Resilient healthcare theory as a lens to research emergency department operations: a protocol for a scoping review

Introduction Emergency departments (EDs) are complex systems that have constant fluctuations in demand, creating mismatches with planned capacity. Despite the complexity of ED operations, quality and safety improvement are often approached in a reactive, linear and reductionist manner. There is increasing interest in adopting Resilient Healthcare (RHC) techniques based on complex systems thinking as a method for quality improvement and research in EDs. However, the evidence for this approach is still developing and it is not clear what techniques have been used so far and which are most effective. This scoping review will be conducted between March 2022 until May 2022. It seeks to examine the international literature for available reports that have adopted RHC theory to study ED operations and identify approaches used and proposed benefits. Methods and analysis The methodology for scoping reviews outlined by Arksey and O’Malley (2005) will be followed, acknowledging refinements made to the scoping review process by Levac et al (2010). The methodology consists of five steps: (1) identifying the research question; (2) identifying the relevant literature; (3) study selection; (4) charting the data; and (5) collating, summarising and reporting the results. A two-stage approach will be undertaken to synthesise and report results: (1) numerical analysis of the nature and distribution of studies (the overall number of studies, country of origin, the most studied core function of ED, type of research design); and (2) a thematic mapping of the literature. Ethics and dissemination Scoping review methodology synthesises published data and, therefore, does not require ethical approval. An article formatted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses forScoping Reviews reporting guidance will be submitted for publication to a scientific journal. Findings will also be presented at relevant advanced practice conferences and disseminated within clinical and academic groups

Helios is a key transcriptional regulator of outer hair cell maturation

The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity

Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery.

High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target proteins or other strategies to provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative ligand-observed NMR assay, which can determine Kd values of fragments in the affinity range of low μM to low mM using transverse relaxation rate R2 as the observable parameter. In this study, we examined the theory and proposed a mathematical formulation to obtain Kd values using non-linear regression analysis. We designed an assay format with automated sample preparation and simplified data analysis. Using tool compounds, we explored the assay reproducibility, accuracy, and detection limits. Finally, we used this assay to triage fragment hits, yielded from fragment screening against the CRBN/DDB1 complex

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss