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.

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.

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.

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.

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.

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.

Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation.

A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.

Identification of a peptide inhibitor for the histone methyltransferase WHSC1.

WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC50 = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC50 values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases.

Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor.

SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).

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.

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.

The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat.

Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.

Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates.

Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers. CARM1 is known to methylate histone H3 and nonhistone substrates. To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors, but no ternary structures with nucleoside and peptide substrates have been reported. Here, the crystal structures of human CARM1 with the S-adenosylmethione (SAM) mimic sinefungin and three different peptide sequences from histone H3 and PABP1 are presented, with both nonmethylated and singly methylated arginine residues exemplified. This is the first example of multiple substrate sequences solved in a single PRMT enzyme and demonstrates how the CARM1 binding site is capable of accommodating a variety of peptide sequences while maintaining a core binding mode for the unmethylated and monomethylated substrates. Comparison of these with other PRMT enzyme-peptide structures shows hydrogen bonding patterns that may be thematic of these binding sites.

Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound.

A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies.

EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.