Delirium represents a significant health care burden, diagnosed in more than 2 million elderly Americans each year. In the surgical population, delirium remains the most common complication among elderly patients, and is associated with longer hospital stays, higher costs of care, increased mortality, and functional impairment. The pathomechanism of disease is poorly understood, with current diagnostic approaches somewhat subjective and arbitrary, and definitive diagnostic biomarkers are currently lacking. Despite the recent interest in delirium research, biomarker discovery for it remains new. Most attempts to discover biomarkers are targeted studies that seek to assess the involvement of one or more members of a focused panel of candidates in delirium. For a more unbiased, system-biology view, we searched literature from Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane Central, Web of Science, SCOPUS, and Dimensions between 2016 and 2021 for untargeted proteomic discovery studies for biomarkers of delirium conducted on human geriatric subjects. Two reviewers conducted an independent review of all search results and resolved discordance by consensus. From an overall search of 1172 publications, 8 peer-reviewed studies met our defined inclusion criteria. The 370 unique perioperative biomarkers identified in these reports are enriched in pathways involving activation of the immune system, inflammatory response, and the coagulation cascade. The most frequently identified biomarker was interleukin-6 (IL-6). By reviewing the distribution of protein biomarker candidates from these studies, we conclude that a panel of proteins, rather than a single biomarker, would allow for discriminating delirium cases from noncases. The paucity of hypothesis-generating studies in the peer-reviewed literature also suggests that a system-biology view of delirium pathomechanisms has yet to fully emerge.

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BackgroundSurvey research, indispensable for assessing subjective outcomes in anesthesiology, can nonetheless be challenging to undertake and interpret.ObjectiveTo present a user-friendly guide for the appraisal of survey-derived evidence, and to apply it to published survey research in the anesthesia literature.MethodsSynthesizing published expert guidance regarding methodology and reporting, we discuss five essential criteria (with subcomponents) for evaluating survey research: (1) relevance of survey outcome to research objective, (2) trustworthiness of the instrument (testing/validation, availability), (3) collecting information well (sampling, administration), (4) representativeness (response rate), and (5) guidance towards interpretation of survey findings (generalizability, interpretation of numerical outcomes). These criteria were subsequently applied by two independent assessors to original research articles reporting survey findings, published in the five highest impact general anesthesia journals (‘Anaesthesia’, ‘Anesthesia & Analgesia’, ‘Anesthesiology’, ‘British Journal of Anaesthesia’ and ‘European Journal of Anaesthesiology’) between July 01, 2016, and December 31, 2017, which were identified using a prespecified PubMed search strategy.ResultsAmong 1107 original articles published, we identified 97 reporting survey research either employing novel survey instruments (58%), established surveys (30%), or sets of single-item scores (12%). The extent to which reader-oriented benchmarks were achieved varied by component and between survey types. Results were particularly mixed for validation (mentioned for 41% of novel and 86% of established surveys) and discussion of generalizability (59% of novel survey reports, 45% of established surveys, and 17% of sets of single-item scores).ConclusionSurvey research is not uncommon in anesthesiology, frequently employs novel survey instruments, and demonstrates mixed results in terms of transparency and interpretability. We provide readers with a practical framework for critical interpretation of survey-derived outcomes.

Delirium represents a significant healthcare burden, diagnosed in over two million elderly Americans each year. In the surgical population, delirium remains the most common complication among elderly patients and is associated with longer hospital stays, higher costs of care, increased mortality and functional impairment. The pathomechanism of disease is poorly understood, with current diagnostic approaches somewhat subjective and arbitrary, and definitive diagnostic biomarkers are currently lacking. Despite the recent interest in delirium research, biomarker discovery for it remains new. Most attempts to discover biomarkers are targeted studies that seek to assess the involvement of one or more members of a focused panel of candidates in delirium. For a more unbiased, systems-biology view, we searched literature from MEDLINE, Cochrane Central, Web of Science, SCOPUS, and Dimensions between 2016 and 2021 for untargeted proteomic discovery studies for biomarkers of delirium conducted on human geriatric subjects. Two reviewers conducted independent review of all search results, and resolved discordance by concensus. From an overall search of 1172 publications, eight peer-reviewed studies met our defined inclusion criteria. The 370 unique peri-operative biomarkers identified in these reports are enriched in pathways involving the activation of the immune system, inflammatory response, and the coagulation cascade. IL-6 was the most commonly identified biomarker. By reviewing the distribution of protein biomarker candidates from these studies, we conclude that a panel of proteins, rather than a single biomarker, would allow for discriminating delirium cases from non-cases. The paucity of hypothesis-generating studies in the peer-reviewed literature also suggests that a systems-biology view of delirium pathomechanisms has yet to fully emerge.

Phosphorylation signaling is an essential post-translational regulatory mechanism that governs almost all eukaryotic biological processes and is controlled by an interplay between protein kinases and phosphatases. Knowledge of direct substrates of kinases provides evidence of mechanisms that relate activity to biological function. Linking kinases to their protein substrates can be achieved by inhibiting or reducing kinase activity and quantitative comparisons of phosphoproteomes in the presence and absence of kinase activity. Unfortunately, most of the human kinases lack chemical inhibitors with selectivity required to unambiguously assign protein substrates to their respective kinases. Here, we develop and validate a chemical proteomics strategy for linking kinase activities to protein substrates via targeted protein degradation and quantitative phosphoproteomics and apply it to the well-studied, essential mitotic regulator polo-like kinase 1 (Plk1). We leveraged the Tir1/auxin system to engineer HeLa cells with endogenously homozygous auxin-inducible degron (AID)-Plk1). We used HeLa cells and determined the impact of AID-tagging on Plk1 activity, localization, protein interactors, and substrate motifs. Using quantitative proteomics, we show that of over 8,000 proteins quantified, auxin addition is highly selective for degrading AID-Plk1 in mitotic cells. Comparison of phosphoproteome changes in response to chemical Plk1 inhibition to auxin-induced degradation revealed a striking degree of correlation. Finally, we explored basal protein turnover as a potential basis for clonal differences in auxin-induced degradation rates for AID-Plk1 cells. Taken together, our work provides a roadmap for the application of AID technology as a general strategy for the kinome-wide discovery of kinase-substrate relationships.