Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.

Mast cells have traditionally been associated with allergic inflammatory responses; however, they play important roles in cutaneous innate immunity and wound healing. The Hidradenitis Suppurativa tissue transcriptome is associated with alterations in innate immunity and wound healing-associated pathways; however, the role of mast cells in the disease is unexplored. We demonstrate that mast cell-associated gene expression (using whole tissue RNAseq) is upregulated, and in-silico cellular deconvolution identifies activated mast cells upregulated and resting mast cells downregulated in lesional tissue. Tryptase/Chymase positive mast cells (identified using IHC) localize adjacent to epithelialized tunnels, fibrotic regions of the dermis and at perivascular sites associated with Neutrophil Extracellular Trap formation and TNF-alpha production. Treatment with Spleen Tyrosine Kinase antagonist (Fostamatinib) reduces the expression of mast cell-associated gene transcripts, associated biochemical pathways and the number of tryptase/chymase positive mast cells in lesional hidradenitis suppurativa tissue. This data indicates that although mast cells are not the most abundant cell type in Hidradenitis Suppurativa tissue, the dysregulation of mast cells is paralleled with B cell/plasma cell inflammation, inflammatory epithelialized tunnels and epithelial budding. This provides an explanation as to the mixed inflammatory activation signature seen in HS, the correlation with dysregulated wound healing and potential pathways involved in the development of epithelialized tunnels.

Baseline clinical, hormonal and molecular markers associated with clinical response to IL-23 antagonism in hidradenitis suppurativa: A prospective cohort study.

Hidradenitis suppurativa is a complex inflammatory disease in which predicting therapeutic response remains challenging. IL-23 interacts with sex hormones but the relationships between the two in HS remains uninvestigated. To assess whether baseline clinical, hormonal or molecular markers are associated with clinical response to IL-23 antagonism with risankizumab in hidradenitis suppurativa. Twenty six individuals with Hurley stage 2/3 disease were administered risankizumab 150 mg Week 0, 4, 12. Baseline sex hormones and skin biopsies were taken. Clinical response at Week 16 assessed by the HiSCR, and differences between responders and non-responders assessed. Eighteen of 26 participants achieved HiSCR50 at week 16 (69.2%). Clinical response to IL-23 antagonism was associated with male gender, elevated total serum testosterone and decreased levels of FSH. Stratification by clinical responders/nonresponders identified differentially expressed genes including PLPP4 and MAPK10. Immunohistochemistry identified elevated numbers of CD11c, IL-17A and IL-17F positive cells compared to nonresponders. CD11c + cells significantly correlated with serum levels of total testosterone and inversely correlated with serum FSH. Clinical response to IL-23 antagonism in HS is associated with serum sex hormones, Th17 polarized inflammation in lesional tissue and CD11c + cells. These potential therapeutic biomarkers require further validation in larger cohorts but may suggest potential targeted HS therapy.

Evaluating structured assessment of anaesthesiologists' non-technical skills.

BACKGROUND: Non-technical skills (NTS) are essential for safe and efficient anaesthesia. Assessment instruments with appropriate validity evidence can be used to ensure that anaesthesiologists possess the NTS necessary to deliver high-standard patient care. The aims were to collect validity evidence using a contemporary validity framework for the assessment instrument Anaesthesiologists' Non-Technical Skills in Denmark (ANTSdk) regarding response process and internal structure (including reliability), and to investigate the effect of rater training on these properties. METHODS: An explorative study was undertaken at the Danish Institute for Medical Simulation, Copenhagen, Denmark. In a 1-day session, using ANTSdk, a convenience sample of 19 anaesthesiologists rated trainee anaesthesiologists' NTS in nine video-recorded simulation scenarios before and after a 3-h training session. RESULTS: Response process evidence: participants considered ANTSdk useful and feasible for NTS assessment. Internal structure evidence: inter-rater reliability (single measures) largely expressed substantial agreement (ICC ≥ 0.55 and ICC ≥ 0.60 for pre- and post-training ratings respectively). Strong internal consistency of ratings was found (Spearman's correlation coefficient ≥ 0.82). Accuracy of participants' ratings compared with reference ratings (± 1 scale point) was notable (76% and 78% for pre- and post-training ratings, respectively). The results indicate that the elements 'Demonstrating self-awareness', 'Reassessing decisions', 'Assessing competencies', and 'Supporting others' need more attention in future rater training. CONCLUSION: The validity evidence collected on content, response process, and internal structure, suggests that ANTSdk is easy to use on video-recorded simulation scenarios, indicating that ANTSdk is a feasible instrument for NTS assessment during anaesthesia training.

Exploring the relationship between anaesthesiologists' non-technical and technical skills.

BACKGROUND: A combination of non-technical skills (NTS) and technical skills (TS) is crucial for anaesthetic patient management. However, a deeper understanding of the relationship between these two skills remains to be explored. We investigated the characteristics of trainee anaesthesiologists' NTS and TS in a simulated unexpected difficult airway management scenario. METHODS: A mixed-method approach was used to explore the relationship between NTS and TS in 25 videos of 2nd year trainee anaesthesiologists managing a simulated difficult airway scenario. The videos were assessed using the customised version of the Anaesthetists' Non-Technical Skills System, ANTSdk, and an adapted TS checklist for calculating the correlation between NTS and TS. Written descriptions of the observed NTS were analysed using directed content analysis. RESULTS: The correlation between the NTS and the TS ratings was 0.106 (two-tailed significance of 0.613). Inter-rater reliability was substantial. Themes characterising good NTS included a systematic approach, planning and communicating decisions as well as responding to the evolving situation. A list of desirable, concrete NTS for the specific airway management situation was generated. CONCLUSION: This study illustrates that anaesthesiologist trainees' NTS and TS were not correlated in this setting, but rather intertwined and how the interplay of NTS and TS can impact patient management. Themes describing the characteristics of NTS and a list of desirable, concrete NTS were developed to aid the understanding, training and use of NTS.

Assessing Nurse Anaesthetists' Non-Technical Skills in the operating room.

BACKGROUND: Incident reporting and fieldwork in operating rooms have shown that some of the errors that arise in anaesthesia relate to inadequate use of non-technical skills. To provide a tool for training and feedback on nurse anaesthetists' non-technical skills, this study aimed to adapt the Anaesthetists' Non-Technical Skills (ANTS) as a behavioural marker system for the formative assessment of nurse anaesthetists' non-technical skills in the operating room. METHODS: A qualitative approach with focus group interviews was used to identify the non-technical skills of nurse anaesthetists in the operating room. The interview data were transcribed verbatim. Directed content analysis was used to code and sort data deductively into the ANTS categories: task management, team working, situation awareness and decision making. The prototype named Nurse Anaesthetists' Non-Technical Skills (N-ANTS) was presented and discussed in a group of subject matter experts to ensure face validity. RESULTS: The N-ANTS system consists of the same four categories as ANTS and 15 underlying elements. Three to five good and poor behavioural markers for each element were identified. The headings and definitions of the categories and elements were adjusted to encompass the behavioural markers in N-ANTS. The differences that emerged mainly reflected statements regarding the establishment of role, competence, and task delegation. CONCLUSION: A behavioural marker system, N-ANTS, for nurse anaesthetists was adapted from a behavioural marker system, ANTS, for anaesthesiologists.

Effect of heterologous expression of acyl-CoA-binding protein on acyl-CoA level and composition in yeast.

We have expressed a bovine synthetic acyl-CoA-binding protein (ACBP) gene in yeast (Saccharomyces cerevisiae) under the control of the GAL1 promoter. The heterologously expressed bovine ACBP constituted up to 6.4% of total cellular protein and the processing was identical with that of native bovine ACBP, i.e. the initiating methionine was removed and the following serine residue was N-acetylated. The expression of this protein did not affect the growth rate of the cells. Determination of the yeast acyl-CoA pool size showed a close positive correlation between the ACBP content of the cells and the size of the acyl-CoA pool. Thus ACBP can act as an intracellular acyl-CoA pool former. Possible physiological functions of ACBP in cells are discussed.