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1. The Social Media Index as an Indicator of Quality for Emergency Medicine Blogs: A METRIQ Study

Author

Brent Thoma, Teresa M. Chan, Puneet Kapur, Derek Sifford, Marshall Siemens, Michael Paddock, Felix Ankel, Andy Grock, Michelle Lin, Charlotte Alexander, Mohammed Alkhalifah, Abdulaziz S. Almehlisi, Saeed Alqahtani, Scott Anderson, Shelaina Anderson, Colin Andrews, Jocelyn Andruko, Nikytha Antony, Diptesh Aryal, Barbra Backus, Jennifer Baird, Andrew Baker, Sarah Batty, Jared Baylis, Braeden Beaumont, Chris Belcher, Brent Benavides, Michael Benham, Julian Botta, Nicholas Bouchard, Victoria Brazil, Emily Brumfield, Anthony Bryson, Wisarut Bunchit, Kat Butler, Lindy Buzikievich, David Calcara, Rob Carey, Stephen Carroll, Louise Cassidy, Kirsty Challen, Kathryn Chan, Tim Chaplin, Natasha Chatham-Zvelebil, Eric Chen, Lucy Chen, Sushant Chhabra, Alvin Chin, Eric Chochi, Tina Choudhri, Jeremy Christensen, Isabelle Colmers-Gray, Kimberly Connors, Veronica Coppersmith, Abby Cosgrove, Gregory Costello, Kevin Cullison, Andrew D'Alessandro, Kerstin de Wit, Marie Decock, Rayan Delbani, William Denq, Julianna Deutscher, Brendan Devine, Maia Dorsett, Taylor Duda, Justin Dueweke, Teresa Dunphy, Sean Dyer, Karthryn T Eastley, Marcia Edmonds, Ken Edwards, Robert Ehrman, Youness Elkhalidy, Preston Fedor, Brian Ficiur, Caley Flynn, Bill Fraser, Meagan Fu, James Fukakusa, Eric Funk, Damjan Gaco, Viktor Gawlik, Kenn Ghaffarian, Laleh Gharahbaghian, Phil Griffith, Andrew Griffith, Andrew Grock, Tanner Gronowski, Cathy Grossman, Jaroslaw Gucwa, Pawan Gupta, Alexandra Gustafson, Andrew Guy, Mary Haas, Stanislaw Haciski, Emina Hajdinjak, Andrew K. Hall, Regina Hammock, Jan Hansel, Alexander Hart, Larissa Hattin, Brandon Herb, SueLin Hilbert, Jesse Hill, Jeff Hill, Amy Ho, Emily House, Nina House, James Huffman, Charlie Inboriboon, Alex Ireland, Ali Jamal, Mohammad Ali Jamil, Victor Jansen, Zach Jarou, Vivian Jia, Levi Johnston, Drew Kalnow, Seth Kelly, Kyle Kelson, William Kent, Rishi Khakhkhar, Jaasmit Khurana, Ashley Kilp, Scott Knapp, Sebastian Kohler, Ivanna Kruhlak, Nadim Lalani, Samantha Lam, Patrick Lank, Zander Laurie, Kristina Lea, Ernest Leber, Ching-Hsing Lee, Haakon Lenes, Nilantha Lenora, Jesse Leontowicz, Kelly Lien, Yingchun Lin, Andrew Little, Ivy Liu, Harry Liu, Steve Liu, Stephanie Louka, Elise Lovell, David Lowe, Ashley Lubberdink, Jessica Luc, Casey Lyons, Sheng-Hsiang Ma, Hugh MacLeod, Nick Mancuso, Anali Maneshi, Jesse May, John Mayo, Mike McDonnell, Susan McLellan, Carolyn McQuarrie, Julia Nood, Therese Mead, Cory Meeuwisse, Patrick Meloy, Perry Menzies, Anne Messman, Stephen Miazga, Logan Mills, Ken Milne, Allan Mix, Steve Montag, Brendan Moore, Justin Morgenstern, Sarah Mott, P. Mukherj, Ali Mulla, Sheena Nandalal, Taylor Nikel, Sean Nugent, Morgan Oakland, Werner Oberholzer, Onyeka Otugo, Taofiq Segun Oyedokun, Mike Paddock, Alim Pardhan, Kinjal Patel, Quinten Paterson, Catherine Patocka, Christine Patterson, James Pearlman, Elyse Berger Pelletier, Alexis Pelletier-Bui, Marc Phan, Zafrina Poonja, Aubrey Powell, Kamini Premkumar, Gregor Prosen, Vishal Puri, Tanis Quaife, Ryan Raffel, Ali Raja, Randi Ramunno, Louise Rang, Suzanne Rannazzisi, Shauna Regan, Salim R. Rezaie, Milan Ridderikhof, Vanessa Rogers, Christine Roh, Dra. Maria Rosa Carrillo, Keith Rosenberg, Marina Roure, Sherri Rudinsky, Joshua Rudner, Adeeb Saleh, Will Sanderson, Owen Scheirer, Paul Schofield, Paul Schunk, Evan Schwarz, Parisa Shahrabadi, Eric Shappell, Julia Sheffield, Jonathan Sherbino, Manpreet Singh, Hector C Singson, Dave Slessor, Sam Smith, Paula Sneath, Robert Sobehart, Kerry Spearing, James Stempien, Britni Sternard, Tara Stratton, Katherine Stuart, Bob Stuntz, Michael Susalla, Colleen Sweeney, Loice Swisher, Henry Swoboda, Shahbaz Syed, Taku Taira, Nikhil Tambe, Richard Tang, Elisha Targonsky, Rachel Taylor, Alan Taylor, Todd Taylor, Paxton Ting, Gerhard Tiwald, Kelvin Tran, Evelyn Tran, Jason Trickovic, Paul Trinquero, Seth Trueger, Aaron Tyagi, Manrique Umana, Patrick Vallance, Patricia Van den Berg, Luis Vargas, Rene Verbeek, Sandra Viggers, Zlata Vlodaver, Matthew Wagner, Noorin Walji, Joe Walter, Miranda Wan, Rachel Wang, Gregory Wanner, Wyatt Warawa, Mike Ward, Jennifer Weekes, Kristen Weersink, Cara Weessies, Anna Whalen-Browne, Brian Whiteside, Matthew Willis, Jonas Wilmer, Nelson Wong, Mark Woodcroft, Rob Woods, Lawrence Yau, Jessica Yee, Calvin Yeh, Simon York Ming Huang, Katherine Yurkiw, Fareen Zaver, Alexander Zozula, Emergency Department, Graduate School, ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism

Subjects
Adult, Male, medicine.medical_specialty, Index (economics), Blogging, Cross-sectional study, media_common.quotation_subject, education, MEDLINE, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, Social media, Quality (business), 030212 general & internal medicine, media_common, Web site, business.industry, 030208 emergency & critical care medicine, Critical appraisal, Cross-Sectional Studies, Emergency medicine, Emergency Medicine, Gestalt psychology, Female, business, Social Media
Abstract

Study objective Online educational resources such as blogs are increasingly used for education by emergency medicine clinicians. The Social Media Index was developed to quantify their relative impact. The Medical Education Translational Resources: Indicators of Quality (METRIQ) study was conducted in part to determine the association between the Social Media Index score and quality as measured by gestalt and previously derived quality instruments. Methods Ten blogs were randomly selected from a list of emergency medicine and critical care Web sites. The 2 most recent clinically oriented blog posts published on these blogs were evaluated with gestalt, the Academic Life in Emergency Medicine Approved Instructional Resources (ALiEM AIR) score, and the METRIQ-8 score. Volunteer raters (including medical students, emergency medicine residents, and emergency medicine attending physicians) were identified with a multimodal recruitment methodology. The Social Media Index was calculated in February 2016, November 2016, April 2017, and December 2017. Pearson's correlations were calculated between the Social Media Index and the average rater gestalt, ALiEM AIR score, and METRIQ-8 score. Results A total of 309 of 330 raters completed all ratings (93.6%). The Social Media Index correlated moderately to strongly with the mean rater gestalt ratings (range 0.69 to 0.76) and moderately with the mean rater ALiEM AIR score (range 0.55 to 0.61) and METRIQ-8 score (range 0.53 to 0.57) during the month of the blog post's selection and for 2 years after. Conclusion The Social Media Index's correlation with multiple quality evaluation instruments over time supports the hypothesis that it is associated with overall Web site quality. It can play a role in guiding individuals to high-quality resources that can be reviewed with critical appraisal techniques.

Published
2018

2. β-Sheet Structure within the Extracellular Domain of C99 Regulates Amyloidogenic Processing

Author

Steven O. Smith, Rémi Opsomer, Stefan N. Constantinescu, Yi Hu, Tzu-Chun Tang, Xiaoshu Pan, Florian Perrin, Jean-Noël Octave, Marie Decock, Pascal Kienlen-Campard, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Models, Molecular, 0301 basic medicine, Amyloid, Proteolysis, Protein domain, Beta sheet, lcsh:Medicine, Sequence (biology), Article, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Protein structure, Protein Domains, Extracellular, medicine, Humans, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, Chemistry, lcsh:R, Small molecule, Peptide Fragments, 030104 developmental biology, Membrane, Biophysics, Protein Conformation, beta-Strand, lcsh:Q, Amyloid Precursor Protein Secretases, 030217 neurology & neurosurgery
Abstract

Familial mutations in C99 can increase the total level of the soluble Aβ peptides produced by proteolysis, as well as the Aβ42/Aβ40 ratio, both of which are linked to the progression of Alzheimer’s disease. We show that the extracellular sequence of C99 forms β-sheet structure upon interaction with membrane bilayers. Mutations that disrupt this structure result in a significant increase in Aβ production and, in specific cases, result in an increase in the amount of Aβ42 relative to Aβ40. Fourier transform infrared and solid-state NMR spectroscopic studies reveal a central β-hairpin within the extracellular sequence comprising Y10-E11-V12 and L17-V18-F19 connected by a loop involving H13-H14-Q15. These results suggest how familial mutations in the extracellular sequence influence C99 processing and provide a structural basis for the development of small molecule modulators that would reduce Aβ production.

Published
2017

3. Conformational Changes Induced by the A21G Flemish Mutation in the Amyloid Precursor Protein Lead to Increased Aβ Production

Author

Marie Decock, Laetitia El Haylani, Yi Hu, Steven O. Smith, Joanne Van Hees, Tzu-Chun Tang, Jean-Noël Octave, Ziao Fu, Stefan N. Constantinescu, and Pascal Kienlen-Campard

Subjects
Mutation, medicine.diagnostic_test, biology, Chemistry, Proteolysis, Mutant, Beta sheet, medicine.disease_cause, Cell biology, Cell membrane, Protein structure, medicine.anatomical_structure, Biochemistry, Structural Biology, medicine, Amyloid precursor protein, biology.protein, Secretion, Molecular Biology
Abstract

SummaryProteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimer’s disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases α-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases Aβ peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.

Published
2014

4. Individual Gestalt Is Unreliable for the Evaluation of Quality in Medical Education Blogs: A METRIQ Study

Author

Brent Thoma, Stefanie S. Sebok-Syer, Keeth Krishnan, Marshall Siemens, N. Seth Trueger, Isabelle Colmers-Gray, Rob Woods, Emil Petrusa, Teresa Chan, Charlotte Alexander, Mohammed Alkhalifah, Saeed Alqahtani, Scott Anderson, Shelaina Anderson, Colin Andrews, Jocelyn Andruko, Felix Ankel, Nikytha Antony, Diptesh Aryal, Barbra Backus, Jennifer Baird, Andrew Baker, Sarah Batty, Jared Baylis, Braeden Beaumont, Chris Belcher, Brent Benavides, Michael Benham, Elyse Berger Pelletier, Julian Botta, Nicholas Bouchard, Victoria Brazil, Emily Brumfield, Anthony Bryson, Wisarut Bunchit, Kat Butler, Lindy Buzikievich, David Calcara, Rob Carey, Stephen Carroll, Casey Lyons, Louise Cassidy, Kirsty Challen, Tim Chaplin, Natasha Chatham-Zvelebil, Eric Chen, Lucy Chen, Sushant Chhabra, Alvin Chin, Eric Chochi, Tina Choudhri, Jeremy Christensen, Kimberly Connors, Veronica Coppersmith, Abby Cosgrove, Gregory Costello, Kevin Cullison, Andrew D'Alessandro, Kerstin de Wit, Marie Decock, Rayan Delbani, William Denq, Julianna Deutscher, Brendan Devine, Maia Dorsett, Taylor Duda, Justin Dueweke, Teresa Dunphy, Sean Dyer, Kathryn T. Eastley, Marcia Edmonds, Ken Edwards, Robert Ehrman, Youness Elkhalidy, Preston Fedor, Brian Ficiur, Caley Flynn, Bill Fraser, Meagan Fu, James Fukakusa, Eric Funk, Damjan Gaco, Viktor Gawlik, Kenn Ghaffarian, Laleh Gharahbaghian, Phil Griffith, Andrew Griffith, Andrew Grock, Tanner Gronowski, Cathy Grossman, Jaroslaw Gucwa, Pawan Gupta, Alexandra Gustafson, Andrew Guy, Mary Haas, Stanislaw Haciski, Emina Hajdinjak, Andrew K. Hall, Regina Hammock, Jan Hansel, Alexander Hart, Larissa Hattin, Brandon Herb, SueLin Hilbert, Jesse Hill, Jeff Hill, Amy Ho, Emily House, Nina House, James Huffman, Charlie Inboriboon, Alex Ireland, Mohammed Ali Jamal, Victor Jansen, Zach Jarou, Vivian Jia, Levi Johnston, Drew Kalnow, Puneet Kapur, Seth Kelly, Kyle Kelson, William Kent, Rishi Khakhkhar, Jaasmit Khurana, Ashley Kilp, Scott Knapp, Sebastian Kohler, Ivanna Kruhlak, Nadim Lalani, Samantha Lam, Patrick Lank, Zander Laurie, Kristina Lea, Ernest Leber, Ching-Hsing Lee, Haakon Lenes, Nilantha Lenora, Jesse Leontowicz, Kelly Lien, Yingchun Lin, Michelle Lin, Andrew Little, Ivy Liu, Harry Liu, Steve Liu, Stephanie Louka, Elise Lovell, David Lowe, Ashley Lubberdink, Jessica Luc, Sheng-Hsiang Ma, Hugh MacLeod, Nick Mancuso, Anali Maneshi, Dra. Maria Rosa Carrillo, Jesse May, John Mayo, Mike McDonnell, Susan McLellan, Carolyn McQuarrie, Julia Nood, Therese Mead, Cory Meeuwisse, Patrick Meloy, Perry Menzies, Anne Messman, Stephen Miazga, Logan Mills, Ken Milne, Allan Mix, Steve Montag, Brendon Moore, Justin Morgenstern, Sarah Mott, P. Mukherj, Ali Mulla, Sheena Nandalal, Taylor Nikel, Sean Nugent, Morgan Oakland, Werner Oberholzer, Onyeka Otugo, Taofiq Segun Oyedokun, Mike Paddock, Alim Pardhan, Kinjal Patel, Quinten Paterson, Catherine Patocka, Christine Patterson, James Pearlman, Alexis Pelletier-Bui, Marc Phan, Zafrina Poonja, Aubrey Powell, Kamini Premkumar, Gregor Prosen, Vishal Puri, Tanis Quaife, Ryan Raffel, Ali Raja, Randi Ramunno, Louise Rang, Suzanne Rannazzisi, Shauna Regan, Milan Ridderikhof, Vanessa Rogers, Christine Roh, Keith Rosenberg, Marina Roure, Sherri Rudinsky, Joshua Rudner, Adeeb Saleh, Will Sanderson, Owen Scheirer, Paul Schofield, Paul Schunk, Evan Schwarz, Parisa Shahrabadi, Eric Shappell, Julia Sheffield, Jonathan Sherbino, Manpreet Singh, Hector C. Singson, Dave Slessor, Sam Smith, Paula Sneath, Robert Sobehart, Kerry Spearing, James Stempien, Britni Sternard, Tara Stratton, Katherine Stuart, Bob Stuntz, Michael Susalla, Colleen Sweeney, Loice Swisher, Henry Swoboda, Shahbaz Syed, Taku Taira, Nikhil Tambe, Richard Tang, Elisha Targonsky, Rachel Taylor, Alan Taylor, Todd Taylor, Paxton Ting, Gerhard Tiwald, Kelvin Tran, Evelyn Tran, Jason Trickovic, Paul Trinquero, Seth Trueger, Aaron Tyagi, Manrique Umana, Patrick Vallance, Patricia Van den Berg, Luis Vargas, Rene Verbeek, Sandra Viggers, Zlata Vlodaver, Matthew Wagner, Noorin Walji, Joe Walter, Miranda Wan, Rachel Wang, Gregory Wanner, Wyatt Warawa, Mike Ward, Jennifer Weekes, Kristen Weersink, Cara Weessies, Anna Whalen-Browne, Brian Whiteside, Matthew Willis, Jonas Wilmer, Nelson Wong, Mark Woodcroft, Lawrence Yau, Jessica Yee, Calvin Yeh, Simon York Ming Huang, Katherine Yurkiw, Fareen Zaver, Alexander Zozula, Graduate School, Emergency Department, ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism

Subjects
Adult, Male, Students, Medical, Blogging, Intraclass correlation, media_common.quotation_subject, education, MEDLINE, Likert scale, 03 medical and health sciences, 0302 clinical medicine, Evaluation methods, Medicine, Humans, Quality (business), Generalizability theory, 030212 general & internal medicine, Reliability (statistics), media_common, Medical education, Education, Medical, business.industry, Internship and Residency, Reproducibility of Results, 030208 emergency & critical care medicine, Gestalt Theory, Emergency Medicine, Gestalt psychology, Female, Clinical Competence, Educational Measurement, business, Social Media
Abstract

Study objective Open educational resources such as blogs are increasingly used for medical education. Gestalt is generally the evaluation method used for these resources; however, little information has been published on it. We aim to evaluate the reliability of gestalt in the assessment of emergency medicine blogs. Methods We identified 60 English-language emergency medicine Web sites that posted clinically oriented blogs between January 1, 2016, and February 24, 2016. Ten Web sites were selected with a random-number generator. Medical students, emergency medicine residents, and emergency medicine attending physicians evaluated the 2 most recent clinical blog posts from each site for quality, using a 7-point Likert scale. The mean gestalt scores of each blog post were compared between groups with Pearson's correlations. Single and average measure intraclass correlation coefficients were calculated within groups. A generalizability study evaluated variance within gestalt and a decision study calculated the number of raters required to reliably (>0.8) estimate quality. Results One hundred twenty-one medical students, 88 residents, and 100 attending physicians (93.6% of enrolled participants) evaluated all 20 blog posts. Single-measure intraclass correlation coefficients within groups were fair to poor (0.36 to 0.40). Average-measure intraclass correlation coefficients were more reliable (0.811 to 0.840). Mean gestalt ratings by attending physicians correlated strongly with those by medical students (r=0.92) and residents (r=0.99). The generalizability coefficient was 0.91 for the complete data set. The decision study found that 42 gestalt ratings were required to reliably evaluate quality (>0.8). Conclusion The mean gestalt quality ratings of blog posts between medical students, residents, and attending physicians correlate strongly, but individual ratings are unreliable. With sufficient raters, mean gestalt ratings provide a community standard for assessment.

Published
2016

5. Glycines from the APP GXXXG/GXXXA transmembrane motifs promote formation of pathogenic Aβ oligomers in cells

Author

Steven O. Smith, Stefan N. Constantinescu, Pascal Kienlen-Campard, Ilse Dewachter, Jean-Noël Octave, Serena Stanga, and Marie Decock

Subjects
0301 basic medicine, Aging, Cognitive Neuroscience, Peptide, amyloid precursor protein, Biology, medicine.disease_cause, Protein–protein interaction, lcsh:RC321-571, GXXXG motifs, 03 medical and health sciences, Beta-amyloid peptide, 0302 clinical medicine, medicine, Extracellular, Amyloid precursor protein, Alzheimer's disease, Neuronal differentiation, Oligomers, Senile plaques, oligomers, neuronal differentiation, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, chemistry.chemical_classification, Mutation, P3 peptide, Transmembrane protein, Cell biology, 030104 developmental biology, Biochemistry, chemistry, biology.protein, Alzheimer’s disease, 030217 neurology & neurosurgery, Neuroscience
Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the β-amyloid peptide (Aβ), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble Aβ oligomers correlate with clinical symptoms associated with the disease. The Aβ sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM α-helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and Aβ production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within Aβ species remains undefined. Here, we describe highly resistant Aβ42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to Aβ42, but not to Aβ40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G(29)XXXG(33) and G(38)XXXA(42) motifs dramatically affect the Aβ oligomerization process. G33 and G38 in these motifs are specifically involved in Aβ oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted Aβ42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these Aβ42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation.

Published
2016

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