Introduction: The Canadian Medical Protective Association (CMPA)'s Commitment to Change in Test-Results Follow-Up (CTC-TRFU) program aims to provide physicians with resources to enhance their test results follow-up systems for improved patient safety. Framed around the Transtheoretical Model, the program involves a 6-month multimodal educational intervention involving individual and group coaching sessions, action planning, and reflection surveys.

Methods: This study evaluates the CTC-TRFU program's impact by analyzing survey responses and course documents, focusing on three main outcomes: physicians' perceived barriers and challenges, changes in their confidence and commitment, and implemented practice changes with perceived impact on patient safety.

Proximal lateral insertion portal of an intra-articular arthroscopic stifle lever: A cadaveric study.

Objective: To (1) Describe the proximal lateral insertion portal for the placement of an intra-articular distraction lever. (2) Assess for associated damage with the insertion of the lever and (3) evaluate the impact of duration of lever use on articular cartilage damage.

Study Design: Ex vivo canine cadaveric experimental study.

Repair of leukemia-associated single nucleotide variants via interallelic gene conversion.

CRISPR-Cas9 is a useful tool for inserting precise genetic alterations through homology-directed repair (HDR), although current methods rely on provision of an exogenous repair template. Here, we tested the possibility of repairing heterozygous single nucleotide variants (SNVs) using the cell's own wild-type allele rather than an exogenous template. Using high-fidelity Cas9 to perform allele-specific CRISPR across multiple human leukemia cell lines as well as in primary hematopoietic cells from patients with leukemia, we find high levels of reversion to wild-type in the absence of exogenous template.

Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia.

Unlabelled: Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy.

TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.

CD47-SIRPa is a myeloid check point pathway that promotes phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in acute myeloid leukemia (AML), with its blockade leading to cell clearance.

LAIR-1 agonism as a therapy for acute myeloid leukemia.

Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models.

Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.

Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation.

Endocytosis of the thrombopoietin receptor Mpl regulates megakaryocyte and erythroid maturation in mice.

( ) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in platelets. Additionally, platelets cannot endocytose the thrombopoietin (TPO) receptor Mpl, leading to elevated circulating TPO levels.

Developing a trigger tool to monitor adverse events during haemodialysis in children: a pilot project.

Background: We developed a paediatric haemodialysis trigger tool (pHTT) for application per haemodialysis (HD) session in children receiving intermittent in-centre HD and systematically monitored adverse events.

Methods: Single-centre quality improvement study performed over two 8-week cycles. Data collected prospectively using a 'per-dialysis session' pHTT tool including 54 triggers across six domains, adapted from a recently described haemodialysis trigger tool (HTT) for adults.

Maximising Grip on Deception and Disguise: Expert Sports Performance During Competitive Interactions.

Expert performers in fast-ball and combat sports continuously interact with their opponents and, if they are to be successful, adapt behaviour in order to gain an advantage. For example, disguise and deception are recognised as skilful behaviours that are employed to disrupt an opponent's ability to successfully anticipate their actions. We contend that such skilled behaviour unfolds during the interaction between opposing players, yet typical research approaches omit and/or artificially script these interactions.

Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase.

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F subcomplex of mitochondrial ATP synthase as the target of apoptolidin A.

Iron status influences the response of cord blood megakaryocyte progenitors to eltrombopag in vitro.

Eltrombopag (ELT) is a thrombopoietic agent approved for immune thrombocytopenia and also a potent iron chelator. Here we found that ELT exhibited dose-dependent opposing effects on in vitro megakaryopoiesis: low concentrations (≤6 µM, ELT6) stimulated megakaryopoiesis, but high concentrations (30 µM, ELT30) suppressed megakaryocyte (MK) differentiation and proliferation. The suppressive effects of ELT30 were reproduced by other iron chelators, supporting iron chelation as a likely mechanism.

A Multisite Preregistered Paradigmatic Test of the Ego-Depletion Effect.

We conducted a preregistered multilaboratory project ( = 36; = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the . Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result ( = 0.

Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis.

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia.

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML.

The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro.

BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia.

Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients.

Qualitative Study of Practices and Challenges of Stepping Down Asthma Medication in Primary Care Across the UK.

Background: Guidelines recommend that asthma treatment should be stepped down to the minimally effective dose that achieves symptom control to prevent medication side effects and reduce unnecessary costs. Little is known about the practice of stepping down and the challenges in primary care, where most asthma patients are managed.

Objective: To explore views, experiences, barriers and ideas, of doctors, nurses and pharmacists working in primary care, related to step down of asthma medication.

A novel mutation in PDE6B in Spanish Water Dogs with early-onset progressive retinal atrophy.

Objective: To identify the underlying mutation in a recently identified early-onset progressive retinal atrophy (PRA) in the Spanish Water Dog (SWD) breed.

Animal Studied: Eighteen SWDs were used in this study. Six SWDs diagnosed with PRA and 12 phenotypically normal SWDs.

Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model.

Background: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies.

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies.

Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant.

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis.