Searching for LINCS to Stress: Using Text Mining to Automate Reference Chemical Curation.

Adaptive stress response pathways (SRPs) restore cellular homeostasis following perturbation but may activate terminal outcomes like apoptosis, autophagy, or cellular senescence if disruption exceeds critical thresholds. Because SRPs hold the key to vital cellular tipping points, they are targeted for therapeutic interventions and assessed as biomarkers of toxicity. Hence, we are developing a public database of chemicals that perturb SRPs to enable new data-driven tools to improve public health. Here, we report on the automated text-mining pipeline we used to build and curate the first version of this database. We started with 100 reference SRP chemicals gathered from published biomarker studies to bootstrap the database. Second, we used information retrieval to find co-occurrences of reference chemicals with SRP terms in PubMed abstracts and determined pairwise mutual information thresholds to filter biologically relevant relationships. Third, we applied these thresholds to find 1206 putative SRP perturbagens within thousands of substances in the Library of Integrated Network-Based Cellular Signatures (LINCS). To assign SRP activity to LINCS chemicals, domain experts had to manually review at least three publications for each of 1206 chemicals out of 181,805 total abstracts. To accomplish this efficiently, we implemented a machine learning approach to predict SRP classifications from texts to prioritize abstracts. In 5-fold cross-validation testing with a corpus derived from the 100 reference chemicals, artificial neural networks performed the best (F1-macro = 0.678) and prioritized 2479/181,805 abstracts for expert review, which resulted in 457 chemicals annotated with SRP activities. An independent analysis of enriched mechanisms of action and chemical use class supported the text-mined chemical associations (p < 0.05): heat shock inducers were linked with HSP90 and DNA damage inducers to topoisomerase inhibition. This database will enable novel applications of LINCS data to evaluate SRP activities and to further develop tools for biomedical information extraction from the literature.

Quality of Carpal Tunnel Syndrome Patient Education Handouts Available on the Internet: A Systematic Analysis of Content and Design.

OBJECTIVE: To evaluate the quality of carpal tunnel syndrome (CTS) patient education handouts and identify the best resources for patients and clinicians. DESIGN: A document content analysis of handouts identified through a systematic internet search using 8 search terms on Google and Bing and a hand search of professional association websites. SETTING: Not applicable. PARTICIPANTS: Documents (N=56) were identified from the top 50 search results across 16 individual searches. Included documents provided general patient education for CTS; descriptive websites, videos, and research studies were excluded. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Content analysis was conducted using the Information Score (IS) tool to evaluate completeness of information (0%-100%) and misleading treatment recommendations were identified. Design analysis was conducted using the Patient Material Assessment Tool for Printable Materials (PEMAT-P) (0%-100%) and 2 widely used readability formulas, Flesch Reading Ease and Flesch Kincaid Grade Level. Using these results, all handouts were rated with a summative 12-point scale. RESULTS: Of 805 unique search results, we included 56 CTS handouts. The average IS was 74.6%±17.9%, and 78.6% of the handouts mentioned non-evidence-based treatment recommendations. The average PEMAT-P score was 70.2%±10.9%, and the average readability grade level was 7.7±1.7. Only 3 handouts were identified as high quality based on the 12-point summative scores, 22 handouts had mixed quality, and 17 handouts had low quality on both content and design. CONCLUSIONS: Findings of this study suggest a lack of high-quality and easily understandable CTS patient education handouts. Most handouts contained unreliable treatment information. Improvements are needed to ensure patients' ability to understand and manage this condition.

"I Have Failed Them and Failed My Duties": Experiences of Hospital Social Workers Discharging Patients into Homelessness.

Homelessness is a long-standing issue at the forefront of healthcare globally, and discharge of homeless patients from hospital settings can exacerbate gaps and burdens in healthcare systems. In hospitals, social workers often take on the majority of responsibility for facilitating patient discharge transitions out of hospital care. Research in this area to date has explored experiences and outcomes of homeless clients, and the experiences of social workers in these roles are not well known. The current study's objective was to elucidate observations and experiences of hospital social workers who discharge patients into homelessness. A total of 112 social workers responded to an online questionnaire, and responses to open-ended questions were analyzed for thematic content. Four overarching themes emerged: (1) complexity of clients, (2) systemic barriers, (3) resource gaps, and (4) negative impact on social workers. It is clear that significant change is required to address the multitude of challenges that intersect to reinforce health inequities. Results can be used by social workers, health authorities, community providers, researchers, and policymakers in discussions about best practices for homeless clients.

The feasibility and effectiveness of virtual reality meditation on reducing chronic pain for older adults with knee osteoarthritis.

There is an urgent need for safe and effective nonpharmacologic approaches to treat chronic knee pain in older adults. Although virtual reality (VR) has shown some effectiveness for acute pain, there is limited evidence on the effects of VR on chronic pain particularly with older adult populations. This single application, within-subject pilot study evaluated the feasibility and effectiveness of VR as a clinical treatment for older adults with chronic osteoarthritis knee pain. Nineteen participants aged 60+ years old participated in a 10-min VR meditation program. Data on pain and affect were collected immediately prior to, post, and 24-48 h after the VR. Results suggest that VR meditation had significant moderate to large analgesic effects on knee pain intensity, primarily during VR (d = 1.10) and post VR (d = 0.99), with some lasting effects into next day (d = 0.58). The findings also suggest VR meditation intervention had a positive effect on affect, with a significant large decrease in negative affect scores pre- to post-VR (d = 1.14). The significant moderate to large decreases in pain interference for normal work (d = 0.71), mood (d = 0.53), sleep (d = 0.67), and enjoyment of life (d = 0.72) suggest that older adults may have a higher ability to participate in meaningful daily activities up to 24-48 h after VR meditation. VR appears to be a feasible and effective nonpharmacological tool for older adults to treat chronic overall and knee-specific pain.

Shared Language for Shared Work in Population Health.

People working on behalf of population health, community health, or public health often experience confusion or ambiguity in the meaning of these and other common terms-the similarities and differences and how they bear on the tasks and division of labor for care delivery and public health. Shared language must be clear enough to help, not hinder people working together as they ultimately come to mutual understanding of roles, responsibilities, and actions in their joint work. Based on an iterative lexicon development process, the authors developed and propose a definitional framework as an aid to navigating among related population and community health terms. These terms are defined, similarities and differences clarified, and then organized into 3 categories that reflect goals, realities, and ways to get the job done. Goals include (a) health as well-being for persons, (b) population health as that goal expressed in measurable terms for groups, and (c) community health as population health for particular communities of interest, geography, or other defining characteristic-groups with shared identity and particular systemic influences on health. Realities are social determinants as influences, health disparities as effects, and health equity as both a goal and a design principle. Ways to get the job done include health care delivery systems for enrollees and public health in population-based civic activities-with a broad zone of collaboration where streams of effort converge in partnership with served communities. This map of terms can enable people to move forward together in a broad zone of collaboration for health with less confusion, ambiguity, and conflict.

COVID-19 Knowledge Extractor (COKE): A Curated Repository of Drug-Target Associations Extracted from the CORD-19 Corpus of Scientific Publications on COVID-19.

The COVID-19 pandemic has catalyzed a widespread effort to identify drug candidates and biological targets of relevance to SARS-COV-2 infection, which resulted in large numbers of publications on this subject. We have built the COVID-19 Knowledge Extractor (COKE), a web application to extract, curate, and annotate essential drug-target relationships from the research literature on COVID-19. SciBiteAI ontological tagging of the COVID Open Research Data set (CORD-19), a repository of COVID-19 scientific publications, was employed to identify drug-target relationships. Entity identifiers were resolved through lookup routines using UniProt and DrugBank. A custom algorithm was used to identify co-occurrences of the target protein and drug terms, and confidence scores were calculated for each entity pair. COKE processing of the current CORD-19 database identified about 3000 drug-protein pairs, including 29 unique proteins and 500 investigational, experimental, and approved drugs. Some of these drugs are presently undergoing clinical trials for COVID-19. The COKE repository and web application can serve as a useful resource for drug repurposing against SARS-CoV-2. COKE is freely available at https://coke.mml.unc.edu/, and the code is available at https://github.com/DnlRKorn/CoKE.

Meta-synthesis of Carpal Tunnel Syndrome Treatment Options: Developing Consolidated Clinical Treatment Recommendations to Improve Practice.

Carpal tunnel syndrome (CTS) treatment contains ambiguities across and within disciplines. This meta-synthesis of professional guidelines consolidates clinical treatment recommendations for CTS treatment and classifies them by strength of evidence. We conducted a search of Google, Google Scholar, and PubMed for published clinical treatment recommendations for CTS. A systematic hand search was completed to identify additional professional organizations with published recommendations. We extracted any mentioned treatment from all sources but developed our final consolidated clinical treatment recommendations only from select rigorous guidelines based on the Institute of Medicine (IOM) criteria for trustworthy guidelines. We translated rating systems of the primary guidelines into a universal rating system to classify recommendations for consolidated clinical treatment recommendations. Our search yielded 30 sources that mentioned a total of 55 CTS treatments. Six of the sources met the IOM inclusion criteria. These primary guidelines provided recommendations for 46 of the 55 treatments, which were consolidated into 12 broad treatment categories. Surgery, positioning, and steroids were strongly supported. Conservative treatments provided by rehabilitation professionals were conditionally supported. Pharmaceuticals, supplements, and alternative treatments were not generally supported. CTS is a complex condition with a wide variety of treatments provided by a multitude of disciplines. Our consolidated clinical treatment recommendations offer a comprehensive outline of available treatments for CTS and contributes to the process of developing best practices for its treatment.

Effectiveness of eccentric strengthening in the treatment of lateral elbow tendinopathy: A systematic review with meta-analysis.

STUDY DESIGN: Meta-analysis. INTRODUCTION: Lateral elbow tendinopathy is a common condition with an annual incidence of up to 3% of the population. Eccentric strengthening has shown promise as a method to treat lateral elbow tendinopathy, but is unclear if it is superior to other forms of treatment. PURPOSE OF THE STUDY: The purpose of this study was to investigate the effectiveness of eccentric strengthening compared with other forms of strengthening and pain-relieving modalities on pain, strength, and function in people with lateral elbow tendinopathy. METHODS: Five electronic databases were searched. Reference lists of selected articles were hand-searched. Outcomes were defined a priori. Meta-analyses were performed using a random effects model with standardized mean differences, test of heterogeneity, and sensitivity analyses. RESULTS: Eight articles were included in this review. When comparing eccentric strengthening to other forms of strengthening and pain-relieving modalities, there were significant large effect size of 1.12 (CI: 0.31-1.93) and 1.22 (CI: 0.25-2.18) in reducing pain and improving function in the short-term, respectively. In long-term, results were inconclusive on all outcomes. DISCUSSION: A treatment program using eccentric strengthening of adequate intensity and duration seemed to be most effective for treating lateral elbow tendinopathy. CONCLUSIONS: The state of science of best care for lateral elbow tendinopathy is still in its infancy. Large, high-quality randomized controlled trials with clearly defined strengthening regime are needed to determine optimal dosage to maximize treatment effects. Recommendations were provided based on careful synthesis of findings from this review and current evidence in literature.

Repurposing Quaternary Ammonium Compounds as Potential Treatments for COVID-19.

The COVID-19 pandemic has highlighted an important role for drug repurposing. Quaternary ammonium compounds such as ammonium chloride, cetylpyridinium and miramistin represent widely accessible antiseptic molecules with well-known broad-spectrum antiviral activities and represent a repurposing opportunity as therapeutics against SARS-CoV-2.

Does Insurance Coverage Affect Use of Tests and Treatments for Working Age Individuals With Carpal Tunnel Syndrome in the United States? Analysis of the National Ambulatory Medical Care Survey (2005-2014).

OBJECTIVE: Carpal tunnel syndrome (CTS) is frequently seen as a work-related disorder. Few studies have examined the treatment of CTS by insurance coverage, and none have used a large, population-based dataset. This study examined the extent to which the use of CTS tests and treatments varied for those on workers' compensation insurance (WCI) vs private insurance and Medicaid, controlling for patient and provider characteristics. DESIGN: Analysis of 10 years of data (2005-2014) from the National Ambulatory Medical Care Survey. SETTING: United States office-based physician practices. PARTICIPANTS: Adults 18-64 years who had a physician visit for CTS (N=23,236,449). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We examined use of 2 diagnostic tests, imaging and electromyography, and 7 treatments: casting, splinting, occupational therapy (OT), physical therapy (PT), carpal tunnel release surgery, steroid injections, and nonsteroidal anti-inflammatory drug (NSAID). RESULTS: Individuals who sought care for CTS were more likely to be covered by private insurance (56.9%) than WCI (9.8%) or Medicaid (6.5%). The most commonly prescribed treatment for all types of insurance coverage was splints, followed by NSAID prescription, and OT or PT therapies. Steroid injections (1.2%) and CTS surgery (4.5%) were used significantly less than other treatment types. Patients on WCI were less likely to receive diagnostic tests, and more likely to receive OT or PT than those on other types of insurance coverage. CONCLUSION: Patients with CTS who seek ambulatory care are most likely to be covered by private insurance. Insurance coverage appears to play a role in treatment and diagnostic choices for CTS.

Chemotext: A Publicly Available Web Server for Mining Drug-Target-Disease Relationships in PubMed.

Elucidation of the mechanistic relationships between drugs, their targets, and diseases is at the core of modern drug discovery research. Thousands of studies relevant to the drug-target-disease (DTD) triangle have been published and annotated in the Medline/PubMed database. Mining this database affords rapid identification of all published studies that confirm connections between vertices of this triangle or enable new inferences of such connections. To this end, we describe the development of Chemotext, a publicly available Web server that mines the entire compendium of published literature in PubMed annotated by Medline Subject Heading (MeSH) terms. The goal of Chemotext is to identify all known DTD relationships and infer missing links between vertices of the DTD triangle. As a proof-of-concept, we show that Chemotext could be instrumental in generating new drug repurposing hypotheses or annotating clinical outcomes pathways for known drugs. The Chemotext Web server is freely available at http://chemotext.mml.unc.edu .

Computational Model of Secondary Palate Fusion and Disruption.

Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from chemical-induced cellular alterations, we built a multicellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGFß, BMP, FGF, EGF, and SHH) in a biological framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion. It effectively simulated higher-level phenotypes (e.g., midline contact, medial edge seam (MES) breakdown, mesenchymal confluence, and fusion defects) in response to genetic or environmental perturbations. Perturbation analysis of various control features revealed model functionality with respect to cell signaling systems and feedback loops for growth and fusion, diverse individual cell behaviors and collective cellular behavior leading to physical contact and midline fusion, and quantitative analysis of the TGF/EGF switch that controls MES breakdown-a key event in morphogenetic fusion. The virtual palate model was then executed with theoretical chemical perturbation scenarios to simulate switch behavior leading to a disruption of fusion following chronic (e.g., dioxin) and acute (e.g., retinoic acid) chemical exposures. This computer model adds to similar systems models toward an integrative "virtual embryo" for simulation and quantitative prediction of adverse developmental outcomes following genetic perturbation and/or environmental disruption.

Arthritis and cognitive impairment in older adults.

Adults aged 65 or older with arthritis may be at increased risk for cognitive impairment [cognitive impairment but not dementia (CIND) or dementia]. Studies have found associations between arthritis and cognition impairments; however, none have examined whether persons with arthritis develop cognitive impairments at higher rates than those without arthritis. Using data from the Health and Retirement Study, we estimated the prevalence of cognitive impairments in older adults with and without arthritis, and examined associations between arthritis status and cognitive impairments. We calculated incidence density ratios (IDRs) using generalized estimating equations to estimate associations between arthritis and cognitive impairments adjusting for age, sex, race/ethnicity, marital status, education, income, depression, obesity, smoking, the number of chronic conditions, physical activity, and birth cohort. The prevalence of CIND and dementia did not significantly differ between those with and without arthritis (CIND: 20.8%, 95% CI 19.7-21.9 vs. 18.3%, 95% CI 16.8-19.8; dementia: 5.2% 95% CI 4.6-5.8 vs. 5.1% 95% CI 4.3-5.9). After covariate control, older adults with arthritis did not differ significantly from those without arthritis for either cognitive outcome (CIND IDR: 1.6, 95% CI = 0.9-2.9; dementia IDR: 1.1, 95% CI = 0.4-3.3) and developed cognitive impairments at a similar rate to those without arthritis. Older adults with arthritis were not significantly more at risk to develop cognitive impairments and developed cognitive impairments at a similar rate as older adults without arthritis over 6 years.

Contrasting Nitrogen Fate in Watersheds Using Agricultural and Water Quality Information.

Surplus nitrogen (N) estimates, principal component analysis (PCA), and end-member mixing analysis (EMMA) were used in a multisite comparison contrasting the fate of N in diverse agricultural watersheds. We applied PCA-EMMA in 10 watersheds located in Indiana, Iowa, Maryland, Nebraska, Mississippi, and Washington ranging in size from 5 to 1254 km with four nested watersheds. Watershed Surplus N was determined by subtracting estimates of crop uptake and volatilization from estimates of N input from atmospheric deposition, plant fixation, fertilizer, and manure for the period from 1987 to 2004. Watershed average Surplus N ranged from 11 to 52 kg N ha and from 9 to 32% of N input. Solute concentrations in streams, overland runoff, tile drainage, groundwater (GW), streambeds, and the unsaturated zone were used in the PCA-EMMA procedure to identify independent components contributing to observed stream concentration variability and the end-members contributing to streamflow and NO load. End-members included dilute runoff, agricultural runoff, benthic-processing, tile drainage, and oxic and anoxic GW. Surplus N was larger in watersheds with more permeable soils (Washington, Nebraska, and Maryland) that allowed greater infiltration, and oxic GW was the primary source of NO load. Subsurface transport of NO in these watersheds resulted in some removal of Surplus N by denitrification. In less permeable watersheds (Iowa, Indiana, and Mississippi), NO was rapidly transported to the stream by tile drainage and runoff with little removal. Evidence of streambed removal of NO by benthic diatoms was observed in the larger watersheds.

Impact of arthritis and multiple chronic conditions on selected life domains - United States, 2013.

About half of U.S. adults have at least one chronic health condition, and the prevalence of multiple (two or more) chronic conditions increased from 21.8% in 2001 to 25.5% in 2012. Chronic conditions profoundly affect quality of life, are leading causes of death and disability, and account for 86% of total health care spending. Arthritis is a common cause of disability, one of the most common chronic conditions, and is included in prevalent combinations of multiple chronic conditions. To determine the impact of having arthritis alone or as one of multiple chronic conditions on selected important life domains, CDC analyzed data from the 2013 National Health Interview Survey (NHIS). Having one or more chronic conditions was associated with significant and progressively higher prevalences of social participation restriction, serious psychological distress, and work limitations. Adults with arthritis as one of their multiple chronic conditions had higher prevalences of adverse outcomes on all three life domains compared with those with multiple chronic conditions but without arthritis. The high prevalence of arthritis, its common co-occurrence with other chronic conditions, and its significant adverse effect on life domains suggest the importance of considering arthritis in discussions addressing the effect of multiple chronic conditions and interventions needed to reduce that impact among researchers, health care providers, and policy makers.

How Your Smartphone or Tablet Can Make You a Smarter Doc.

Increasingly, physicians and medical students are integrating apps that run on smartphones and tablets into their clinical work. This article describes a small anecdotal study of app use among third-year University of Minnesota medical students and their faculty preceptors. We describe apps used by the students and physicians we interviewed and offer guidance for choosing apps that are reliable, useful and up to date.

Arthritis among veterans - United States, 2011-2013.

Arthritis is among the most common chronic conditions among veterans and is more prevalent among veterans than nonveterans. Contemporary population-based estimates of arthritis prevalence among veterans are needed because previous population-based studies predate the Persian Gulf War, were small, or studied men only despite the fact that women comprise an increasing proportion of military personnel and typically have a higher prevalence of arthritis than men. To address this knowledge gap, CDC analyzed combined 2011, 2012, and 2013 Behavioral Risk Factor Surveillance System (BRFSS) data among all adults aged ≥18 years, by veteran status, to estimate the total and sex-specific prevalence of doctor-diagnosed arthritis overall and by sociodemographic categories, and the state-specific prevalence (overall and sex-specific) of doctor-diagnosed arthritis. This report summarizes the results of these analyses, which found that one in four veterans reported that they had arthritis (25.6%) and that prevalence was higher among veterans than nonveterans across most sociodemographic categories, including sex (prevalence among male and female veterans was 25.0% and 31.3%, respectively). State-specific, age-standardized arthritis prevalence among veterans ranged from 18.8% in Hawaii to 32.7% in West Virginia. Veterans comprise a large and important target group for reducing the growing burden of arthritis. Those interested in veterans' health can help to improve the quality of life of veterans by ensuring that they have access to affordable, evidence-based, physical activity and self-management education classes that reduce the adverse effects of arthritis (e.g., pain and depression) and its common comorbidities (e.g., heart disease and diabetes).

Falls and fall injuries among adults with arthritis--United States, 2012.

Falls are the leading cause of injury-related morbidity and mortality among older adults, with more than one in three older adults falling each year, resulting in direct medical costs of nearly $30 billion. Some of the major consequences of falls among older adults are hip fractures, brain injuries, decline in functional abilities, and reductions in social and physical activities. Although the burden of falls among older adults is well-documented, research suggests that falls and fall injuries are also common among middle-aged adults. One risk factor for falling is poor neuromuscular function (i.e., gait speed and balance), which is common among persons with arthritis. In the United States, the prevalence of arthritis is highest among middle-aged adults (aged 45-64 years) (30.2%) and older adults (aged ≥65 years) (49.7%), and these populations account for 52% of U.S. adults. Moreover, arthritis is the most common cause of disability. To examine the prevalence of falls among middle-aged and older adults with arthritis in different states/territories, CDC analyzed data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) to assess the state-specific prevalence of having fallen and having experienced a fall injury in the past 12 months among adults aged ≥45 years with and without doctor-diagnosed arthritis. This report summarizes the results of that analysis, which found that for all 50 states and the District of Columbia (DC), the prevalence of any fall (one or more), two or more falls, and fall injuries in the past 12 months was significantly higher among adults with arthritis compared with those without arthritis. The prevalence of falls and fall injuries is high among adults with arthritis but can be addressed through greater dissemination of arthritis management and fall prevention programs in clinical and community practice.

A computational model predicting disruption of blood vessel development.

Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology.