Assessing the Quality of Online Health Information and Trend Data for Colorectal Malignancies.

INTRODUCTION: Patients often refer to the internet to learn about different health conditions. This study aims to assess the landscape of online health information on malignant colorectal conditions, focusing on the popularity, quantity, and quality of internet resources pertaining to these conditions. This information can be used as a guide for surgeons to supplement patient information at the time of surgical evaluation and to help design optimal online health information. METHODS: The terms "colon cancer," "rectal cancer," "anal cancer," and "colorectal cancer" were searched using the Google search engine. The number of search results or "hits" obtained per search term was recorded and the first 50 websites for each search term were reviewed. Included websites did not have a password requirement, were in English, and were free. Quality assessments were performed using the DISCERN instrument, and mean DISCERN scores were compared using analysis of variance. The popularity of each search term was determined using Google Trends, which generates a relative search volume score. RESULTS: A total of 431 million hits were obtained for the term "colon cancer," 72.5 million for "rectal cancer," 244 million for "anal cancer," and 194 million for "colorectal cancer." Mean DISCERN scores for reviewed websites ranged between 39.7 and 40.6, and were thus within the "fair" category. There were no significant differences in mean DISCERN scores across search terms (P = 0.5). Colon cancer had the highest relative search volume score (61.8), followed by colorectal cancer (43.4/100), rectal cancer (42.5/100), and anal cancer (41.7/100). CONCLUSIONS: Although there is a large amount of online information on malignant colorectal conditions, the quality of the available information is inadequate. Clinician guidance to resources aimed at higher quality from guidance of the DISCERN tool may be of value for patient education.

Intraoperative Ultrasound Guidance With an Ultrasound-Visible Clip: A Practical and Cost-effective Option for Breast Cancer Localization.

OBJECTIVES: In partial mastectomy (PM) or lumpectomy, ultrasound (US) localization avoids discomfort and additional procedures associated with wire localization. The purpose of this study was to evaluate the association between ultrasound-visible clip (UVC) use at the time of biopsy and US use during resection, hypothesizing that UVCs facilitate US localization and reduce costs compared with traditional radiopaque clips or no clip placement. METHODS: The study population consisted of adult female patients with breast cancer undergoing PM or lumpectomy at our institution between 2014 and 2016. The core biopsy clip type and localization method during PM were characterized as wire localization versus US localization, and associations were estimated with multivariable regression models. For the cost evaluation, breast biopsy data were obtained from the Department of Radiology. RESULTS: Among 674 patients, 490 had data on localization and the clip type. Ultrasound-visible clip placement at biopsy increased US use during resection by 13% (95% confidence interval, 6%-21%). There was no difference in the total specimen weight with US versus wire localization. The cost savings for using UVCs for the 2209 patients who underwent breast biopsy from 2014 to 2016 was $36,000. CONCLUSIONS: This study demonstrates that US localization for PM is feasible at a single institution and cost-effective when facilitated by UVCs. Placement of a UVC at the time of biopsy is recommended, as it is cost-effective and avoids the discomfort and inconvenience of wire localization.

Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP.

The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, the initiator E2, Ube2w, and the specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating, and terminating the CHIP ubiquitination cycle. Monoubiquitination of CHIP by Ube2w stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the length of chains attached to CHIP substrates. Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating the reaction. Our results suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point of regulation in ubiquitin-dependent protein quality control. In addition, the results shed light on disease pathogenesis in SCA3, a neurodegenerative disorder caused by polyglutamine expansion in ataxin-3.

Clinical predictors of accurate prehospital stroke recognition.

BACKGROUND AND PURPOSE: Prehospital activation of in-hospital stroke response hastens treatment but depends on accurate emergency medical services (EMS) stroke recognition. We sought to measure EMS stroke recognition accuracy and identify clinical factors associated with correct stroke identification. METHODS: Using EMS and hospital records, we assembled a cohort of EMS-transported suspect, confirmed, or missed ischemic stroke or transient ischemic attack cases. The sensitivity and positive predictive value (PPV) for EMS stroke recognition were calculated using the hospital discharge diagnosis as the gold standard. We used multivariable logistic regression analysis to determine the association between Cincinnati Prehospital Stroke Scale use and EMS stroke recognition. RESULTS: During a 12-month period, 441 EMS-transported patients were enrolled; of which, 371 (84.1%) were EMS-suspected strokes and 70 (15.9%) were EMS-missed strokes. Overall, 264 cases (59.9%) were confirmed as either ischemic stroke (n=186) or transient ischemic attack (n=78). The sensitivity of EMS stroke recognition was 73.5% (95% confidence interval, 67.7-78.7), and PPV was 52.3% (95% confidence interval, 47.1-57.5). Sensitivity (84.7% versus 30.9%; P<0.0001) and PPV (56.2% versus 30.4%; P=0.0004) were higher among cases with Cincinnati Prehospital Stroke Scale documentation. In multivariate analysis, Cincinnati Prehospital Stroke Scale documentation was independently associated with EMS sensitivity (odds ratio, 12.0; 95% confidence interval, 5.7-25.5) and PPV (odds ratio, 2.5; 95% confidence interval, 1.3-4.7). CONCLUSIONS: EMS providers recognized 3 quarters of the patients with ischemic stroke and transient ischemic attack; however, half of EMS-suspected strokes were false positives. Documentation of a Cincinnati Prehospital Stroke Scale was associated with higher EMS stroke recognition sensitivity and PPV.

The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N terminus of substrates.

Attachment of ubiquitin to substrate is typically thought to occur via formation of an isopeptide bond between the C-terminal glycine residue of ubiquitin and a lysine residue in the substrate. In vitro, Ube2w is nonreactive with free lysine yet readily ubiquitinates substrate. Ube2w also contains novel residues within its active site that are important for its ability to ubiquitinate substrate. To identify the site of modification, we analyzed ubiquitinated substrates by mass spectrometry and found the N-terminal -NH2 group as the site of conjugation. To confirm N-terminal ubiquitination, we generated lysine-less and N-terminally blocked versions of one substrate, the polyglutamine disease protein ataxin-3, and showed that Ube2w can ubiquitinate a lysine-less, but not N-terminally blocked, ataxin-3. This was confirmed with a second substrate, the neurodegenerative disease protein Tau. Finally, we directly sequenced the N terminus of unmodified and ubiquitinated ataxin-3, demonstrating that Ube2w attaches ubiquitin to the N terminus of its substrates. Together these data demonstrate that Ube2w has novel enzymatic properties that direct ubiquitination of the N terminus of substrates.

Prokinetic actions of luminally acting 5-HT4 receptor agonists.

BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.

Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex.

Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-ß protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets.