Redeployment to critical care during the COVID-19 pandemic: A phenomenological study.

BACKGROUND: The redeployment of staff which involves moving staff from one clinical setting to another is a key feature of health care management. Rising demand associated with chronic disease and seasonal variation makes redeployment increasingly commonplace. During the COVID-19 pandemic preparation for the influx of patients included sourcing equipment and resources and the redeployment of staff to respiratory wards and critical care. AIM: The aim of this study was to explore the lived experience of redeployment to critical care during the COVID-19 pandemic from the perspective of those individuals who were moved to help and critical care core staff. STUDY DESIGN: A transcendental phenomenological study involving semi-structured interviews with staff redeployed and critical care core staff was conducted. Data were collected from staff in one critical care department of a large NHS Trust in England between the second and third pandemic wave (April-June 2021). RESULTS: Analysis of the data led to the identification of seven meaning units: intention, apprehension, expectations, familiarity, preparation, support, and own work. Intention related to the decisions made by managers regarding whom to redeploy and the reasons why people were chosen. Apprehension and expectations were closely linked and related to critical care skills and knowledge as well as anxiety about infection risk. Familiarity was a key element of people feeling comfortable and the confidence core staff had in colleagues who had come to help. Support and preparation helped but staff were anxious about their own work and concerned about the open-ended nature of redeployment. CONCLUSION: Familiarity and recency of critical care experience played a significant role in how useful redeployed staff were. Redeployed staff were concerned about assumptions being made and expectations of themselves as well as detachment from their usual support network. RELEVANCE TO CLINICAL PRACTICE: Continued shortages of registered nurses globally combined with the need to create additional critical care capacity during emergencies such as infection outbreaks means that redeployment of staff will continue for some time. Identifying the impact of redeployment on staff will enable services to better prepare and support registered nurses who are redeployed to critical care.

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

Characterization of the Enzymatic Activity of SETDB1 and Its 1:1 Complex with ATF7IP.

The protein methyltransferase (PMT) SETDB1 is a strong candidate oncogene in melanoma and lung carcinomas. SETDB1 methylates lysine 9 of histone 3 (H3K9), utilizing S-adenosylmethionine (SAM) as the methyl donor and its catalytic activity, has been reported to be regulated by a partner protein ATF7IP. Here, we examine the contribution of ATF7IP to the in vitro activity and substrate specificity of SETDB1. SETDB1 and ATF7IP were co-expressed and 1:1 stoichiometric complexes were purified for comparison against SETDB1 enzyme alone. We employed both radiometric flashplate-based and SAMDI mass spectrometry assays to follow methylation on histone H3 15-mer peptides, where lysine 9 was either unmodified, monomethylated, or dimethylated. Results show that SETDB1 and the SETDB1:ATF7IP complex efficiently catalyze both monomethylation and dimethylation of H3K9 peptide substrates. The activity of the binary complex was 4-fold lower than SETDB1 alone. This difference was due to a decrease in the value of kcat as the substrate KM values were comparable between SETDB1 and the SETDB1:ATF7IP complex. H3K9 methylation by SETDB1 occurred in a distributive manner, and this too was unaffected by the presence of ATF7IP. This finding is important as H3K9 can be methylated by HMTs other than SETDB1 and a distributive mechanism would allow for interplay between multiple HMTs on H3K9. Our results indicate that ATF7IP does not directly modulate SETDB1 catalytic activity, suggesting alternate roles, such as affecting cellular localization or mediating interaction with additional binding partners.

CARM1 Preferentially Methylates H3R17 over H3R26 through a Random Kinetic Mechanism.

CARM1 is a type I arginine methyltransferase involved in the regulation of transcription, pre-mRNA splicing, cell cycle progression, and the DNA damage response. CARM1 overexpression has been implicated in breast, prostate, and liver cancers and therefore is an attractive target for cancer therapy. To date, little about the kinetic properties of CARM1 is known. In this study, substrate specificity and the kinetic mechanism of the human enzyme were determined. Substrate specificity was examined by testing CARM1 activity with several histone H3-based peptides in a radiometric assay. Comparison of kcat/KM values reveals that methylation of H3R17 is preferred over that of H3R26. These effects are KM-driven as kcat values remain relatively constant for the peptides tested. Shortening the peptide at the C-terminus by five amino acid residues greatly reduced binding affinity, indicating distal residues may contribute to substrate binding. CARM1 appears to bind monomethylated peptides with an affinity similar to that of unmethylated peptides. Monitoring of the CARM1-dependent production of monomethylated and dimethylated peptides over time by self-assembled monolayer and matrix-assisted laser desorption ionization mass spectrometry revealed that methylation by CARM1 is distributive. Additionally, dead-end and product inhibition studies suggest CARM1 conforms to a random sequential kinetic mechanism. By defining the kinetic properties and mechanism of CARM1, these studies may aid in the development of small molecule CARM1 inhibitors.

Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.

Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity, (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide). The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.

DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells.

EPZ-5676 [(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4), and SKM-1 (non-MLL-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents cytarabine or daunorubicin in MOLM-13 and MV4-11 MLL-r cell lines. EPZ-5676 is selective for MLL-r cell lines as demonstrated by its lack of effect either alone or in combination in the nonrearranged SKM-1 cell line. In MLL-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin-modifying drugs also revealed a consistent combination benefit, including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics, including AML SOC drugs and DNA hypomethylating agents in MLL-r cells.

A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.

EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered.

Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys²7 methylation by human polycomb repressive complex 2 and vSET.

H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure-function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need.

Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor.

(2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol (EPZ-5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half-life (t1/2 ) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro-in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu -corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ-5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N-dealkylated product (M4) as well as an N-oxide (M6).

Beauty is in the nose of the beholder: Fragrance modulates attractiveness, confidence and femininity ratings and neural responses to faces of self and others.

Previous research investigated cross-modal influence of olfactory stimuli on perception and evaluation of faces. However, little is known about the neural dynamics underpinning this multisensory perception, and no research examined perception for images of oneself, and others, in presence of fragrances. This study investigated the neural mechanisms of olfactory-visual processing using electroencephalography (EEG) and subjective evaluations of self- and other-images. 22 female participants evaluated images of female actors and themselves while being exposed to the fragrance of a commercially available body wash or clean air delivered via olfactometer. Participants rated faces for attractiveness, femininity, confidence and glamorousness on visual analogue scales. EEG data was recorded and event-related potentials (ERPs) associated with onset of face stimuli were analysed to consider effects of fragrance presence on face processing, and interactions between fragrance and self-other image-type. Subjective ratings of confidence, attractiveness and femininity were increased for both image-types in pleasant fragrance relative to clean air condition. ERP components covering early-to-late stages of face processing were modulated by the presence of fragrance. Findings also revealed a cross-modal fragrance-face interaction, with pleasant fragrance particularly affecting ERPs to self-images in mid-latency ERP components. Results showed that the pleasant fragrance of the commercially available body wash impacted how participants perceived faces of self and others. Self- and other-image faces were subjectively rated as more attractive, confident and feminine in the presence of the pleasant fragrance compared to an un-fragranced control. The pleasant fragrance also modulated underlying electrophysiological activity. For the first time, an effect of pleasant fragrance on face perception was observed in the N1 component, suggesting impact within 100 ms. Pleasant fragrance also demonstrated greater impact on subsequent neural processing for self, relative to other-faces. The findings have implications for understanding multisensory integration during evaluations of oneself and others.

Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas.

EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k(cat)/K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function.

Identifying Sources of Moral Distress Amongst Critical Care Staff During the Covid-19 Pandemic Using a Naturalistic Inquiry.

Introduction: Moral distress can have a significant impact on the mental health and well-being of practitioners. Causes of moral distress in critical care have been identified as futile treatment, conflict between family members and staff, lack of resources, and dysfunctional teams. Objectives: This study explores the sources of moral distress during the COVID-19 pandemic and the meaning that staff attached to these events. The study aims to examine whether the sources of moral distress are similar, or different, to those that commonly occur in critical care departments. Methods: Naturalistic inquiry using semi-structured individual interviews with 17 participants drawn from nursing (n = 12), medicine (n = 3), and the allied health professions (n = 2). The interviews were recorded and transcribed verbatim. The transcripts were analyzed using reflexive thematic analysis. Results: The results suggested that while there were some similar sources of moral distress including caring for dying patients and not being able to provide the usual standard of care, the nature of the disease trajectory and frequency of death had a significant impact. In addition, the researchers found that providing care which was counter-intuitive, concerns about the risks to the staff and their families and the additional burdens associated with leading teams in times of uncertainty were identified as sources of moral distress. Conclusion: This study explored the potential sources of moral distress during the pandemic and the meaning that practitioners attached to their experiences. There were some similarities with the sources of moral distress in critical care which occur outside of a pandemic. However, the frequency and intensity of the experiences are likely to be different during a pandemic, with staff describing high volumes of deaths without family members present. In addition, new sources of moral distress related to uncertainty, counter-intuitive care and concerns about personal and family risk of infection were identified.

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome.

BACKGROUND: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking. MATERIALS AND METHODS: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety. RESULTS: Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs. CONCLUSION: We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.

Impact of enzyme concentration and residence time on apparent activity recovery in jump dilution analysis.

Jump dilution analysis is commonly used to evaluate the reversibility of inhibition and to quantify the residence time of the inhibitor-enzyme complex. During hit and lead characterization, one sometimes observes apparently linear progress curves after jump dilution that display activity recoveries that are intermediate between those expected for fully reversible and irreversible inhibition. Computer simulations of progress curves after jump dilution indicate that seemingly linear progress curves can result when dealing with tight-binding inhibitors if substoichiometric concentrations of inhibitor are preincubated with enzyme. In this situation, the activity recovered is comparable to that expected for instantaneously reversible inhibitors. In addition, simulations demonstrate that intermediate values of activity recovery may be observed for compounds with modestly slow dissociation rates (i.e., residence times >0min but ≤20min) when the attending curvature of the data is not accounted for. The observation of intermediate values of recovery can, thus, serve as an indication of either modest residence time or a contaminating inactivator within an inhibitor sample, in either case prompting greater scrutiny of the test compound.

Lessons From Other Disciplines About Communication, Human Performance and Situational Awareness While Wearing Personal Protective Equipment.

INTRODUCTION: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) has quickly accelerated into a pandemic. As COVID-19 has swept across the globe, health systems have adapted, including the cessation of routine surgery and the re-deployment of staff to critical care settings. Prompt interventions such as endotracheal (ET) intubation, are deemed essential in patients with Acute Respiratory Distress Syndrome. Intubation requires a coordinated approach and effective teamwork, as it is a high-risk procedure not least because it is an aerosol-generating intervention with increased infection risk. As a result, teams responsible for performing ET intubation are required to wear Personal Protective Equipment (PPE), which in turn hinders communication and situational awareness, and can hamper team work. METHOD: This review considers the effects of wearing PPE on performance and situational awareness in a healthcare environment. Drawing on literature from the fire service and military, the review will explore approaches to improving communication and situational awareness for teams who, at times, are unfamiliar with one another. The review will consider human factors and, identify approaches that assist teams, including teams that are unfamiliar with one another, to adapt to new ways of working while performing high-risk procedures. CONCLUSION: Literature indicates that standardisation, pre-brief and training are important elements of developing improved situational awareness and team working in individuals whose senses may be affected by PPE. In addition, checklists provide a useful way of standardising procedures and can form the basis of a structured pre-brief. Checklists exist for both intubation and patient proning, which, alongside simulation-based team training, provide a useful method of preparing an often unfamiliar workforce for their roles during an epidemic or pandemic. The multi-phase nature of most pandemics provides an opportunity to review processes and implement such procedures, and to develop staff using team-based training during the post-peak period.

AN ASSESSMENT OF THE CONTRACTILE PROPERTIES OF THE SHOULDER MUSCULATURE IN ELITE VOLLEYBALL PLAYERS USING TENSIOMYOGRAPHY.

BACKGROUND: In volleyball, offensive (Hitters) and defensive players (Non-Hitters) perform differing actions that vary both kinematically and in terms of intensity. This may impose contrasting demands on the musculature involved in performing these actions. Previous research has identified differences in the muscle activation and contractile properties of the lower-body musculature between positions. Additionally, asymmetries between dominant and non-dominant limbs of the upper-body musculature has been observed in athletes performing overhead movements. PURPOSE: The aim of this study was to use Tensiomyography (TMG) to examine the contractile properties of the shoulder musculature in elite volleyball players. STUDY DESIGN: Cross-sectional study. METHODS: Thirty-one elite volleyball players participated in this study (Age: 23 ± 2 yrs, Body Mass: 76.5 ± 9.8 kg, Stature: 181 ± 9.3 cm), 26 of which displayed right-limb dominance and five displayed left-limb dominance. Contractile properties of the shoulder musculature including the anterior deltoid (AD), biceps brachii (BB), posterior deltoid (PD), and the upper trapezius (UT) were assessed bilaterally using TMG measures on one occasion prior to any training or exercise. The contractile measures provided by TMG included the maximal displacement (Dm), contraction time (Tc), delay time (Td), sustain time (Ts), and the relaxation time (Tr). RESULTS: No statistically significant differences were observed between positions or limbs, except that Hitters displayed a significantly lower Ts of the left AD compared to Non-hitters (p = 0.01, ES = 1.02), and significant differences between dominant and non-dominant sides in the Td of the UT in Non-hitters were present (p = 0.05, ES = 0.8). CONCLUSION: These data suggest that irrespective of playing position and limb dominance, contractile properties of the shoulder musculature in elite volleyball players, as measured using TMG, display few significant differences. LEVELS OF EVIDENCE: 3b.

Critical Incident Techniques and Reflection in Nursing and Health Professions Education: Systematic Narrative Review.

BACKGROUND: The terms critical incident technique and reflection are widely used but often not fully explained, resulting in ambiguity. PURPOSE: The aims of this review were to map and describe existing approaches to recording or using critical incidents and reflection in nursing and health professions literature over the last decade; identify challenges, facilitating factors, strengths, and weaknesses; and discuss relevance for nursing education. METHODS: A systematic narrative review was undertaken. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature were searched using MeSH terms, returning 223 articles (2006-2017). After exclusions, 41 were reviewed. RESULTS: Articles were categorized into 3 areas: descriptions of the development of an original tool or model, critical incidents or reflection on events used as a learning tool, and personal reflections on critical incidents. CONCLUSIONS: Benefits have been identified in all areas. More attention is needed to the pedagogy of reflection and the role of educators in reflection.

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.

Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.