H3K56 acetylation affects Candida albicans morphology and secreted soluble factors interacting with the host.

In recent years, epigenetics has been revealed as a mechanism able to modulate the expression of virulence traits in diverse pathogens, including Candida albicans. Indeed, epigenetic regulation can sense environmental changes, leading to the rapid and reversible modulation of gene expression with consequent adaptation to novel environments. How epigenetic changes can impact expression and signalling output, including events associated with mechanisms of morphological transition and virulence, is still poorly studied. Here, using nicotinamide as a sirtuin inhibitor, we explored how the accumulation of the H3K56 acetylation, the most prominent histone acetylation in C. albicans, might affect its interaction with the host. Our experiments demonstrate that H3K56 acetylation profoundly affects the production and/or secretion of soluble factors compromising actin remodelling and cytokine production. ChIP- and RNA-seq analyses highlighted a direct impact of H3K56 acetylation on genes related to phenotypic switching, biofilm formation and cell aggregation. Direct and indirect regulation also involves genes related to cell wall protein biosynthesis, ß-glucan and mannan exposure, and hydrolytic secreted enzymes, supporting the hypothesis that the fluctuations of H3K56 acetylation in C. albicans might impair the macrophage response to the yeast and thus promote the host-immune escaping.

Ten simple rules to make computable knowledge shareable and reusable.

Computable biomedical knowledge (CBK) is: "the result of an analytic and/or deliberative process about human health, or affecting human health, that is explicit, and therefore can be represented and reasned upon using logic, formal standards, and mathematical approaches." Representing biomedical knowledge in a machine-interpretable, computable form increases its ability to be discovered, accessed, understood, and deployed. Computable knowledge artifacts can greatly advance the potential for implementation, reproducibility, or extension of the knowledge by users, who may include practitioners, researchers, and learners. Enriching computable knowledge artifacts may help facilitate reuse and translation into practice. Following the examples of 10 Simple Rules papers for scientific code, software, and applications, we present 10 Simple Rules intended to make shared computable knowledge artifacts more useful and reusable. These rules are mainly for researchers and their teams who have decided that sharing their computable knowledge is important, who wish to go beyond simply describing results, algorithms, or models via traditional publication pathways, and who want to both make their research findings more accessible, and to help others use their computable knowledge. These rules are roughly organized into 3 categories: planning, engineering, and documentation. Finally, while many of the following examples are of computable knowledge in biomedical domains, these rules are generalizable to computable knowledge in any research domain.

An Integrated Multilevel Approach Unveils Complex Seed-Nanoparticle Interactions and Their Implications for Seed Priming.

Nanotechnology has the potential to revolutionize agriculture with the introduction of engineered nanomaterials. However, their use is hindered by high cost, marginal knowledge of their interactions with plants, and unpredictable effects related to massive use in crop cultivation. Nanopriming is an innovative seed priming technology able to match economic, agronomic, and environmental needs in agriculture. The present study was focused on unveiling, by a multilevel integrated approach, undisclosed aspects of seed priming mediated by iron oxide magnetic nanoparticles in pepper seeds (Capsicum annuum), one of the most economically important crops worldwide. Inductively coupled plasma atomic emission mass spectrometry and scanning electron microscopy were used to quantify the MNP uptake and assess seed surface changes. Magnetic resonance imaging mapped the distribution of MNPs prevalently in the seed coat. The application of MNPs significantly enhanced the root and vegetative growth of pepper plants, whereas seed priming with equivalent Fe concentrations supplied as FeCl3 did not yield these positive effects. Finally, global gene expression by RNA-sequencing identified more than 2,200 differentially expressed genes, most of them involved in plant developmental processes and defense mechanisms. Collectively, these data provide evidence on the link between structural seed changes and an extensive transcriptional reprogramming, which boosts the plant growth and primes the embryo to cope with environmental challenges that might occur during the subsequent developmental and growth stages.

Effects of Hst3p inhibition in Candida albicans: a genome-wide H3K56 acetylation analysis.

Candida spp. represent the third most frequent worldwide cause of infection in Intensive Care Units with a mortality rate of almost 40%. The classes of antifungals currently available include azoles, polyenes, echinocandins, pyrimidine derivatives, and allylamines. However, the therapeutical options for the treatment of candidiasis are drastically reduced by the increasing antifungal resistance. The growing need for a more targeted antifungal therapy is limited by the concern of finding molecules that specifically recognize the microbial cell without damaging the host. Epigenetic writers and erasers have emerged as promising targets in different contexts, including the treatment of fungal infections. In C. albicans, Hst3p, a sirtuin that deacetylates H3K56ac, represents an attractive antifungal target as it is essential for the fungus viability and virulence. Although the relevance of such epigenetic regulator is documented for the development of new antifungal therapies, the molecular mechanism behind Hst3p-mediated epigenetic regulation remains unrevealed. Here, we provide the first genome-wide profiling of H3K56ac in C. albicans resulting in H3K56ac enriched regions associated with Candida sp. pathogenicity. Upon Hst3p inhibition, 447 regions gain H3K56ac. Importantly, these genomic areas contain genes encoding for adhesin proteins, degradative enzymes, and white-opaque switching. Moreover, our RNA-seq analysis revealed 1330 upregulated and 1081 downregulated transcripts upon Hst3p inhibition, and among them, we identified 87 genes whose transcriptional increase well correlates with the enrichment of H3K56 acetylation on their promoters, including some well-known regulators of phenotypic switching and virulence. Based on our evidence, Hst3p is an appealing target for the development of new potential antifungal drugs.

Dashboards in Health Care Settings: Protocol for a Scoping Review.

BACKGROUND: Health care organizations increasingly depend on business intelligence tools, including "dashboards," to capture, analyze, and present data on performance metrics. Ideally, dashboards allow users to quickly visualize actionable data to inform and optimize clinical and organizational performance. In reality, dashboards are typically embedded in complex health care organizations with massive data streams and end users with distinct needs. Thus, designing effective dashboards is a challenging task and theoretical underpinnings of health care dashboards are poorly characterized; even the concept of the dashboard remains ill-defined. Researchers, informaticists, clinical managers, and health care administrators will benefit from a clearer understanding of how dashboards have been developed, implemented, and evaluated, and how the design, end user, and context influence their uptake and effectiveness. OBJECTIVE: This scoping review first aims to survey the vast published literature of "dashboards" to describe where, why, and for whom they are used in health care settings, as well as how they are developed, implemented, and evaluated. Further, we will examine how dashboard design and content is informed by intended purpose and end users. METHODS: In July 2020, we searched MEDLINE, Embase, Web of Science, and the Cochrane Library for peer-reviewed literature using a targeted strategy developed with a research librarian and retrieved 5188 results. Following deduplication, 3306 studies were screened in duplicate for title and abstract. Any abstracts mentioning a health care dashboard were retrieved in full text and are undergoing duplicate review for eligibility. Articles will be included for data extraction and analysis if they describe the development, implementation, or evaluation of a dashboard that was successfully used in routine workflow. Articles will be excluded if they were published before 2015, the full text is unavailable, they are in a non-English language, or they describe dashboards used for public health tracking, in settings where direct patient care is not provided, or in undergraduate medical education. Any discrepancies in eligibility determination will be adjudicated by a third reviewer. We chose to focus on articles published after 2015 and those that describe dashboards that were successfully used in routine practice to identify the most recent and relevant literature to support future dashboard development in the rapidly evolving field of health care informatics. RESULTS: All articles have undergone dual review for title and abstract, with a total of 2019 articles mentioning use of a health care dashboard retrieved in full text for further review. We are currently reviewing all full-text articles in duplicate. We aim to publish findings by mid-2022. Findings will be reported following guidance from the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. CONCLUSIONS: This scoping review will provide stakeholders with an overview of existing dashboard tools, highlighting the ways in which dashboards have been developed, implemented, and evaluated in different settings and for different end user groups, and identify potential research gaps. Findings will guide efforts to design and use dashboards in the health care sector more effectively. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34894.

Categorizing metadata to help mobilize computable biomedical knowledge.

INTRODUCTION: Computable biomedical knowledge artifacts (CBKs) are digital objects conveying biomedical knowledge in machine-interpretable structures. As more CBKs are produced and their complexity increases, the value obtained from sharing CBKs grows. Mobilizing CBKs and sharing them widely can only be achieved if the CBKs are findable, accessible, interoperable, reusable, and trustable (FAIR+T). To help mobilize CBKs, we describe our efforts to outline metadata categories to make CBKs FAIR+T. METHODS: We examined the literature regarding metadata with the potential to make digital artifacts FAIR+T. We also examined metadata available online today for actual CBKs of 12 different types. With iterative refinement, we came to a consensus on key categories of metadata that, when taken together, can make CBKs FAIR+T. We use subject-predicate-object triples to more clearly differentiate metadata categories. RESULTS: We defined 13 categories of CBK metadata most relevant to making CBKs FAIR+T. Eleven of these categories (type, domain, purpose, identification, location, CBK-to-CBK relationships, technical, authorization and rights management, provenance, evidential basis, and evidence from use metadata) are evident today where CBKs are stored online. Two additional categories (preservation and integrity metadata) were not evident in our examples. We provide a research agenda to guide further study and development of these and other metadata categories. CONCLUSION: A wide variety of metadata elements in various categories is needed to make CBKs FAIR+T. More work is needed to develop a common framework for CBK metadata that can make CBKs FAIR+T for all stakeholders.

Clinical Decision Support Systems in Otolaryngology-Head and Neck Surgery: A State of the Art Review.

OBJECTIVE: To offer practical, evidence-informed knowledge on clinical decision support systems (CDSSs) and their utility in improving care and reducing costs in otolaryngology-head and neck surgery. This primer on CDSSs introduces clinicians to both the capabilities and the limitations of this technology, reviews the literature on current state, and seeks to spur further progress in this area. DATA SOURCES: PubMed/MEDLINE, Embase, and Web of Science. REVIEW METHODS: Scoping review of CDSS literature applicable to otolaryngology clinical practice. Investigators identified articles that incorporated knowledge-based computerized CDSSs to aid clinicians in decision making and workflow. Data extraction included level of evidence, Osheroff classification of CDSS intervention type, otolaryngology subspecialty or domain, and impact on provider performance or patient outcomes. CONCLUSIONS: Of 3191 studies retrieved, 11 articles met formal inclusion criteria. CDSS interventions included guideline or protocols support (n = 8), forms and templates (n = 5), data presentation aids (n = 2), and reactive alerts, reference information, or order sets (all n = 1); 4 studies had multiple interventions. CDSS studies demonstrated effectiveness across diverse domains, including antibiotic stewardship, cancer survivorship, guideline adherence, data capture, cost reduction, and workflow. Implementing CDSSs often involved collaboration with health information technologists. IMPLICATIONS FOR PRACTICE: While the published literature on CDSSs in otolaryngology is finite, CDSS interventions are proliferating in clinical practice, with roles in preventing medical errors, streamlining workflows, and improving adherence to best practices for head and neck disorders. Clinicians may collaborate with information technologists and health systems scientists to develop, implement, and investigate the impact of CDSSs in otolaryngology.

Integrating Lean Thinking and Implementation Science Determinants Checklists for Quality Improvement: A Scoping Review.

It is not known how often lean tools and implementation determinants frameworks or checklists are used concurrently in health care quality improvement activities. The authors systematically reviewed the literature for studies that used a lean tool along with an implementation science determinants framework (January 1999 through August 2018). Seven studies (8 publications) were identified, inclusive of 2 protocols and 6 research articles across multiple continents. All included studies used the consolidated framework for implementation research as their implementation science determinants framework. Lean tools included in more than 1 publication were process mapping (4 publications), process redesign (3 publications), and 5S standardization (2 publications). Only 1 study proposed using a lean tool concurrently with an implementation science determinants framework in the design and execution of the QI project. Few published studies utilize both an implementation science determinants framework or checklist and 1 or more lean tool in their study design.

The Impact Of Structured Exercise Programs On Metabolic Syndrome And Its Components: A Systematic Review.

BACKGROUND: The metabolic syndrome (MetS) is highly prevalent and associated with higher risk of diabetes and cardiovascular events. Exercise programs have been shown to improve components of MetS, but the optimal design of a structured exercise program for treatment of the MetS remains unclear. PURPOSE: To assess the impact of different exercise programs on the MetS and its components. METHODS: MEDLINE via PubMed and Embase was searched. Randomized controlled trials of supervised exercise alone and in combination with nutrition programs compared with usual care in adults with the MetS were selected. Two authors independently reviewed articles to select eligible studies and performed data abstraction. Eight studies representing 1218 patients were included. The participants had a median age of 51, median BMI of 29 kg/m2, and were 55% male. Mean weight loss increased with program duration. For combination programs, the mean weight loss was -2.6 kg, -3.7 kg, and -6.5 kg for 3, 6, and 12 months, respectively. The components of the MetS most frequently statistically significantly improved were waist circumference (6/6 studies), blood pressure (4/6 studies), and high-density lipoprotein cholesterol (3/6 studies). LIMITATIONS: Studies did not include long-term follow-up post program completion to evaluate persistence of benefit. It is unknown whether the same results would be found in an older, more obese population. CONCLUSION: Supervised exercise programs yield significant resolution of components of the MetS, particularly in reducing waist circumference. Longer program duration and frequent interval sessions appear to have highest benefit and thus may help reduce cardiovascular risk and diabetes associated with the MetS.

Molecular and Functional Characterization of the Somatic PIWIL1/piRNA Pathway in Colorectal Cancer Cells.

PIWI-like (PIWIL) proteins and small non-coding piRNAs, involved in genome regulation in germline cells, are found aberrantly expressed in human tumors. Gene expression data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the European Genome-Phenome Archive (EGA) indicate that the PIWIL1 gene is ectopically activated in a significant fraction of colorectal cancers (CRCs), where this is accompanied by promoter demethylation, together with germline factors required for piRNA production. Starting from this observation, the PIWIL/piRNA pathway was studied in detail in COLO 205 CRC cells, which express significant levels of this protein, to investigate role and significance of ectopic PIWIL1 expression in human tumors. RNA sequencing and cell and computational biology led to the demonstration that PIWIL1 localizes in a nuage-like structure located in the perinuclear region of the cell and that a significant fraction of the piRNAs expressed in these cells are methylated, and, therefore, present in an active form. This was further supported by RNA immunoprecipitation, which revealed how several piRNAs can be found loaded into PIWIL1 to form complexes also comprising their target mRNAs. The mature transcripts associated with the PIWIL-piRNA complex encode key regulatory proteins involved in the molecular mechanisms sustaining colorectal carcinogenesis, suggesting that the PIWI/piRNA pathway may actively contribute to the establishment and/or maintenance of clinico-pathological features of CRCs.

Globalization and changing trends of biomedical research output.

The US continues to lead the world in research and development (R&D) expenditures, but there is concern that stagnation in federal support for biomedical research in the US could undermine the leading role the US has played in biomedical and clinical research discoveries. As a readout of research output in the US compared with other countries, assessment of original research articles published by US-based authors in ten clinical and basic science journals during 2000 to 2015 showed a steady decline of articles in high-ranking journals or no significant change in mid-ranking journals. In contrast, publication output originating from China-based investigators, in both high- and mid-ranking journals, has steadily increased commensurate with significant growth in R&D expenditures. These observations support the current concerns of stagnant and year-to-year uncertainty in US federal funding of biomedical research.

Early Versus Delayed Feeding in Patients With Acute Pancreatitis: A Systematic Review.

BACKGROUND: Acute pancreatitis is among the most common and costly reasons for hospitalization in the United States. Bowel rest, pain control, and intravenous fluids are the cornerstones of treatment, but early feeding might also be beneficial. PURPOSE: To compare length of hospital stay, mortality, and readmission in adults hospitalized with pancreatitis who received early versus delayed feeding. DATA SOURCES: MEDLINE via Ovid, EMBASE, the Cochrane Library, CINAHL, and Web of Science through January 2017. STUDY SELECTION: Two authors independently reviewed and selected studies if they were randomized clinical trials, included adults hospitalized with acute pancreatitis, and compared early versus delayed feeding (≤48 vs. >48 hours after hospitalization). DATA EXTRACTION: Two investigators independently extracted study data and rated risk of bias using the Cochrane Collaboration tool. DATA SYNTHESIS: Eleven randomized trials (8 peer-reviewed publications, 3 abstract-only presentations) that included 948 patients were eligible. Seven trials (3 with low risk of bias) enrolled patients with mild to moderate pancreatitis. Four trials (1 with low risk of bias) included patients with predicted severe pancreatitis. Routes used for early feeding included oral (4 studies), nasogastric (2 studies), nasojejunal (4 studies), and oral or nasoenteric (1 study). Among patients with mild to moderate pancreatitis, early feeding was associated with reduced length of stay in 4 of 7 studies (including 2 of 3 with low risk of bias). Other outcomes were heterogeneous and variably reported, but no study showed an increase in adverse events with early feeding. Among patients with severe pancreatitis, limited evidence revealed no statistically significant difference in outcomes between early and delayed feeding. LIMITATION: Heterogeneity of feeding protocols and outcomes, scant data, and unclear or high risk of bias in several studies. CONCLUSION: Limited data suggest that early feeding in patients with acute pancreatitis does not seem to increase adverse events and, for patients with mild to moderate pancreatitis, may reduce length of hospital stay. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42015016193).

Are antimicrobial peripherally inserted central catheters associated with reduction in central line-associated bloodstream infection? A systematic review and meta-analysis.

BACKGROUND: Antimicrobial peripherally inserted central catheters (PICCs) may reduce the risk of central line-associated bloodstream infection (CLABSI). However, data regarding efficacy are limited. We aimed to evaluate whether antimicrobial PICCs are associated with CLABSI reduction. METHODS: MEDLINE, EMBASE, CINHAL, and Web of Science were searched from inception to July 2016; conference proceedings were searched to identify additional studies. Study selection and data extraction were performed independently by 2 authors. RESULTS: Of 597 citations identified, 8 studies involving 12,879 patients met eligibility criteria. Studies included adult and pediatric patients from intensive care, long-term care, and general ward settings. The incidence of CLABSI in patients with antimicrobial PICCs was 0.2% (95% confidence interval [CI], 0.0%-0.5%), and the incidence among nonantimicrobial catheters was 5.3% (95% CI, 2.6%-8.8%). Compared with noncoated PICCs, antimicrobial PICCs were associated with a significant reduction in CLABSI (relative risk [RR], 0.29; 95% CI, 0.10-0.78). Statistical heterogeneity (I2, 71.6%; T2 = 1.07) was resolved by publication type, with peer-reviewed articles showing greater reduction in CLABSI (RR, 0.21; 95% CI, 0.06-0.74). Twenty-six patients (95% CI, 21-75) need to be treated with antimicrobial PICCs to prevent 1 CLABSI. Studies of adults at greater baseline risk of CLABSI experienced greater reduction in CLABSI (RR, 0.20; P = .003). CONCLUSIONS: Available evidence suggests that antimicrobial PICCs may reduce CLABSI, especially in high-risk subgroups. Randomized trials are needed to assess efficacy across patient populations.

International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology.

Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.

Use of decision aids for shared decision making in venous thromboembolism: A systematic review.

BACKGROUND: Optimal care of patients with venous thromboembolism requires the input of patient preferences into clinical decision-making. However, the availability and impact of decision aids to facilitate shared decision making in care of venous thromboembolism is not well known. OBJECTIVES: To assess the availability, clinical impact and outcomes associated with the use of decision aids in patients with or at risk for venous thromboembolism. PATIENTS/METHODS: A systematic review of the literature was performed exploring the use of decision aids in patients with venous thromboembolism. Criteria for primary inclusion required use of patient values clarification in the decision aid. A secondary review without the requirement of a patient values clarification was performed to be more inclusive. The data was summarized such that knowledge gaps and opportunities for enquiry were identified. RESULTS: The primary review identified one study that explored the decision to extend anticoagulation in patients with a recent venous thromboembolism beyond the stipulated 3-month duration. The secondary review identified an additional study exploring the decision to undergo computer tomography testing in patients at low risk for pulmonary embolism in an emergency department setting. Both studies were of modest quality given a lack of control group for comparison analysis. CONCLUSIONS: Despite numerous calls to increase use of shared decision-making, a paucity of data exists to help patients engage in the treatment decisions for venous thromboembolism. Future studies of additional VTE clinical decisions with longer-term clinical outcomes appear necessary.

Internet-Delivered Cognitive Behavioral Therapy to Treat Insomnia: A Systematic Review and Meta-Analysis.

BACKGROUND: Insomnia is of major public health importance. While cognitive behavioral therapy is beneficial, in-person treatment is often unavailable. We assessed the effectiveness of internet-delivered cognitive behavioral therapy for insomnia. OBJECTIVES: The primary objectives were to determine whether online cognitive behavioral therapy for insomnia could improve sleep efficiency and reduce the severity of insomnia in adults. Secondary outcomes included sleep quality, total sleep time, time in bed, sleep onset latency, wake time after sleep onset, and number of nocturnal awakenings. DATA SOURCES: We searched PubMed/MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo, Cochrane Library, Embase, and the Web of Science for randomized trials. METHODS: Studies were eligible if they were randomized controlled trials in adults that reported application of cognitive behavioral therapy for insomnia via internet delivery. Mean differences in improvement in sleep measures were calculated using the Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis. RESULTS: We found 15 trials, all utilizing a pretest-posttest randomized control group design. Sleep efficiency was 72% at baseline and improved by 7.2% (95% CI: 5.1%, 9.3%; p<0.001) with internet-delivered cognitive behavioral therapy versus control. Internet-delivered cognitive behavioral therapy resulted in a decrease in the insomnia severity index by 4.3 points (95% CI: -7.1, -1.5; p = 0.017) compared to control. Total sleep time averaged 5.7 hours at baseline and increased by 20 minutes with internet-delivered therapy versus control (95% CI: 9, 31; p = 0.004). The severity of depression decreased by 2.3 points (95% CI: -2.9, -1.7; p = 0.013) in individuals who received internet-delivered cognitive behavioral therapy compared to control. Improvements in sleep efficiency, the insomnia severity index and depression scores with internet-delivered cognitive behavioral therapy were maintained from 4 to 48 weeks after post-treatment assessment. There were no statistically significant differences between sleep efficiency, total sleep time, and insomnia severity index for internet-delivered versus in-person therapy with a trained therapist. CONCLUSION: In conclusion, internet-delivered cognitive behavioral therapy is effective in improving sleep in adults with insomnia. Efforts should be made to educate the public and expand access to this therapy. Registration Number, Prospero: CRD42015017622.