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While some speculation surrounds annual private practice incomes of anaesthetists, little is known of the hours of work needed to generate any presumed income (the hourly rate). The benefit maxima of five private medical insurers are published in fee schedules and data on the duration of common operations are now also known. In this study we combined these to generate estimates for hourly rates of reimbursement across 78 common operations in eight surgical subspecialties, for anaesthetists and surgeons. We expected to find significant differences between insurers as a result of market competition, and we expected differences between anaesthetists and surgeons. The median (IQR [range]) rate of reimbursement for anaesthetists was pound167 (132-211 [68-570]).h(-1) with significant variation across subspecialties (p < 0.001); for example, cardiac surgery was best reimbursed at pound283 (257-308 [229-398]).h(-1) and orthopaedics the least at pound146 (133-159 [81-246]).h(-1). Contrary to expectations, the rates of payment to anaesthetists by insurers were similar (p > 0.17). Patterns of reimbursement for surgeons were similar to those for anaesthetists, except that surgeons were reimbursed at about twice the rate. We conclude there is a confluence of insurer reimbursement levels and we discuss potential implications of this finding. Our results also have implications for how incentives between the NHS and private practice, or within a private practice group, might be optimally managed. [ABSTRACT FROM AUTHOR]

A simple algorithm has been produced to assist front line ground ambulance personnel, air ambulance crews, and immediate care doctors attending trauma patients in selecting the most appropriate mode of transport from the incident scene to hospital. [ABSTRACT FROM AUTHOR]

Abstract Background Inflammation in adipose tissue (AT) during obesity causes impaired AT function. Although multiple extracellular matrix (ECM) proteins are expressed in AT their potential role in adipose tissue inflammation is unclear. Biglycan, a pro-inflammatory ECM gene, is highly enriched in adipose tissue. However, whether it is correlated with adipose tissue inflammation is unknown. We provide evidence in support of a strong association between biglycan expression and inflammatory status of adipose tissue. Methods C57BL6 mice were fed either a control (10% fat calories) or a high fat diet (HFD) (60% fat calories) for 8 weeks. Adipose tissue was analyzed for the expression of biglycan, IL-6 and TNFα. Biglycan knockout or wild type were also fed a high fat diet for 8 weeks and the expression of inflammatory genes in the mesenteric adipose tissue was examined. To test anti-inflammatory treatment on biglycan expression, a group of mice were fed either the low fat or high fat diet for eight weeks supplemented with either saline or sodium salicylate @ 25mg/100ml in their drinking water. Results Mice on HFD had an increase in ECM genes (BGN and COL1A1), inflammatory genes (IL-6 and TNFα) in both the subcutaneous and epididymal depots. However, correlation analysis only shows a positive correlation between biglycan, IL-6 and TNFα expression. In addition, lower expression of IL-6 and CD68 was found in the mesenteric adipose tissue of biglycan knockout mice compared to the wild type. Sodium salicylate treatment reduced subcutaneous adipose tissue expression of BGN, COL1A1, and COL6A1 and a concurrent downregulation of TNFα and IL-6 and TLR4 expression. Salicylate also lowered the serum TGFβ1 levels. Conclusion Biglycan expression correlates with adipose tissue inflammation, especially in the subcutaneous depot compared to the epididymal depot. This is supported by the greater effect of sodium salicylate in attenuating both inflammatory and ECM gene expression the subcutaneous adipose depot compared to the epididymal depot. These results show that inflammatory state may explain the induction of biglycan, and perhaps, other ECM genes in adipose tissue.

Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, with personalized medicine, systems biology, and biomedical applications. The application of MS-based proteomics advances our understanding of protein function, cellular signaling, and complex biological systems. MS data analysis is a critical process that includes identifying and quantifying proteins and peptides and then exploring their biological functions in downstream analysis. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets with DIA-NN preinstalled. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analyses. ProtPipe provides downstream analyses, including protein and peptide differential abundance identification, pathway enrichment analysis, protein-protein interaction analysis, and Major histocompatibility complex (MHC) -peptide binding affinity analysis. ProtPipe generates annotated tables and visualizations by performing statistical postprocessing and calculating fold changes between predefined pairwise conditions in an experimental design. It is an open-source, well-documented tool available online at https://github.com/NIH-CARD/ProtPipe, with a user-friendly web interface., (Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Background/objectives: Predicting patient readmission is an important task for healthcare risk management, as it can help prevent adverse events, reduce costs, and improve patient outcomes. In this paper, we compare various conventional machine learning models and deep learning models on a multimodal dataset of electronic discharge records from an Irish acute hospital., Methods: We evaluate the effectiveness of several widely used machine learning models that leverage patient demographics, historical hospitalization records, and clinical diagnosis codes to forecast future clinical risks. Our work focuses on addressing two key challenges in the medical fields, data imbalance and the variety of data types, in order to boost the performance of machine learning algorithms. Furthermore, we also employ SHapley Additive Explanations (SHAP) value visualization to interpret the model predictions and identify both the key data features and disease codes associated with readmission risks, identifying a specific set of diagnosis codes that are significant predictors of readmission within 30 days., Results: Through extensive benchmarking and the application of a variety of feature engineering techniques, we successfully improved the area under the curve (AUROC) score from 0.628 to 0.7 across our models on the test dataset. We also revealed that specific diagnoses, including cancer, COPD, and certain social factors, are significant predictors of 30-day readmission risk. Conversely, bacterial carrier status appeared to have minimal impact due to lower case frequencies., Conclusions: Our study demonstrates how we effectively utilize routinely collected hospital data to forecast patient readmission through the use of conventional machine learning while applying explainable AI techniques to explore the correlation between data features and patient readmission rate.

Background: A near miss event (NME) in healthcare is an event that did not happen but would have caused serious harm if it did. The operating room (OR) is prone to risk and incidents, with estimates that 50% of all hospital adverse events occur in the OR, yet reporting of NME is uncommon in the OR., Objective: To carry out a systematic review of studies with mixed methods to establish what is known about NME reporting in the OR., Method: Inclusion criteria will be those studies of mixed methods design, which have been conducted in the OR, with teams of surgeons, anaesthetists or nurses alone or in any combination. Using a publication timeframe of 2001-2023, the following databases were searched: Medline (OVID), CINAHL, Pubmed and Google Scholar. Selected papers for the review were assessed using the Quality Assessment Tool for Studies of Diverse Designs., Results: Fourteen papers were included in the review. NMEs are common occurrences that are underreported in the OR. When NMEs occur in multiples for the same patient, the risk of serious harm increases. Feedback and education about NME helps to improve reporting; ORs with high rates of NME reporting have less serious patient harm events., Discussion: The implications of the findings for improving healthcare safety are discussed and in particular the adoption of the science of Human Factors Ergonomics into healthcare., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Innovative approaches are needed for managing risk and system change in healthcare. This paper presents a case study of a project that took place over two years, taking a systems approach to managing the risk of healthcare acquired infection in an acute hospital setting, supported by an Access Risk Knowledge Platform which brings together Human Factors Ergonomics, Data Science, Data Governance and AI expertise. Evidence for change including meeting notes and use of the platform were studied. The work on the project focused on first systematically building a rich picture of the current situation from a transdisciplinary perspective. This allowed for understanding risk in context and developing a better capability to support enterprise risk management and accountability. From there a linking of operational and risk data took place which led to mapping of the risk pattern in the hospital.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: People who interact with healthcare services have an ethical and legal right to control their own lives, to make informed decisions, and to consent to what happens to them. For consent to be considered ethically and legally valid, three key criteria must be met: consent must be given voluntarily; people must be sufficiently informed of all options; and people should have capacity to make the decision to give or withhold their consent., Aim: This study set out to explore, through the use of surveys, the perspectives of patients and public in relation to consent., Method: Surveys were developed for patients and the public and administered paper based (patients) and through social media (public)., Results: One hundred and forty surveys were posted to patients, with a 38% response rate; 104 responses were received from the public. Ninety-six percent of patients were satisfied that the decision they made was informed; 100% felt they had made a voluntary decision; 98% felt the clinician seemed knowledgeable about the procedure. What matters most to the public were being informed about the risks associated with the proposed procedure and being assured that whatever choice they make they will receive the best care possible., Conclusions: The results highlight interesting similarities and differences in relation to consent between members of the public thinking about a possible treatment, surgery, or procedure and those patients who have actually been through the process in the past 12 months. Recommendations have been developed on the basis of these findings to co-design improvements in consent practices., (© 2024. The Author(s).)

Introduction: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization., Methods: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling., Results: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways., Discussion: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity., Highlights: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objectives: People with disabilities, people experiencing homelessness, and people who have substance use disorders face unique health challenges. Gaps in public health surveillance data limit the identification of public health needs of these groups and data-driven action. This study aimed to identify current practices, challenges, and opportunities for collecting and reporting COVID-19 surveillance data for these populations., Methods: We used a rapid qualitative assessment to explore COVID-19 surveillance capacities. From July through October 2021, we virtually interviewed key informants from the Centers for Disease Control and Prevention, state and local health departments, and health care providers across the United States. We thematically analyzed and contextualized interview notes, peer-reviewed articles, and participant documents using a literature review., Results: We identified themes centered on foundational structural and systems issues that hinder actionable surveillance data for these and other populations that are disproportionately affected by multiple health conditions. Qualitative data analysis of 61 interviews elucidated 4 primary challenges: definitions and policies, resources, data systems, and articulation of the purpose of data collection to these groups. Participants noted the use of multisector partnerships, automated data collection and integration, and data scorecards to circumvent challenges., Conclusions: This study highlights the need for multisector, systematic improvements in surveillance data collection and reporting to advance health equity. Improvements must be buttressed with adequate investment in data infrastructure and promoted through clear communication of how data are used to protect health., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we developed a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrated that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We found that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a new mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protected mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a powerful platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and new focus for therapeutic intervention.

In neurons, RNA granules are transported along the axon for local translation away from the soma. Recent studies indicate that some of this transport involves hitchhiking of RNA granules on lysosome-related vesicles. In the present study, we leveraged the ability to prevent transport of these vesicles into the axon by knockout of the lysosome-kinesin adaptor BLOC-one-related complex (BORC) to identify a subset of axonal mRNAs that depend on lysosome-related vesicles for transport. We found that BORC knockout causes depletion of a large group of axonal mRNAs mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This depletion results in mitochondrial defects and eventually leads to axonal degeneration in human induced pluripotent stem cell (iPSC)-derived and mouse neurons. Pathway analyses of the depleted mRNAs revealed a mechanistic connection of BORC deficiency with common neurodegenerative disorders. These results demonstrate that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Safety Culture (SC) has become a key priority for safety improvement in healthcare. Studies have identified links between positive SC and improved patient outcomes. Mixed-method measurements of SC are needed to account for diverse social, cultural, and subcultural contexts within different healthcare settings. The aim of the study was to triangulate data on SC from three sources in an Intensive Care Unit (ICU) in a large acute teaching hospital. A mixed-methods approach was used, including analysing the Hospital Survey for Patient Safety Culture results, retrospective chart reviews using the Global Trigger Tool (GTT) for the ICU, and staff reporting of adverse events (AE). There was a 47% (101/216) response rate for the survey. Further, 98% of respondents stated a positive patient safety rating. The GTT identified 16 AEs and 11 AEs that were reported in the same timeframe. The triangulation of the data demonstrates the complexity of understanding components of SC in particular: learning, reporting, and just culture.

Background: The coronavirus disease 2019 (COVID-19) pandemic dramatically impacted the delivery of hospital care in terms of quality and safety., Objectives: To examine complaints from two time points, quarter 4 (Q4) 2019 (pre-pandemic) and Q4 2020 (second wave), and explore whether there was a difference in the frequency and/or content of complaints., Methods: A retrospective analysis of complaints from one Irish hospital was conducted using the Healthcare Complaints Analysis Tool (HCAT). Within each complaint, the content, severity, harm reported by the patient, and stage of care were categorised. The complaints were analysed using descriptive statistics and chi-square tests of independence., Results: There were 146 complaints received in Q4 2019 and 114 in Q4 2020. Complaint severity was significantly higher in Q4 2019 as compared to Q4 2020. However, there were no other significant differences. Institutional processes (e.g. staffing, resources) were the most common reason for complaints (30% in Q4 2019 and 36% in Q4 2020). The majority of complaints were concerned with care on the ward (23% in Q4 2019 and 31% in Q4 2020)., Conclusions: The severity of complaints was significantly higher in Q4 2019 than in Q4 2020, which requires further exploration as the reasons for this are unclear. The lack of a difference in the frequency and content of complaints during the two time periods was unexpected. However, this may be linked to a number of factors, including public support for the healthcare system, existing system-level issues in the hospital, or indeed increased staff collaboration in the context of the COVID-19 crisis., (© 2023. The Author(s).)

Background: Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear., Methods: We developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i 3 Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i 3 Neurons for the first time., Results: Leveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome's degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN-null i 3 Neurons and frontotemporal dementia patient-derived i 3 Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases., Conclusion: This study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of progranulin deficiency, these newly developed proteomic methods in neurons and brain tissues provided useful tools and data resources for the field to study the highly dynamic neuronal lysosome biology., (© 2023. The Author(s).)