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.

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).

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.

Evaluation of Pharmacologic Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Systematic Review.

BACKGROUND & AIMS: There is controversy over the efficacy of pharmacologic agents for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (PEP). We performed a systematic review of PEP pharmacoprevention to evaluate safety and efficacy. METHODS: We performed a systematic search of the literature for randomized controlled trials (RCTs) and meta-analyses of PEP pharmacoprevention through February 2014. After identifying relevant studies, 2 reviewers each extracted information on study characteristics, clinical outcomes, and risk of bias. A research classification scale was developed to identify pharmacologic agents ready for clinical use, agents for which a confirmatory RCT should be considered a high priority, agents for which exploratory studies are still necessary, and agents for which additional research should be of low priority. Clinical and research recommendations for each agent were made by consensus after considering research classification results and other important factors such as magnitude of benefit, safety, availability, and cost. RESULTS: After screening 851 citations and 263 potentially relevant articles, 2 reviewers identified 85 RCTs and 28 meta-analyses that were eligible. On the basis of these studies, rectal nonsteroidal anti-inflammatory drugs were found to be appropriate for clinical use, especially for high-risk cases. Sublingual nitroglycerin, bolus-administered somatostatin, and nafamostat were found to be promising agents for which confirmatory research is warranted. Additional research was found to be required to justify confirmatory RCTs for topical epinephrine, aggressive intravenous fluids, gabexate, ulinastatin, secretin, and antibiotics. CONCLUSIONS: On the basis of a systematic review, NSAIDs are appropriate for use in prevention of PEP, especially for high-risk cases. Additional research is necessary to clarify the role of other pharmacologic agents. These findings could inform future research and guide clinical decision-making and policy.

Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.

BACKGROUND: Comparative effectiveness data pertaining to competing colorectal cancer (CRC) screening tests do not exist but are necessary to guide clinical decision making and policy. OBJECTIVE: To perform a comparative synthesis of clinical outcomes studies evaluating the effects of competing tests on CRC-related mortality. DESIGN: Traditional and network meta-analyses. Two reviewers identified studies evaluating the effect of guaiac-based fecal occult blood testing (gFOBT), flexible sigmoidoscopy (FS), or colonoscopy on CRC-related mortality. INTERVENTIONS: gFOBT, FS, colonoscopy. MAIN OUTCOME MEASUREMENTS: Traditional meta-analysis was performed to produce pooled estimates of the effect of each modality on CRC mortality. Bayesian network meta-analysis (NMA) was performed to indirectly compare the effectiveness of screening modalities. Multiple sensitivity analyses were performed. RESULTS: Traditional meta-analysis revealed that, compared with no intervention, colonoscopy reduced CRC-related mortality by 57% (relative risk [RR] 0.43; 95% confidence interval [CI], 0.33-0.58), whereas FS reduced CRC-related mortality by 40% (RR 0.60; 95% CI, 0.45-0.78), and gFOBT reduced CRC-related mortality by 18% (RR 0.82; 95% CI, 0.76-0.88). NMA demonstrated nonsignificant trends favoring colonoscopy over FS (RR 0.71; 95% CI, 0.45-1.11) and FS over gFOBT (RR 0.74; 95% CI, 0.51-1.09) for reducing CRC-related deaths. NMA-based simulations, however, revealed that colonoscopy has a 94% probability of being the most effective test for reducing CRC mortality and a 99% probability of being most effective when the analysis is restricted to screening studies. LIMITATIONS: Randomized trials and observational studies were combined within the same analysis. CONCLUSION: Clinical outcomes studies demonstrate that gFOBT, FS, and colonoscopy are all effective in reducing CRC-related mortality. Network meta-analysis suggests that colonoscopy is the most effective test.

Flipping the classroom to teach systematic reviews: the development of a continuing education course for librarians.

OBJECTIVE: The researchers used the flipped classroom model to develop and conduct a systematic review course for librarians. SETTING: The research took place at an academic health sciences library. METHOD: A team of informationists developed and conducted a pilot course. Assessment informed changes to both course components; a second course addressed gaps in the pilot. MAIN RESULTS: Both the pilot and subsequent course received positive reviews. Changes based on assessment data will inform future iterations. CONCLUSION: The flipped classroom model can be successful in developing and implementing a course that is well rated by students.

Increased co-first authorships in biomedical and clinical publications: a call for recognition.

There has been a dramatic increase in the number and percentage of publications in biomedical and clinical journals in which two or more coauthors claim first authorship, with a change in some journals from no joint first authorship in 1990 to co-first authorship of >30% of all research publications in 2012. As biomedical and clinical research become increasingly complex and team-driven, and given the importance attributed to first authorship by grant reviewers and promotion and tenure committees, the time is ripe for journals, bibliographic databases, and authors to highlight equal first author contributions of published original research.

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.

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.

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.

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.

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.

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.

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.

Immunological and clinical aspects of lymphocytic hypophysitis.

LYH (lymphocytic hypophysitis) is an autoimmune disease of the pituitary gland which can present with varying degrees of pituitary hormonal impairment and/or with symptoms related to pituitary enlargement. In this review, we provide an overview of the epidemiology, diagnosis, pathogenesis, treatment, and the role of organ-specific and antipituitary antibodies as potential markers of LYH. In addition, although the mechanisms underlying LYH are not completely understood, the role of prolactin, which plays an important part in maintaining immune system homoeostasis and is increased in the disease, is considered.