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1. Noncurative microsurgery for cerebral aneurysms: a systematic review and meta-analysis of wrapping, residual, and recurrence rates

Author: Sajal Medha K Akkipeddi, Thomas K Mattingly, Tarun Bhalla, Derrek Schartz, Nathaniel Ellens, Redi Rahmani, and Matthew T. Bender
Subjects: medicine.medical_specialty, Subarachnoid hemorrhage, business.industry, medicine.medical_treatment, General Medicine, Publication bias, Cochrane Library, Microsurgery, medicine.disease, Surgery, Study heterogeneity, Aneurysm, Meta-analysis, Medicine, business, Craniotomy
Abstract: OBJECTIVE Microsurgery for cerebral aneurysms is called definitive, yet some patients undergo a craniotomy that results in noncurative treatment. Furthermore, the overall rate of noncurative microsurgery for cerebral aneurysms is unclear. The objective of this study was to complete a systematic review and meta-analysis to quantify three scenarios of noncurative treatment: aneurysm wrapping, postclipping remnants, and late regrowth of completely obliterated aneurysms. METHODS A PRISMA-guided systematic literature review of the MEDLINE and Cochrane Library databases and meta-analysis was completed. Studies were included that detailed rates of aneurysm wrapping, residua confirmed with imaging, and regrowth after confirmed total occlusion. Pooled rates were subsequently calculated using a random-effects model. An assessment of statistical heterogeneity and publication bias among the included studies was also completed for each analysis, with resultant I2 values and p values determined with Egger’s test. RESULTS Sixty-four studies met the inclusion criteria for final analysis. In 41 studies, 573/15,715 aneurysms were wrapped, for a rate of 3.5% (95% CI 2.7%–4.2%, I2 = 88%). In 43 studies, 906/13,902 aneurysms had residual neck or dome filling, for a rate of 6.4% (95% CI 5.2%–7.6%, I2 = 93%). In 15 studies, 71/2568 originally fully occluded aneurysms showed regrowth, for a rate of 2.1% (95% CI 1.2%–3.1%, I2 = 58%). Together, there was a total rate of noncurative surgery of 12.0% (95% CI 11.5%–12.5%). Egger’s test suggested no significant publication bias among the studies. Meta-regression analysis revealed that the reported rate of aneurysm wrapping has significantly declined over time, whereas the rates of aneurysm residua and recurrence have not significantly changed. CONCLUSIONS Open microsurgery for cerebral aneurysm results in noncurative treatment approximately 12% of the time. This metric may be used to counsel patients and as a benchmark for other treatment modalities. This investigation is limited by the high degree of heterogeneity among the included studies.
Published: 2022
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2. A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia

Author: Ione O.C. Woollacott, Cristina Polito, Philip Van Damme, Mathieu Vandenbulcke, Rose Bruffaerts, Diana Duro, Chiara Fenoglio, David M. Cash, Maria Rosário Almeida, Sonja Schönecker, C. Ferreira, Sónia Afonso, Matthis Synofzik, Sara Prioni, Marta Cañada, Mikel Tainta, Miguel Tábuas-Pereira, Christin Andersson, Caroline Graff, Miguel Castelo-Branco, Enrico Premi, Håkan Thonberg, Fabrizio Tagliavini, Rachelle Shafei, Benjamin Bender, Ana Gorostidi, Maria João Leitão, Jennifer M. Nicholas, Elise G.P. Dopper, Silvana Archetti, Esther E. Bron, Ana Verdelho, Ron Keren, Isabel Santana, Christen Shoesmith, Pietro Tiraboschi, Sergi Borrego-Écija, Michela Pievani, Sandro Sorbi, Rick van Minkelen, Hans-Otto Karnath, Albert Lladó, Caroline V. Greaves, Jaume Olives, Alessandro Padovani, Miren Zulaica, Giuliano Binetti, Martin Rosser, Pedro Rosa-Neto, Vesna Jelic, Alexander Gerhard, Rosa Rademakers, Sandra E. Black, Wiro J. Niessen, Tobias Hoegen, Rhian S Convery, Janne M. Papma, Maria Carmela Tartaglia, Emily Todd, Adrian Danek, Rita Guerreiro, Robart Bartha, Linn Öijerstedt, Giuseppe Di Fede, Sebastien Ourselin, Núria Bargalló, James B. Rowe, Christopher C Butler, Giorgio G. Fumagalli, Valentina Bessi, Alberto Benussi, Nick C. Fox, Beatriz Santiago, Ekaterina Rogaeva, Alazne Gabilondo, Giacomina Rossi, Mircea Balasa, David L. Thomas, Benedetta Nacmias, Veronica Redaelli, Anna Antonell, Vikram Venkatraghavan, Jonathan D. Rohrer, Jackie M. Poos, Yolande A.L. Pijnenburg, Lieke H.H. Meeter, Carlo Wilke, Sandra V. Loosli, Elio Scarpini, Tobias Langheinrich, Alina Díez, Elisa Semler, Elizabeth Finger, Begoña Indakoetxea, Jessica L. Panman, Carolyn Timberlake, Gemma Lombardi, Luisa Benussi, Morris Freedman, Barbara Borroni, Ricardo Taipa, Johannes Levin, Thomas E. Cope, Paul M. Thompson, Giorgio Giaccone, Valentina Cantoni, Arabella Bouzigues, Jose Bras, Serge Gauthier, Andrea Arighi, Stefan Klein, Fermin Moreno, Markus Otto, Georgia Peakman, Emma L. van der Ende, David F. Tang-Wai, Sarah Anderl-Straub, Jason D. Warren, Alexandre de Mendonça, Camilla Ferrari, Elisabeth Wlasich, Catharina Prix, Michele Veldsman, Raquel Sánchez-Valle, Sara Mitchell, Carolina Maruta, Robert Laforce, Paola Caroppo, Jorge Villanua, Imogen J Swift, Harro Seelaar, Henrik Zetterberg, Simon Mead, Simon Ducharme, Myriam Barandiaran, Katrina M. Moore, John C. van Swieten, Gabriel Miltenberger, Mario Masellis, Timothy Rittman, Lize C. Jiskoot, Daniela Galimberti, Rik Vandenberghe, Carolin Heller, Stefano Gazzina, Aitana Sogorb-Esteve, Roberto Gasparotti, Martina Bocchetta, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Radiology & Nuclear Medicine, and Neurosurgery
Subjects: Oncology, medicine.medical_specialty, Medizin, tau Proteins, Disease, medicine.disease_cause, frontotemporal dementia, biomarker, disease progression model, event-based modelling, neurofilament light chain, Biomarkers, C9orf72 Protein, Complement C1q, Cross-Sectional Studies, Disease Progression, Glial Fibrillary Acidic Protein, Humans, Longitudinal Studies, Mutation, Frontotemporal Dementia, diagnosis [Frontotemporal Dementia], Settore BIO/13 - Biologia Applicata, C9orf72, Internal medicine, Medicine, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], business.industry, medicine.disease, Astrogliosis, genetics [tau Proteins], Cohort, Biomarker (medicine), Neurology (clinical), Sample collection, business, Frontotemporal dementia
Abstract: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.
Published: 2022
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3. Cell-Inspired Biomaterials for Modulating Inflammation

Author: Chelsea Kraynak, Wenbai Huang, Elizabeth Cathleen Bender, and Laura J. Suggs
Subjects: Cell, Biomedical Engineering, Biocompatible Materials, Bioengineering, Inflammation, Biochemistry, Biomaterials, Neoplasms, medicine, Humans, Macrophage, Review Articles, Pathogen, business.industry, Macrophages, fungi, food and beverages, Cancer, medicine.disease, medicine.anatomical_structure, Cancer research, Cytokines, medicine.symptom, business, Wound healing
Abstract: Inflammation is a crucial part of wound healing and pathogen clearance. However, it can also play a role in exacerbating chronic diseases and cancer progression when not regulated properly. A subset of current innate immune engineering research is focused on how molecules such as lipids, proteins, and nucleic acids native to a healthy inflammatory response can be harnessed in the context of biomaterial design to promote healing, decrease disease severity, and prolong survival. The engineered biomaterials in this review inhibit inflammation by releasing anti-inflammatory cytokines, sequestering proinflammatory cytokines, and promoting phenotype switching of macrophages in chronic inflammatory disease models. Conversely, other biomaterials discussed here promote inflammation by mimicking pathogen invasion to inhibit tumor growth in cancer models. The form that these biomaterials take spans a spectrum from nanoparticles to large-scale hydrogels to surface coatings on medical devices. Cell-inspired molecules have been incorporated in a variety of creative ways, including loaded into or onto the surface of biomaterials or used as the biomaterials themselves. IMPACT STATEMENT: Chronic inflammatory diseases and cancers are widespread health care concerns. Treatment plans for these diseases can be complicated and the outcomes are often mixed due to off-target effects. Current research efforts in immune engineering and biomaterials are focused on utilizing the body's native immune response to return to homeostasis as a therapeutic approach. This review collects many of the most current findings in the field as a resource for future research.
Published: 2022
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4. The Impact of Adherence and Health Literacy on Difficult-to-Control Asthma

Author: Rachelle R. Ramsey, Bruce G. Bender, Sandra E. Zaeh, Kevin A. Hommel, Cynthia S. Rand, and Giselle Mosnaim
Subjects: medicine.medical_specialty, business.industry, Nebulizers and Vaporizers, Inhaler, Control (management), Psychological intervention, Context (language use), Health literacy, Asthma management, medicine.disease, Article, Asthma, Health Literacy, Medication Adherence, respiratory tract diseases, Family medicine, Health care, Humans, Immunology and Allergy, Medicine, business
Abstract: Medication nonadherence and health literacy are key factors that influence the management of difficult-to-control asthma. Adherence, or the extent to which a patient follows a treatment plan, extends beyond asthma medication use and includes appropriate inhaler technique. Assessment of adherence is critical prior to making a diagnosis of severe asthma and stepping up asthma therapy but is challenging in the clinical context. Health literacy, or the degree to which individuals can obtain, process, and understand health information and services needed to make health care decisions, is additionally important for asthma management and has been shown to impact medication adherence. Initiatives aiming to improve difficult-to-control asthma should address medication adherence and health literacy. Universal health literacy precautions are recommended while communicating with patients, in addition to the creation of low health literacy asthma action plans. To improve adherence, a comprehensive assessment of adherence should be conducted. Additional evidence based interventions aiming to improve adherence focus on appropriate inhaler use, improved access to medications, the use of digital platforms, school based asthma interventions, and the implementation of culturally tailored interventions. Data is limited regarding the use of these initiatives in patients with severe or difficult-to-control asthma.
Published: 2022
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5. A modified Camel and Cactus Test detects presymptomatic semantic impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Moore, Katrina, Convery, Rhian, Bocchetta, Martina, Neason, Mollie, Cash, David M., Greaves, Caroline, Russell, Lucy L., Clarke, Mica T. M., Peakman, Georgia, van Swieten, John, Jiskoot, Lize, Moreno, Fermin, Barandiaran, Myriam, Sanchez-Valle, Raquel, Borroni, Barbara, Laforce, Robert, Dore, Marie-Claire, Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Galimberti, Daniela, Rowe, James B., Finger, Elizabeth, Synofzik, Matthis, Karnath, Hans-Otto, Vandenberghe, Rik, de Mendonca, Alexandre, Maruta, Carolina, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Danek, Adrian, Otto, Markus, Warren, Jason D., Rohrer, Jonathan D., Rossor, Martin N., Fox, Nick C., Woollacott, Ione O. C., Shafei, Rachelle, Heller, Carolin, Guerreiro, Rita, Bras, Jose, Thomas, David L., Nicholas, Jennifer, Mead, Simon, Meeter, Lieke, Panman, Jessica, Papma, Janne, van Minkelen, Rick, Pijnenburg, Yolande, Indakoetxea, Begona, Gabilondo, Alazne, Tainta, Mikel, de Arriba, Maria, Gorostidi, Ana, Zulaica, Miren, Villanua, Jorge, Diaz, Zigor, Borrego-Ecija, Sergi, Olives, Jaume, Llado, Albert, Balasa, Mircea, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Cosseddu, Maura, Gazzina, Stefano, Padovani, Alessandro, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, Keren, Ron, Tang-Wa, David, Oijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Thonberg, Hakan, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Bender, Benjamin, Bruffaerts, Rose, Van Damme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B., Miltenberger, Gabriel, Verdelho, Ana, Afonso, Sonia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro, Diana, Almeida, Maria Rosario, Castelo-Branco, Miguel, Leitao, Maria Joao, Tabuas-Pereira, Miguel, Santiago, Beatriz, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Flanagan, Toby, Prix, Catharina, Hoegen, Tobias, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Semler, Elisa, Anderl-Straub, Sarah, Neurology, Clinical Psychology, Clinical Genetics, Moore, Katrina [0000-0002-4458-8390], Convery, Rhian [0000-0002-9477-1812], Bocchetta, Martina [0000-0003-1814-5024], Neason, Mollie [0000-0001-9419-7171], Greaves, Caroline [0000-0002-6446-1960], Russell, Lucy L [0000-0001-5023-5893], Clarke, Mica TM [0000-0003-0570-4296], Peakman, Georgia [0000-0002-3319-138X], Galimberti, Daniela [0000-0002-9284-5953], Otto, Markus [0000-0003-4273-4267], Rohrer, Jonathan D [0000-0002-6155-8417], and Apollo - University of Cambridge Repository
Subjects: Oncology, Cactaceae, medicine.medical_specialty, Camelus, Semantic dementia, Temporal lobe, Atrophy, Progranulins, ddc:150, complications [Frontotemporal Dementia], C9orf72, Internal medicine, Developmental and Educational Psychology, medicine, MAPT, progranulin, Semantic memory, Animals, Humans, genetics, genetics [Frontotemporal Dementia], semantic knowledge, C9orf72 Protein, Cognition, medicine.disease, Semantics, Neuropsychology and Physiological Psychology, Frontal lobe, Frontotemporal Dementia, Psychology, Frontotemporal dementia
Abstract: Impaired semantic knowledge is a characteristic feature of some forms of frontotemporal dementia (FTD), particularly the sporadic disorder semantic dementia. Less is known about semantic cognition in the genetic forms of FTD caused by mutations in the genes MAPT, C9orf72, and GRN. We developed a modified version of the Camel and Cactus Test (mCCT) to investigate the presence of semantic difficulties in a large genetic FTD cohort from the Genetic FTD Initiative (GENFI) study. Six-hundred-forty-four participants were tested with the mCCT including 67 MAPT mutation carriers (15 symptomatic, and 52 in the presymptomatic period), 165 GRN mutation carriers (33 symptomatic, 132 presymptomatic), and 164 C9orf72 mutation carriers (56 symptomatic, 108 presymptomatic) and 248 mutation-negative members of FTD families who acted as a control group. The presymptomatic mutation carriers were further split into those early and late in the presymptomatic period (more than vs. within 10 years of expected symptom onset). Groups were compared using a linear regression model, adjusting for age and education, with bootstrapping. Performance on the mCCT had a weak negative correlation with age (rho = −0.20) and a weak positive correlation with education (rho = 0.13), with an overall abnormal score (below the 5th percentile of the control population) being below 27 out of a total of 32. All three of the symptomatic mutation groups scored significantly lower than controls: MAPT mean 22.3 (standard deviation 8.0), GRN 24.4 (7.2), C9orf72 23.6 (6.5) and controls 30.2 (1.6). However, in the presymptomatic groups, only the late MAPT and late C9orf72 mutation groups scored lower than controls (28.8 (2.2) and 28.9 (2.5) respectively). Performance on the mCCT correlated strongly with temporal lobe volume in the symptomatic MAPT mutation group (rho > 0.80). In the C9orf72 group, mCCT score correlated with both bilateral temporal lobe volume (rho > 0.31) and bilateral frontal lobe volume (rho > 0.29), whilst in the GRN group mCCT score correlated only with left frontal lobe volume (rho = 0.48). This study provides evidence for presymptomatic impaired semantic knowledge in genetic FTD. The different neuroanatomical associations of the mCCT score may represent distinct cognitive processes causing deficits in different groups: loss of core semantic knowledge associated with temporal lobe atrophy (particularly in the MAPT group), and impaired executive control of semantic information associated with frontal lobe atrophy. Further studies will be helpful to address the longitudinal change in mCCT performance and the exact time at which presymptomatic impairment occurs.
Published: 2022
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6. Cognitive composites for genetic frontotemporal dementia: GENFI-Cog

Author: Poos, Jackie M, Moore, Katrina M, Seelaar, Harro, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B, Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Pijnenburg, Yolande A L, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Duro, Diana, Almeida, Maria Rosario, Castelo-Branco, Miguel, Leitão, Maria João, Tabuas-Pereira, Miguel, Santiago, Beatriz, Moreno, Fermin, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Thompson, Paul, Langheinrich, Tobias, Prix, Catharina, Hoegen, Tobias, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Sanchez-Valle, Raquel, Anderl-Straub, Sarah, Lombardi, Jolina, Bargalló, Nuria, Benussi, Alberto, Cantoni, Valentina, Bertoux, Maxime, Bertrand, Anne, Brice, Alexis, Camuzat, Agnès, Colliot, Olivier, Borroni, Barbara, Sayah, Sabrina, Funkiewiez, Aurélie, Rinaldi, Daisy, Lombardi, Gemma, Nacmias, Benedetta, Saracino, Dario, Bessi, Valentina, Ferrari, Camilla, Cañada, Marta, Deramecourt, Vincent, Laforce, Robert, Kuchcinski, Gregory, Lebouvier, Thibaud, Ourselin, Sebastien, Polito, Cristina, Rollin, Adeline, Masellis, Mario, Tartaglia, Carmela, Graff, Caroline, Galimberti, Daniela, Nicholas, Jennifer, Rowe, James B, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tiraboschi, Pietro, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alexander, Russell, Lucy L, Levin, Johannes, Danek, Adrian, Otto, Markus, Le Ber, Isabel, Pasquier, Florence, van Swieten, John C, Rohrer, Jonathan D, Initiative, Genetic FTD, Bouzigues, Arabella, Rossor, Martin N, Peakman, Georgia, Fox, Nick C, Warren, Jason D, Bocchetta, Martina, Swift, Imogen J, Shafei, Rachelle, Heller, Carolin, Todd, Emily, Cash, David, Woollacott, Ione, Zetterberg, Henrik, Convery, Rhian S, Nelson, Annabel, Guerreiro, Rita, Bras, Jose, Thomas, David L, Mead, Simon, Meeter, Lieke, Panman, Jessica, van Minkelen, Rick, Barandiaran, Myriam, Indakoetxea, Begoña, Jiskoot, Lize C, Gabilondo, Alazne, Tainta, Mikel, Gorostidi, Ana, Zulaica, Miren, Díez, Alina, Villanua, Jorge, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, van der Ende, Emma, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Gazzina, Stefano, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, van den Berg, Esther, Keren, Ron, Tang-Wai, David, Thonberg, Hakan, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Papma, Janne M, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnarth, Hans-Otto, Bender, Benjamin, Bruffaerts, Rose, Neurology, Amsterdam Neuroscience - Neurodegeneration, Medical Research Council, Clinical Genetics, Rowe, James [0000-0001-7216-8679], Rohrer, Jonathan D [0000-0002-6155-8417], and Apollo - University of Cambridge Repository
Subjects: PROGRESSION, Neuropsychological Tests, Composite score, Genetic FTD Initiative (GENFI), diagnosis [Frontotemporal Dementia], Cognition, CRITERIA, Attention, genetics [Frontotemporal Dementia], 11 Medical and Health Sciences, Language, Executive function, Frontotemporal dementia, Memory, Neuropsychology, Social cognition, Humans, Mutation, Prodromal Symptoms, Sample Size, tau Proteins, Frontotemporal Dementia, CARRIERS, Neurology, Psychology, Life Sciences & Biomedicine, CLINICAL-TRIALS, RC321-571, medicine.medical_specialty, Cognitive Neuroscience, Clinical Neurology, genetics [Mutation], Neurosciences. Biological psychiatry. Neuropsychiatry, Physical medicine and rehabilitation, Cog, mental disorders, medicine, ddc:610, RC346-429, Science & Technology, Research, Neurosciences, medicine.disease, genetics [tau Proteins], Neurosciences & Neurology, Neurology (clinical), Neurology. Diseases of the nervous system
Abstract: Funder: Alzheimer's Research UK, Funder: Alzheimer's Society, Funder: Brain Research UK, Funder: the Wolfson Foundation, Funder: NIHR UCL/H Biomedical Research Centre, Funder: Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: UK Dementia Research Institute, Funder: UK Medical Research Council, Funder: Bluefield project, Funder: the Association for Frontotemporal Dementias Research Grant 2009, BACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR�� plus NACC-FTLD �� 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR�� plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR�� plus NACC-FTLD �� 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR�� plus NACC-FTLD = 0.5 to �� 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR�� plus NACC-FTLD 0.5 to �� 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR�� plus NACC FTLD 0.5 to �� 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
Published: 2022
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7. Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG

Author: Subodh Verma, Deepak L. Bhatt, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Nitish K. Dhingra, Steven B. Ketchum, Rebecca A. Juliano, Lixia Jiao, Ralph T. Doyle, Craig Granowitz, C. Michael Gibson, Duane Pinto, Robert P. Giugliano, Matthew J. Budoff, R. Preston Mason, Jean-Claude Tardif, Christie M. Ballantyne, Fabrice M.A.C. Martens, Astrid Schut, Brian Olshansky, Mina Chung, Al Hallstrom, Lesly Pearce, Cyrus Mehta, Rajat Mukherjee, Anjan K. Chakrabarti, Eli V. Gelfand, Megan Carroll Leary, Duane S. Pinto, Yuri B. Pride, Steven Ketchum, Ramakrishna Bhavanthula, Gertrude Chester, Christina Copland, Katelyn Diffin, Ralph Doyle, Kurt Erz, Alex Giaquinto, Paula Glanton, Angela Granger, Richard H. Iroudayassamy, Rebecca Juliano, James Jin, Dimitry Klevak, Hardik Panchal, Robert Wang, Shin-Ru Wang, Gerard Abate, Peggy J. Berry, Rene Braeckman, Declan Doogan, Anne Elson, Amy HauptmannBaker, Isabel Lamela, Catherine Lubeck, Mehar Manku, Sabina Murphy, Monica Sanford, William Stirtan, Paresh Soni, Arnaud Bastien, Demetria Foster, Evangelito Gascon, Judith Johnson, Lasbert Latona, Gang Liu, Sandra Palleja, Nelly Sanjuan, Jimmy Shi, William Stager, Mukund Venkatakrishnan, Ahmed Youssef-Agha, Julie Zhu, Leela Aertker, Suresh Ankolekar, Lisa Goldberg, Natasa Rajicic, Jianfen Shu, Heng Zou, Magdy Mikhail, Gamil Dawood, N. Mathew Koshy, Sandip K. Mukherjee, Rafik Abadier, Andrea L. Lawless, William P. McGuinn, Howard Weintraub, Kathryn Rohr, Edmund Claxton, Robert J. Weiss, Terry D. Klein, Mani Nallasivan, Stephen Crowley, Marilyn King, Anthony D. Alfieri, David Fitz-Patrick, Irving Loh, Nolan J. Mayer, Rakesh Prashad, Samuel Lederman, Debra Weinstein, Harold E. Bays, Keith Chu, Alireza Maghsoudi, Paul D. Thompson, Jeff Carstens, Anna Chang, Kenneth R. Cohen, Julius Dean, Howard S. Ellison, Bernard Erickson, Enrique A. Flores, Daniel W. Gottlieb, Paul Grena, John R. Guyton, Peter H. Jones, John M. Joseph, Norman E. Lepor, Sam Lerman, Robert D. Matheney, Theodore R. Pacheco, Michael B. Russo, John Rubino, Edward S. Pereira, Albert A. Seals, Eduardo Viera, Alan D. Steljes, Jason Thompson, Shaival Kapadia, Michael McIvor, Jorge E. Salazar, Jose O. Santiago, Ralph Vicari, Martin R. Berk, William A. Kaye, Marcus McKenzie, David Podlecki, Brian D. Snyder, Stephen Nash, David M. Herrington, Wallace Johnson, Joseph R. Lee, Ronald Blonder, Alpa M. Patel, Ramon Castello, Susan Greco, Dean J. Kereiakes, Venkatesh K. Nadar, Mark Nathan, Ranganatha P. Potu, Robert Sangrigoli, Richard Smalling, Mitchell Davis, Robert Braastad, James McCriskin, Kunal Bodiwala, Joe L. Hargrove, Mark W. Graves, George Emlein, Raegan W. Durant, James W. Clower, Rohit Arora, Narendra Singh, Lisa Warsinger Martin, W Herbert Haught, Marc P. Litt, Michael D. Klein, Peter Hoagland, Michael Goldstein, Marco S. Mazzella, Daniel H. Dunker, Brian H. Kahn, Carlos S. Ince, Frank A. McGrew, Jay Lee, David Pan, Salman A. Khan, Uri Elkayam, Wasim Deeb, Anne C. Goldberg, Christopher S. Brown, Wayne N. Leimbach, Thomas S. Backer, David R. Sutton, Joel Gellman, Anu R. George, Alan S. Hoffman, Mark Kates, Kishlay Anand, Robert Bear, Brendan J. Cavanaugh, Ramon G. Reyes, Rodolfo Sotolongo, Kenneth Sabatino, Kevin Gallagher, Ehab Sorial, Chris Geohas, Kathleen E. Magness, Bernard P. Grunstra, Frederik A. Martin, William S. Knapp, Mel E. Lucas, John J. Champlin, Jason Demattia, Patrick H. Peters, Judith Kirstein, William J. Randall, Cezar S. Staniloae, Jennifer G. Robinson, Alexander Adler, Christopher Case, Andrew J. Kaplan, Gregory F. Lakin, Krishan K. Goyle, Michael J. DiGiovanna, Chester L. Fisher, Michael Lillestol, Michael Robinson, Robert G. Perry, Lawrence S. Levinson, Brian G. Everhart, Robert D. Madder, Earl F. Martin, Earl E. Martin, Imtiaz Alam, Jose Mari L. Elacion, Robina Poonawala, Taddese T. Desta, Jerome A. Robinson, Gilbert J. Martinez, Jakkidi S. Reddy, Jeffrey D. Wayne, Samuel Mujica Trenche, Westbrook I. Kaplan, Rubin H. Saavedra, Michael D. DiGregorio, Barry D. Bertolet, Neil J. Fraser, Terence T. Hart, Ronald J. Graf, David A. Jasper, Michael Dunn, Dan A. Streja, David J. Strobl, Nan Jiang, Vicki Kalen, Richard Mascolo, Mercedes B. Samson, Michael Stephens, Bret M. Bellard, Mario Juarez, Patrick J. McCarthy, John B. Checton, Michael Stillabower, Edward Goldenberg, Amin H. Karim, Naseem Jaffrani, Robert C. Touchon, Erich R. Fruehling, Clayton J. Friesen, Pradipta Chaudhuri, Frank H. Morris, Robert E. Broker, Rajesh J. Patel, Susan Hole, Randall P. Miller, Francisco G. Miranda, Sadia Dar, Shawn N. Gentry, Paul Hermany, Charles B. Treasure, Miguel E. Trevino, Raimundo Acosta, Anthony Japour, Samuel J. Durr, Thomas Wang, Om P. Ganda, Perry Krichmar, James L. Arter, Douglas Jacoby, Michael A. Schwartz, Amer Al-Karadsheh, Nelson E. Gencheff, John A. Pasquini, Richard Dunbar, Sarah Kohnstamm, Hector F. Lozano, Francine K. Welty, Thomas L. Pitts, Brian Zehnder, Salah El Hafi, Mark A. King, Arnold Ghitis, Marwan M. Bahu, Hooman Ranjbaran Jahromi, Ronald P. Caputo, Robert S. Busch, Michael D. Shapiro, Suhail Zavaro, Munib Daudjee, Shahram Jacobs, Vipul B. Shah, Frank Rubalcava, Mohsin T. Alhaddad, Henry Lui, Raj T. Rajan, Fadi E. Saba, Mahendra Pai N Gunapooti, Tshiswaka B. Kayembe, Timothy Jennings, Robert A. Strzinek, Michael H. Shanik, Pradeep K. Singh, Alastair C. Kennedy, Howard Rubenstein, Ramin Manshadi, Joanne Ladner, Lily Kakish, Ashley Kakish, Amy L. Little, Jaime Gerber, Nancy J. Hinchion, Janet Guarino, Denise Raychok, Susan Budzinski, Kathleen Kelley-Garvin, April Beckord, Jessica Schlinder, Arthur Schwartzbard, Stanley Cobos, Deborah Freeman, David Abisalih, Dervilla McCann, Kylie Guy, Jennifer Chase, Stacey Samuelson, Madeline Cassidy, Marissa Tardif, Jaime Smith, Brenna Sprout, Nanette Riedeman, Julie Goza, Lori Johnson, Chad Kraske, Sheila Hastings, Chris Dutka, Stephanie Smith, Toni McCabe, Kathleen Maloney, Paul Alfieri, Vinay Hosemane, Chanhsamone Syravanh, Cindy Pau, April Limcoiloc, Tabitha Carreira, Taryn S. Kurosawa, Razmig Krumian, Krista Preston, Ashraf Nashed, Daria Schneidman-Fernandez, Jack Patterson, John Tsakonas, Jennifer Esaki, Lynn Sprafka, Porous Patel, Brian Mitchell, Erin M. Ross, Donna Miller, Akash Prashad, Kristina M. Feyler, Natasha Juarbe, Sandra Herrera, Sarah M. Keiran, Becky Whitehead, Whitney Asher, Coury Hobbs, Abbey Elie, Jean Brooks, Amanda L. Zaleski, Brenda Foxen, Barb Lapke, Philippa Wright, Bristol Pavol, Gwen Carangi, Marla Turner, Katharine W. Sanders, Rikita S. Delamar, Virginia L. Wilson, Sarah M. Harvel, Alison M. Cartledge, Kaitlyn R. Bailey, Kathleen Mahon, Timothy Schuchard, Jen Humbert, Mark C. Hanson, Michael P. Cecil, James S. Abraham, Lorie Benedict, Claudia Slayton, Curtis S. Burnett, Rachel W. Ono-Lim, Sharon Budzinski, Shubi A. Khan, Sharon Goss, Terry Techmanski, Farida Valliani, Rimla Joseph, Edith Flores, Laurn Contreras, Ana Aguillon, Carrie-Ann Silvia, Maria Martin, Edmund K. Kerut, Leslie W. Levenson, Louis B. Glade, Brian J. Cospolich, Maureen W. Stein, Stephen P. LaGuardia, Thelma L. Sonza, Tracy M. Fife, Melissa Forschler, Jasmyne Watts, Judy Fritsch, Emese Futchko, Sarah Utech, Scott B. Baker, Miguel F. Roura, Scott A. Segel, James S. Magee, Cathy Jackson, Rebecca F. Goldfaden, Liudmila Quas, Elizabeth C. Ortiz, Michael Simpson, Robert Foster, Christopher Brian, James Trimm, Michael Bailey, Brian Snoddy, Van Reeder, Rachel Wilkinson, Harold Settle, Cynthia Massey, Angela Maiola, Michele Hall, Shelly Hall, Wanda Hall, Mark Xenakis, Janet Barrett, Giovanni Campanile, David Anthou, Susan F. Neill, Steven Karas, Enrique Polanco, Norberto Schechtman, Grace Tischner, Kay Warren, Cynthia St Cyr, Menna Kuczinski, Latrina Alexander, Maricruz Ibarra, Barry S. Horowitz, Jaime Steinsapir, Jeanette Mangual-Coughlin, Brittany Mooney, Precilia Vasquez, Kathleen Rodkey, Alexandria Biberstein, Christine Ignacio, Irina Robinson, Marcia Hibberd, Lisa B. Hoffman, Daniel J. Murak, Raghupathy Varavenkataraman, Theresa M. Ohlson Elliott, Linda A. Cunningham, Heather L. Palmerton, Sheri Poole, Jeannine Moore, Helene Wallace, Ted Chandler, Robert Riley, Farah Dawood, Amir Azeem, Michael Cammarata, Ashleigh Owen, Shivani Aggarwal, Waqas Qureshi, Mohamed Almahmoud, Abdullahi Oseni, Adam Leigh, Erin Barnes, Adam Pflum, Amer Aladin, Karen Blinson, Vickie Wayne, Lynda Doomy, Michele Wall, Valerie Bitterman, Cindi Young, Rachel Grice, Lioubov Poliakova, Jorge Davalos, David Rosenbaum, Mark Boulware, Heather Mazzola, J. Russell Strader, Russell Linsky, David Schwartz, Elizabeth Graf, Alicia Gneiting, Melissa Palmblad, Ashley Donlin, Emily Ensminger, Hillary Garcia, Dawn Robinson, Carolyn Tran, Jeffrey Jacqmein, Darlene Bartilucci, Michael Koren, Barbara Maluchnik, Melissa Parks, Jennifer Miller, Cynthia DeFosse, Albert B. Knouse, Amy Delancey, Stephanie Chin, Thomas Stephens, Mag Sohal, Juana Ingram, Swarooparani Kumar, Heather Foley, Nina Smith, Vera McKinney, Linda Schwarz, Judith Moore, Hildreth Vernon Anderson, Stefano Sdringola-Maranga, Ali Denktas, Elizabeth Turrentine, Rhonda Patterson, John Marshall, Terri Tolar, Donna Patrick, Pamela Schwartzkopf, Anthony M. Fletcher, Frances R. Harris, Sherry Clements, Tiffany Brown, William Smith, Stacey J. Baehl, Robin Fluty, Daniel VanHamersveld, Dennis Breen, Nancy Bender, Beverly Stafford, Tamika Washington, Margaret N. Pike, Mark A. Stich, Evyan Jawad, Amin Nadeem, Jill Nyland, Rhonda Hamer, Kendra Calhoun, Charlotte Mall, Samuel Cadogan, Kati Raynes, Richard Katz, Lorraine Marshall, Rashida Abbas, Jay L. Dinerman, John T. Hartley, Beth Lamb, Lisa Eskridge, Donna Raymond, Kristy Clemmer, Denise M. Fine, Paula Beardsley, Janet Werner, Bette Mahan, Courtney VanTol, Robert Herman, Christine Raiser-Vignola, Felicia McShan, Stefanie A. Neill, David R. Blick, Michael J. Liston, Denetta K. Nelson, Sandra K. Dorrell, Patricia Wyman, Ambereen Quraishi, Fernando Ferro, Frank Morris, Vicki J. Coombs, Autumn M. Mains, Austin A. Campbell, Jeanne Phelps, Cheryl A. Geary, Ellen G. Sheridan, Jean M. Downing, Arie Swatkowski, Tish Redden, Brian Dragutsky, Susan Thomas, Candace Mitchell, Diana Barker, Elanie Turcotte, Deborah Segerson, Jill Guy, Karena De La Mora, Jennifer Hong, Dennis Do, Rose Norris, Faisal Khan, Hector Montero, Stacy Kelly-White, Alan Cleland, Rosalyn Alcalde-Crawford, Melissa Morgan, Brijmohan Sarabu, Megan Minor, Shweta Kamat, Stephanie M. Estes, Nancee Harless, Alicia Disney, Jodi L. Pagano, Chad M. Alford, Noel W. Bedwell, Warren D. Hardy, Kevin DeAndrade, Jessica G. Elmore, Eric Auerbach, Anthony W. Haney, Miriam H. Brooks, Jose Torres, Lois Roper, Terry Backer, Katie Backer, John G. Evans, Ricardo A. Silva, Lorraine H. Dajani, Veronica Yousif, Tammy Ross, Sion K. Roy, Ronald Oudiz, Sajad Hamal, Ferdinand Flores, Amor Leahy, Debra Ayer, Swapna George, Chrisi Carine Stewart, Elvira Orellana, Cristina Boccalandro, Mary Rangel, Suzanne Hennings, Carl Vanselow, Teri Victor, Darlene Birdwell, Paul Haas, Anthony Sandoval, Gina Ciavarella, Caroline Saglam, Amy Bird, Keith Beck, Brian Poliquin, David Dominguez, Brittany Tenorio, Harvonya Perkins, Esther San Roman, Paris Bransford, Christy Lowrance, Marcy Broussard, Mary Ellis, Bobbi Skiles, Jessica Hamilton, Kathryn Hall, Diego Olvera, Julee A. Hartwell, Nevien Sorial, Mary Rickman, Kevin Berman, Nirav Mehta, Annie Laborin, Rodger Rothenberger, Sarah Beauvilliers, Kathy Morrell, Michael P. Schachter, Cindy L. Perkins, Elizabeth A. Gordon, Jennifer Lauer, Kim Bichsel, Kelly Oliver, Leslie J. Mellor, Candice Demattia, Jennifer Schomburg, Yenniffer Moreno, Eduardo Mansur-Garza, Lena Rippstein, Lorie Chacon, Andrea Pena, Michelle King, Susan Richardson, Annette Jessop, Nicole Tucker, Whitney Royer, Gilbert Templeton, Ann Moell, Christine Weller, Melissa J. Botts, Gretel Hollon, Elsa Homberg-Pinassi, Paula Forest, Aref Bin Abhulhak, Devona Chun-Furlong, Deborah Harrington, Emily Harlynn, Marjorie Schmitt, Constance Shelsky, Patricia Feldick, Mary Cherrico, Courtney Jagle, Nicholas Warnecke, Debra Myer, Deanna J. Ruder, Albina Underwood, Alan Rauba, George Carr, Barbara Oberhaus, Jessica Vanderfeltz, Mary Jo Stucky-Heil, Dale R. Gibson, Vonnie Fuentes, Kimberly L. Talbot, William C. Simon, Katlyn J. Grimes, Christina R. Wheeler, Cassaundra Shultz, Rhonda A. Metcalf, Jennifer L. Hill, Michelle R. Oliver, Basharat Ahmad, Fouzal Azeem, Abdul Rahim, George H. Freeman, Dawn Bloch, Heather Freeman, Jamie Brown, Sarah Rosbach, Pamela Melander, Nick Taralson, Alex Liu, Katlyn Harms, Mahfouz Michale, Jose Lopez, Maria Revoredo, Shari Edevane, Sarah Shawley, Timothy L. Jackson, Michael J. Oliver, Dina DeSalle, Patricia J. Matlock, Ionna M. Beraun, Heather Hendrix, Garrett Bromley, Ashley Niemerski, Gabby Teran, Sonia Guerrero, Murtaza Marvi, Zehra Palanpurwala, Andrea Torres, Patty Gloyd, Michelle Conger, Aziz Laurent, Olia Nayor, Catalina S. Villanueva, Munira Khambati, Tabetha J. Mumford, Melanie J. Castillo, Taddese Desta, Jerome Robinson, La Shawn Woods, Anita Bahri, Nancy Herrera, Cecilia Casaclang, Jeffrey R. Unger, Geraldine Martinez, Mia K. Moon, Stephen M. Mohaupt, Larry Sandoval, Louisito Valenzuela, Victora Ramirez, Nelly Mata, Veronica Avila, Marisol Patino, Cynthia Montano-Pereira, Omar Barnett, William M. Webster, Lorraine M. Christensen, Leighna Bofman, Melanie Livingston, Stacey Adams, Joseph Hobbs, Leesa Koskela, Mia Katz, Samuel Mujica-Trenche, Franklin Cala, Noreen T. Rana, Jennifer Scarlett, Milagros Cala Anaya, Marsha R. Jones, Kelly D. Hollis, Debbie Roth, Kristin Eads, Tina Watts, Judy Perkins, Alice Arnold, Daniel C. Ginsberg, Denise Quinn, Nicole Cureton, David B. Fittingoff, Mohammed I. Iqbal, Stephen R. White, Edith Sisneros, Michelle Ducca, David Streja, Danny Campos, Jennifer L. Boak, Farzeen Amir, Felice Anderson, James J. Kmetzo, Mary O. Bongarzone, Dawn Scott, Mary Grace De Leon, Cynthia Buda, William Graettinger, Michelle Alex, Erika Hess, James Govoni, Melissa Bartel, Travis L. Monchamp, Julie S. Roach, Sara Gibson, Amy M. Allfrey, Kristen Timpy, Kathy Bott, Karin A. Soucy, Jean Willis, Cecilia A. Valerio, Anusha Chunduri, Rebecca Coker, Nicole Vidrine, Ellen A. Thompson, Mark A. Studeny, Melissa K. Marcum, Tammy S. Monway, Douglas L. Kosmicki, Melissa J. Kelley, Corey M. Godfrey, Susan L. Krenk, Randy R. Holcomb, Deb K. Baehr, Mary K. Trauernicht, David Rowland Lowry, Betty Bondy Herts, Jeanne E Phelps, Jean-Marie Downing, Carol Gamer Dignon, Elisabeth S. Cockrill, Pravinchandra G. Chapla, Diane Fera, Margaret Chang, Patricia Fredette, Tamie Ashby, Renee Bergin, Zebediah A. Stearns, David B. Ware, Rachael M. Boudreaux, Joanna Rodriguez, Robert McKenzie, Amanda Huber, Rebecca Sommers, Heather Rowe, Stacy McLallen, Michale Haynes, Ashley Adamson, Janice Henderson, Lori McClure, Beverly A. Harris, Laura Ference, Sue Meissner-Dengler, Lisa Treasure, Doreen Nicely, Timothy L. Light, Tracey A. Osborn, Kimberly J. Mai, Pablo Vivas, Jose Rios, Dunia Rodriguez, Roger DeRaad, James Walder, Oscar Bailon, Denice Hockett, Debbie Anderson, Kelli McIntosh, Amber Odegard, Andrew Shepherd, Mary Seifert, Laurence Kelley, Rajendra Shetty, Michael Castine, David Brill, Gregory Fisher, Nicole Richmond, Kathleen Gray, Patricia Miller, Charlene Coneys, Yarixa Chanza, Monica Sumoza, Victoria M. Caudill, Kelly D. Harris, Courtney A. Manion, Melody J. Lineberger-Moore, Julie J. Wolfe, Barbara J. Rosen, Patricia DiVito, Janet L. Moffat, Christina Michaelis, Prashant Koshy, Diana Perea, Ghaith Al Yacoub, Stephanie Sadeghi, Thomas D. LeGalley, Rudolph F. Evonich, William J. Jean, Gary M. Friesen, John M. Pap, David A. Pesola, Mark D. Cowan, Kristofer M. Dosh, Dianna Larson, Adele M. Price, Jodi A. Nease, Jane E. Anderson, Lori A. Piggott, Robert Iwaoka, Kevin Sharkey, Edward McMillan, Laurie Lowder, Latisha Morgan, Kyle Davis, Tara Caldwell, Erica Breglio, Jasmine Summers, Rachel Poulimas, Muhammad Zahid, Hamid Syed, Maria Escobar, Jacob Levy, Rahma Warsi, Carol Ma, Puxiao Cen, Kimberly A. Cawthon, Delores B. Barnes, Deanna G. Allen, Margaret L. Warrington, Carol R. Stastny, Robin J. Michaels, Mohamad Saleh, John Sorin, Sunny Rathod, Urakay Juett, Steven Spencer, Aziza Keval, Jill McBride, Shane Young, Catherine Baxter, Carol Rasmussen, Shari L. Coxe, Luis Campos, Shahin Tavackoli, Diana Beckham, Darlynee Sanchez, Karanjit Basrai, Dorian Helms, Erica Clinton, Kasie Smith, Henry Cusnir, Mary Klaus Clark, Madhavagopal V. Cherukuri, Ameta Scarfaru, Stephen D. Nash, Loretta C. Grimm, Anna Grace, Kylie McElheran, Dino Subasic, Zedrick Buhay, Janet Litvinoff, Deepak Shah, Shannon Cervantes, Freda Usher, Farra Yasser, Theodore Trusevich, Ronnie L. Garcia, Jamison Wyatt, Rahul Bose, Holllilyn Miska, Traci Spivey, Amy B. Wren, Katie E. Vance, Lani L. Holman, Pam Gibbons, Elaine Eby, Sandra Shepard, Soratree Charoenthongtrakul, Brett Snodgrass, Mohammed Nazem, Shelly Keteenburg, Prathima Murthy, Frederic Prater, Ashley Rumfelt, Christina Eizensmits, Lisa Iannuzzi, Pourus R. Patel, Clellia Bergamino, Elizabeth McFeaters, Botros Rizk, Emiljia Pflaum, Danny Kalish, Rex Ambatali, Mona Ameli, Delaina Sanguinetti, Rakesh Vaidya, Martinus A.W. Broeders, Dorman Henrikus, Adrianus F.M. Kuijper, Nadea Al-Windy, Michael Magro, Karim Hamraoui, Ismail Aksoy, Guy L.J. Vermeiren, H.W.O. Roeters van Lennep, Gerard Hoedemaker, Johannes Jacobus Remmen, Kjell Bogaard, Dirk van der Heijden, Nicole MJ Knufman, Joost Frederiks, Johannes Willem Louwerenburg, Piet van Rossum, Johannes Milhous, Peter van der Meer, Arno van der Weerdt, Rob Breedveld, Mitran Keijzers, Walter Hermans, Ruud van de Wal, Peter A.G. Zwart, Marc M.J.M. van der Linden, Gerardus Zwiers, Dirk J. Boswijk, Jan Geert Tans, Jacob van Eck, Maarten V. Hessen, Barnabas J.B. Hamer, Stieneke Zoet-Nugteren, Lucien Theunissen, E.A. van Beek, Remco Nijmeijer, Pieter R. Nierop, Gerard Linssen, H.P. Swart, Timo Lenderink, Gerard L. Bartels, Frank den Hartog, Brian J. Berg van den, Wouter van Kempen, Susanne Kentgens, Gloria M. Rojas Lingan, Martinus M. Peeters, Hilligje Keterberg, Melchior Nierman, Annemieke K. den Hollander, Jacqueline Hoogendijk, Christine Voors-Pette, Vicdan Kose, Peter Viergever, Larysa Yena, Viktor Syvolap, Mykola P. Kopytsya, Olga Barna, Svitlana S. Panina, Mykhailo I. Lutai, Oxana V. Shershnyova, Iryna Luzkiv, Larysa S. Bula, Sergii Zotov, Ivan Vyjhovaniuk, Olena Lysunets, Volodymyr I. Koshlia, Nataliya Sydor, Myroslava F. Vayda, Olexiy Ushakov, Mykola Rishko, Viktor P. Shcherbak, Yevgeniya Svyshchenko, Vira Tseluyko, Andriy Yagensky, Viktoriia I. Zolotaikina, Olga Godlevska, Larysa Ivanova, Olena Koval, Olena I. Mitchenko, Galyna Y. Kardash, Yurii S. Rudyk, Mykola Stanislavchuk, Volodymyr Ivanovych Volkov, Olena G. Karlinskaya, Susanna A. Tykhonova, Nikolay Vatutin, Ganna Smirnova, Volodymyr M. Kovalenko, Viktor Lizogub, Denys Sebov, Oleksandr Dyadyk, Svetlana Andrievskaya, Mykola P. Krasko, Alexander N. Parkhomenko, Lidiya Horbach, Iryna G. Kupnovytska, Tetyana Pertseva, Oleksandr Karpenko, Dmytro Reshotko, Svitlana V. Zhurba, Leonid Rudenko, Viktoriia Yu Zharinova, Valerii B. Shatylo, Yuriy I. Karpenko, Mariya A. Orynchak, Tatiana R. Kameneva, Elena Zherlitsina, Diana N. Alpenidze, Grigoriy P. Arutyunov, Elena Baranova, Boris Bart, Dmitriy I. Belenkiy, Svetlana A. Boldueva, Elena A. Demchenko, Vera V. Eltishcheva, Alexander M. Gofman, Boris M. Goloshchekin, Ivan Gennadyevich Gordeev, Nikolay Gratsianskiy, Gadel Kamalov, Niyaz R. Khasanov, Irina M. Kholina, Zhanna D. Kobalava, Elena V. Kobeleva, Alexandra O. Konradi, Victor A. Kostenko, Andrey Dmitrievich Kuimov, Polina Y. Ermakova, Sofia K. Malyutina, Alexey V. Panov, Natalia V. Polezhaeva, Olga Reshetko, Nataliya P. Shilkina, Sergey B. Shustov, Elena A. Smolyarchuk, Raisa I. Stryuk, Elena Yurievnar Solovieva, Andrey V. Susekov, Natalia Vezikova, Svetlana N. Ivanova, Alexander A. Petrov, Vladimir O. Konstantinov, Alina S. Agafina, Victor Gurevich, Konstantin N. Zrazhevskiy, Tatiana V. Supryadkina, Nikita B. Perepech, Vadim L. Arkhipovskiy, Dmitry Yu Butko, Irina A. Zobenko, Olga V. Orlikova, Viktor Mordovin, Olga L. Barbarash, Anastasiya Lebedeva, Vladimir Nosov, Oleg V. Averkov, Elena P. Pavlikova, Yuri B. Karpov, Marina Lvovna Giorgadze, Oleg A. Khrustalev, Mikhail Arkhipov, Tatiana A. Raskina, Julia V. Shilko, Yulia Samoilova, Elena D. Kosmacheva, Sergey V. Nedogoda, Kathleen Coetzee, Lesley J. Burgess, F.C.R. Theron, Iftikhar O. Ebrahim, Gerbrand A. Haasbroek, Maria Pretorius, Julien S. Trokis, Dorothea V. Urbach, Mark J. Abelson, Adrian R. Horak, Aysha E. Badat, Ellen M. Makotoko, Hendrik Du Toit Theron, Padaruth Ramlachan, Clive H. Corbett, Ismail H. Mitha, Hendrik F.M. Nortje, Dirkie J. Jansen van Rensburg, Peter J. Sebastian, F.C.J. Bester, Louis J. van Zyl, Brian L. Rayner, Elżbieta Błach, Magda Dąbrowska, Grzegorz Kania, Agata E. Kelm-Warchol, Leszek P. Kinasz, Janusz Korecki, Mariusz Kruk, Ewa Laskowska-Derlaga, Andrzej Madej, Krzysztof Saminski, Katarzyna Wasilewska, Katarzyna Szymkowiak, Małgorzata Wojciechowska, Natalia Piorowska, Andrzej Dyczek, Rajpal K. Abhaichand, Ramesh B. Byrapaneni, Basavanagowdappa Hattur, Malipeddi Bhaskara Rao, Nitin Ghaisas, Sujit Shankar Kadam, Jugal B. Gupta, Santhosh M. Jayadev, V.A. Kothiwale, Atul Mathur, Vijay Bhaskar, Ravi K. Aluri, Udaya P. Ponangi, Mukesh K. Sarna, Sunil Sathe, Manish K. Sharma, Jilendra Pal Singh Sawhney, Chakrabhavi B. Keshavamurthy, Arun Srinivas, Hemant P. Thacker, A. Sharda, Johny Joseph, Sunil Dwivedi, Viswanathan Mohan, Rajendra K. Premchand, Jacques Bedard, Jean Bergeron, Ronald Collette, David Crowley, Richard Dumas, Sam Henein, Geoff Moran, William F. O’Mahony, Michael O’Mahony, Sammy Chan, Mark H. Sherman, Graham C. Wong, Brian D. Carlson, Milan K. Gupta, David Borts, Sean R. Peterson, Martyn Chilvers, Allan J. Kelly, Jean C. Gregoire, Simon Kouz, Josep Rodés Cabau, Minodora Andor, Mircea Cinteza, Radu Ciudin, Radu I. Cojan, Roxana O. Darabont, Dan-Lucian Dumitrascu, Carmen Fierbinteanu-Braticievici, Ana Gabriela Fruntelata, Constantin Militaru, Bogdon E. Minescu, Doina Luminita Serban, Florin Mitu, Dorel Nastase Melicovici, Ovidiu Petrascu, Octavian M. Pirvu, Cristian Podoleanu, Calin Pop, Rodica-Valentina V. Stanescu-Cioranu, Adrian Tase, Cristina Voiculet, Constantine N. Aroney, Anthony M. Dart, Timothy Davis, Karam Kostner, David N. O’Neal, Peter W. Purnell, Bhuwanendu B. Singh, David R. Sullivan, Peter Thompson, Gerald F. Watts, Adam F. Blenkhorn, John V. Amerena, Rafeeq Samie, Randall Hendriks, Joseph Proietto, Nikolai Petrovsky, Alan Whelan, David Colquhoun, Russell S. Scott, Simon C. Young, Tammy Pegg, Samuel JS Wilson, Andrew W. Hamer, Richard A. Luke, Hamish H. Hart, Gerard P. Devlin, Gerard T. Wilkins, Ian F. Ternouth, Samraj Nandra, Bruno S. Loeprich, Nicole McGrath, Stuart L. Tie, Rob J. Bos, Alexandra Wils, Tamara Jacobs, Erik A. Badings, Lillian A. Ebels-Tuinbeek, Mayke L. Scholten, Esther Bayraktar-Verver, Debby Zweers, Manoek Schiks, Carolien Kalkman, Tineke Tiemes, Jeanette Mulderij, Katarzyna Dabrowska, Wilma Wijnakker, Riny Van de Loo, Jeanne de Graauw, Giny Reijnierse, Mirjam van der Zeijst, Mariska Scholten, Henk R. Hofmeijer, Antoinette van Dijk-van der Zanden, Dineke J. van Belle, Jan Van Es, Gera Van Buchem, Wendy Zijda, Harald Verheij, Linnea Oldenhof-Janssen, Martina Bader, Marije Löwik, Sandra Stuij, Pascal Vantrimpont, Krista van Aken, Karen Hamilton, Han Blömer, Gabriela van Laerhoven, Raymond Tukkie, Maarten Janssen, Gerard Verdel, Jon Funke Küpper, Bob van Vlies, Caroline Kalkman, Joke Vooges, Marinella Vermaas, Rachel Langenberg, Niek Haenen, Frans Smeets, Arko Scheepmaker, Marcel Grosfeld, Ilvy Van Lieshout, Marleen van den Berg, Marian Wittekoek, Petra Mol, Antionette Stapel, Margaretha Sierevogel, Nancy van der Ven, Annemiek Berkelmans, Eric Viergever, Hanneke Kramer, Wilma Engelen, Karen V. Houwelingen, Thierry X. Wildbergh, Arend Mosterd, Coriet Hobé-Rap, Marjan van Doorn, Petra Bunschoten, Michel Freericks, Mireille Emans, Petra Den Boer-Penning, Els Verlek, Christine Freericks, Cornelis de Nooijer, Christina Welten, Ingrid Groenenberg, Claudia van der Horst, Esther Vonk, Geert Tjeerdsma, Gerard M. Jochemsen, Corinne van Daalen, Ingrid Y. Danse, Lucy Kuipers, Anke Pieterse, Antonius Oomen, Daan de Waard, Willem Jan Flu, Zusan Kromhout, Petra Van der Bij, Rob Feld, Brigitta Hessels-Linnemeijer, Rob Lardinois, Jan L. Posma, Zwanette R. Aukema-Wouda, Marjolijn Hendriks-van Woerden, Desiree van Wijk, Driek P. Beelen, Ingrid H. Hendriks, Jan J. Jonker, Stefanie Schipperen, Vicdan Köse, Gloria Rojas, Linda Goedhart, Hanneke van Meurs, Jacqueline Rijssemus, Lindy Swinkels-Diepenmaat, Marloes de Louw-Jansen, Dominique Bierens-Peters, Willem W. van Kempen, Marianne E. Wittekoek, Irmaina Agous, Geert Schenk, Janneke Wittekoek, Kevin Cox, Deborah F. Julia, Jan J.C. Jonker, Roel Janssen, Melchor Nierman, Hilligje Katerberg, Irene van der Haar, Willem W. Van Kempen, Taco van Mesdag, Leyda M. Alvarez Costa, Manon Schensema, Salomé Zweekhorst, Deborah Font Julia, Lauri Hanewinckel, Joyce Olsthoorn, Johan C. Berends, Arie C. van der Spek, Roy van der Berg, Rob J. Timmermann, Ingrid Boerema, Iryna Mudruk, Anna Khrystoforova, Serhii Kyselov, Yaroslava V. Hilova, Pavlo Logoida, Nataliia A. Sanina, Ilona P. Golikova, Olena O. Nemchyna, Ivan I. Isaichikov, Olga B. Potapova, Iurii V. Gura, Larysa Berestetska, Olena O. Kulianda, Oleksandr Tantsura, Oleksandr S. Kulbachuk, Volodymyr Petsentiy, Ihor Biskub, Tetyana Handych, Oleg Lagkuti, Alyna Gagarina, Taras Chendey, Oksana F. Bilonko, Olena Matova, Larysa Bezrodna, Olena Yarynkina, Tetiana Ovdiienko, Volodymyr Randchenko, Maryna Mospan, Olena Butko, Olga Romanenko, Mykhailo Pavelko, Iryna Sichkaruk, Svitlana O. Lazareva, Olena A. Kudryk, Inessa M. Koltsun, Tetiana Magdalits, Sergei Zadorozhniy, Kira Kompaniiets, Andrii Ivanov, Sergiy Romanenko, Pavlo Kaplan, Vadym Y. Romanov, Oksana P. Mykytyuk, Nataliia S. Zaitseva, Sergiy N. Pyvovar, Lyudmyla Burdeuna, Emerita Serdobinska, Tatiana I. Shevchenko, Igor I. Ivanytskyi, Olena V. Khyzhnyak, Nataliya Kalinkina, Olena Keting, Olena Sklyanna, Olga Kashanska, Anna Shevelok, Marina Khristichenko, Ievgenii Y. Titov, Danilenko O. Oleksander, Nataliia S. Polenova, Nataliia Altunina, Viktoriia Kororaieva, Stanislav Zborovskiy, Leonid Kholopov, Iurii Suliman, Lanna Lukashenko, Stanislav Shvaykin, Olexandr M. Glavatskiy, Roman O. Sychov, Roman L. Kulynych, Oleksandr A. Skarzhevskyi, Nataliia V. Dovgan, Marta Horbach, Olga Cherkasova, Iryna Tyshchenko, Liudmyla Todoriuk, Svitlana Kizim, Nataliia Brodi, Oleksandr Ivanko, Olga Garbarchuk, Liudmyla Alieksieieva, Tetiana L. Shandra, Olena Beregova, Larisa An Bodretska, Svitlana S. Naskalova, Ivanna A. Antoniuk-Shcheglova, Olena V. Bondarenko, Natalia G. Andreeva, Iryna I. Vakalyuk, Olha S. Chovganyuk, Nataliya R. Artemenko, Kiril A. Maltsev, Natalia Kalishevich, Natalia G. Kondratyeva, Svetlana A. Nikitina, Maria V. Martjanova, Anna V. Sokolova, Dmitrii O. Dragunov, Olga Kolesnik, Vera Larina, Oxana V. Tsygankova, Maria Ivanova, Illia A. Karpov, Elena M. Aronova, Ekaterina S. Vedernikova, Ekaterina I. Lubinskaya, Taras Y. Burak, Sergey I. Skichko, Farhad Rasulev, Ekaterina B. Soldatova, Alexander L. Fenin, Ilya I. Laptev, Elena E. Luchinkina, Alexandr Akatov, Natalia V. Polenova, Natalia N. Slavina, Irina N. Korovnika, Marina Yu Prochorova, Regina Shakirova, Elena N. Andreicheva, Olga A. Krasnova, Tinatin V. Lobzhanidze, Tatiana B. Dmitrova, Viktoriya V. Stakhiv, Maria I. Pechatnikova, Alexandra V. Panova, Maria Y. Tipikina, Oxana P. Rotar, Nikolay A. Bokovin, Saule K. Karabalieva, Farid Y. Tumarov, Elena V. Vasileva, Natalya Gennadevna Lozhkina, Ekaterina V. Filippova, Alisa I. Sharkaeva, Ekanerina V. Filippova Deilik, Natalia Yu Tolkacheva, Elena N. Domracheva, Andrey N. Ryabikov, Inga T. Abesadze, Marianna Z. Alugishvili, Elena P. Nikolaeva, Nadezda V. Smirnova, Valentina I. Rodionova, Polina V. Dolovstaya, Igor E. Yunonin, Sergey V. Kadin, Tatyana S. Sveklina, Anna V. Bushmanova, Elena L. Barkova, Irina S. Gomova, Yana V. Brytkova, Tatiana B. Ivanova, Marina Y. Zubareva, Inga Skopets, Lybov A. Galashevskaya, Emilia D. Butinskaya, Olga G. Gusarova, Natalia B. Kalishevich, Yana R. Pavlova, Marianna P Serebrenitskaya, Vitalina F. Grygorieva, Gulnara R. Kuchaeva, Inna A. Vasileva, Gulnara I. Ospanova, Yulia V. Vahrusheva, Irina A. Semenova, Irina E.E. Mikhailova, Olga O. Kvasova, Valeria D. Shurygina, Alexey E. Rivin, Alexey O. Savelyev, Alexey A. Savelyev, Olesya O. Milyaeva, Nadezhda N. Lapshina, Ninel A. Lantsova, Pavel V. Alexandrov, Evgeniy A. Orlikov, Alla Falkovskaya, Tatiana Ripp, Sergei Triss, Stanislav Pekarskiy, Sitkova Ekaterina, Evgeniya N. Zhuravleva, Olga Perova, Galina Kovaleva, Liubov Koroleva, Lydia Mishchenko, Boris P. Garshin, Svetlana A. Kutuzova, Lyudmila I. Provotorova, Igor P. Zadvorny, Olga V. Okhapkina, Anatoly O. Khrustalev, Tatiana Suvorova, Elena S. Shaf, Varvara A. Vershinina, Andrey A. Kozulin, Oxana A. Oleynik, Irina Y. Martynova, Natalia V. Kizhvatova, Alla S. Salasyuk, Vera V. Tsoma, Alla A. Ledyaeva, Elena V. Chumachek, S.C. Blignaut, Tersia Y. Alexander, Chano Du Plessis, Thirumani Govender, Samatha M. Du Toit, Leya Motala, Areesh Gassiep, Christina Naude (Smit), Marli Terblanche, Marlien Snoer (Kruger), Berenice Pillay, De Vries Basson, Marisa E. Theron, Bianca Fouche, Mareli E. Coetzee, Pieter Odendall, Frederik H. Van Wijk, Anna-Mari Conradie, Trudie Van der Westhuizen, Carine Tredoux, Mohamed S. Mookdam, Andie J. Van der Merwe, Karin Snyman, Gerda Smal, Yvonne De Jager, Thomas A. Mabin, Annusca King, Lindy L. Henley, Brenda M. Zwane, Jane Robinson, Marinda Karsten, Andonia M. Page, Valerie Nsabiyumva, Charmaine Krahenbuhl, Jaiprakash D. Patel, Yunus E. Motala, Ayesha Dawood, Nondumiso B. Koza, Lenore M.S. Peters, Shavashni Ramlachan, Wilhelm J. Bodenstein, Pierre Roux, Lizelle Fouche, Cecilia M. Boshoff, Haroon M. Mitha, Fathima Khan, Henry P. Cyster, Helen Cyster, E. C. Wessels, Florence J. Jacobs, Melanie A. Sebastian, Deborah A. Sebastian, Nadia Mahomed, Ignatius P. Immink, Celia Cotzee, Tanja Cronje, Madele Roscher, Maria Le Roux, Yvonne A. Trinder, Renata Wnętrzak-Michalska, Magdalena Piszczek, Andrzej Piela, Ewa Czernecka, Dorota Knychas, Alina Walczak, Izabella Gładysz, Katarzyna Filas, Ewelina Kiluk, Krzysztof Świgło, Iwona Jędrzejczyk, Kamila Łuczyńska, Katarzyna Tymendorf, Wojciech Piesiewicz, Wojciech L. Kinasz, Stefan Samborski, Ilona Bartuś, Gramzyna Latocha Korecka, Ewa Gulaj, Jolanta Sopa, Bogusław Derlaga, Marcin Baisiak, Allicia Kowalisko, Edyta Stainszewska-Marasazlek, Bartosz Szafran, Malgorzata Swiatkiewicz, Artur Racewicz, Sławomir Grycel, Jerzy Supronik, Sylwia Walendziuk, Magdalena Tarantowicz, Agata Stasiak, Anna Sidorowicz-Białynicka, Marek Dwojak, Ewa Jaźwińska-Tarnawska, Katarzyna Kupczyk, Kamila Martowska, Kamila Kulon, Katarzyna Gajda, Bivin Wilson, Krithika Velusamy, Swaidha S. Sadhiq, Bhavani Siddeshi, M. Bhanukumar, Abhishek Srivatsav, Madhan Ramesh, Sri Harsha Chalasani, Mini Johnson, Prashanth Gopu, Jeesa George, Sowmya Reddy, Swetha Tessy Thara Eleena, Damodara Rao Kodem, Haritha N. Nakkella, Padma Kumari Mandula, Anjan Kumar Vuriya, Syamala Rajana, Aruna Kale, Tiwari Rajeev, Raina Jain, Vipin Jain, Srilakshmi Mandayam Adhyapak, Lumin Sheeba, Uma C R, Ramya R, Aditya V. Kulkarni, M.S. Ganachari, Ruma Sambrekar, Mohammad Bilal, Kalyan Chakravarthy, Ravi Badhavath, Sravan Kumar, Meenakshi Simhadri, Farooque Salamuddin, Venkat Prasad, Vivek Dwivedi, Sudha Sarna, Tilak Arora, Deepak Chawla, Archana Sathe, Chaware Gayatree, Ajeet Nanda, Ram Avtar, Jyoti Sharma, Vaibhavi P S, Sasirekha D, Deepthi Kobbajji, Ramya Ningappa, Shwetha Shree, Chandrashekar K, Nandini M R, Sowjanya S, Devika I G, Yashaswini N, Sonika G, Rathna L, Priyanka R, Rupal J. Shrimanker, Lakshmi Vinutha Reddy, K. Sumathi, Babitha Devi, Bina N. Naik, Rohini Manjunath, Rajeshwari Ashok, Tony V. Kunjumon, Jesline Thomas, Shaik Samdhani, Kasthuri Selvam, Poongothai Subramani, Nandakumar Parthasarathy, Nirmal K. Bohra, Anvesh K. Gatla, Cheryl Horbatuk, Julie Sills, E B. Davey, Liz Paramonczyk, Olga Racanelli, Sandy Strybosch, Andre Belanger, Jean Palardy, Alicia Schiffrin, Sylvie Gauthier, Norman Kalyniuk, Shawn D. Whatley, Heather Lappala, Grishma Patel, Matthew Reeve, Catherine Moran, Jody Everitt, Teresa Ferrari, Christine Bouffard, Jirir Frohlich, Gordon Francis, John Mancini, Gregory Bondy, Debbie DeAngelis, Patricia Fulton, David W. Blank, Angela Lombardo, Mylène Roy, Jackie Chow, Hyman Fox, William J. Grootendorst, Angela Hutchinson, Sharon M. Chan, Christie Fitzgerald, Lynn Wilkins, Rebecca L. Raymond, Arlene Reyes, Lavoie Marc André, Denis Fortin, Hélène Ouimet, Thanh-Thao Tôn-Nu, Martine Dussureault, Marie-Hélène Blain, Madeleine Roy, Nathalie Kopajko, Chantal Fleury, Karine Maheux, Gabriela Valentina Ciobotaru, Maria C. Constantinescu, Carmen-Lucia Gherghinescu, Ana-Maria Avram, Ioan Manitiu, Aura Sinpetrean, Lucian Pop, Delia Lupu, Radu Usvat, Ana Petrisor, Nicoleta Dumitru, Camelia Moruju, Adelina Gheorghita, Magda V. Mitu, Cosmin Macarie, Ana Maria Pop, Maria-Catalina Diaconu, Iulia Grancea, Mihaela Cosma, Mihaela Crisan, Elizabeth Herron, Paul Nestel, Sally B. Kay, Kaye S. Carter, Imran Badshah, Ashley Makepeace, Jocelyn Drinkwater, Michelle England, Azette Rafei, Kylie Patterson, Alicia Jenkins, Sybil McAuley, Sue M. Kent, Joy E. Vibert, Leonie Perrett, Thomas David, Samantha L. Kaye, Monika O’Connor, Nimalie J. Perera, Nicole T. Lai, Kerry A. Kearins, Christinia Dicamillo, Heather Anderson, Louise Ferguson, Sharon D. Radtke, Charles T. Thamarappillil, Janice M. Boys, Anita K. Long, Toni Shanahan, Michael Nyguyen, Nicole Forrest, Gill Tulloch, Della Greenwell, Sarah L. Price, Aye N. Tint, Priya K. Sumithran, Tamara L. Debreceni, Lisa Walker, Mary Caruana, Kira Edwards, Maria Stathopoulos, Cilla Haywood, Dimitar Sajkov, Sharen Pringle, Anne Tabner, Kathrina Bartolay, Chamindi Abeyratne, Kylie Bragg, Patrick Mulhern, Peter Purnell, Lyn Williams, Jane Hamlyn, Aurelia Connelly, Jan Hoffman, Samantha Bailey, Jane Kerr, Zarnia Morrison, Sarah Maeder, Roberta McEwan, Prasanna Kunasekera, Patrice McGregor, Jo Young, Sharon Berry, Rick Cutfield, Michelle Choe, Catherine McNamara, Narrinder K. Shergill, Petra Crone, Miles G. Williams, Keith Dyson, Diana H. Schmid, Audrey C. Doak, Melissa Spooner, Colin Edwards, Anne Turner, Grainne M. McAnnalley, Raewyn A. Fisher, Fraser B. Hamilton, Denis H. Friedlander, Melissa R. Kirk, Jayne E. Scales, Marguerite A. McLelland, Neelam A. Dalman, Cathy E. Vickers, Carolyn Jackson, Wendy Coleman, Phillip I. Garden, and Wendy F. Arnold
Subjects: Male, medicine.medical_specialty, Rate ratio, Double-Blind Method, Ischemia, Risk Factors, Physiology (medical), Internal medicine, medicine, Clinical endpoint, Humans, Myocardial infarction, Coronary Artery Bypass, Stroke, Aged, business.industry, Unstable angina, Hazard ratio, Absolute risk reduction, Middle Aged, medicine.disease, Eicosapentaenoic Acid, Number needed to treat, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.
Published: 2021
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8. Factors influencing utilization of cancer rehabilitation services among older breast cancer survivors in the USA: a qualitative study

Author: Mackenzi Pergolotti, Elizabeth R. Skidmore, Kathleen Doyle Lyons, Catherine M. Bender, Natalie E. Leland, Robert J. Ferguson, Pamela Toto, Rachelle Brick, and Rachel Eilers
Subjects: medicine.medical_specialty, Rehabilitation, Referral, business.industry, medicine.medical_treatment, Cancer, medicine.disease, Social support, Breast cancer, Oncology, Geriatric oncology, Family medicine, Health care, medicine, business, Qualitative research
Abstract: Purpose Many older breast cancer survivors experience long-term disability due to cancer and cancer-related treatments. However, less than 20% of older breast cancer survivors utilize cancer rehabilitation services to address cancer-related disability. Further understanding of survivor experiences may reveal strategies to improve uptake cancer rehabilitation services in the USA. Methods Older breast cancer survivors were recruited from university-based registries, previous breast cancer research studies at our institution, community support groups, and geriatric oncology clinics. Participants completed a brief online survey to capture demographic and clinical characteristics. Semi-structured telephone-based interviews were recorded, transcribed, and thematically analyzed. Interviews facilitated conversation about access to rehabilitation and indications for cancer rehabilitation. Results Participants (n = 14) were, on average, 71 years old, primarily White, and an average of 36.5 months post-diagnosis. Five participants had formally received rehabilitation for a cancer-related concern. Participants described seven factors that influenced utilization of cancer rehabilitation services: (1) emerging awareness of disability; (2) coping styles; (3) comparison of cancer experience with others; (4) provider interaction; (5) perceptions of cancer diagnosis; (6) social support; and (7) cost of rehabilitation. Conclusions Older breast cancer survivors consider multiple factors when determining utilization of cancer rehabilitation services. Development of shared decision-making tools addressing the seven described factors may enhance communication and referral to cancer rehabilitation services. Intervention research should adopt frameworks that enhance healthcare accessibility to improve relevance of intervention content and delivery features for older breast cancer survivors.
Published: 2021
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9. A Pilot Study of a Collaborative Palliative and Oncology Care Intervention for Patients with Head and Neck Cancer

Author: Marie Welsh, Areej El-Jawahri, Kathleen Murphy, Marcin Chwistek, Leigh Kinczewski, Sheila Amrhein, Lauren A Lucas, Jennifer S. Temel, Jessica Bauman, Thomas J. Galloway, Carolyn Y. Fang, Jacqueline Kelly, Florence P Bender, Matthew A Farren, Jessie Panick, John A. Ridge, Brian L. Egleston, Molly E. Collins, Mollie Clark Omilak, and Katherine A Schuster
Subjects: Oncology, medicine.medical_specialty, Coping (psychology), Palliative care, Pilot Projects, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Quality of life (healthcare), 030502 gerontology, Intervention (counseling), Internal medicine, Health care, medicine, Humans, Prospective Studies, General Nursing, business.industry, Palliative Care, Head and neck cancer, Original Articles, General Medicine, medicine.disease, Anesthesiology and Pain Medicine, Mood, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Quality of Life, 0305 other medical science, business
Abstract: BACKGROUND: Palliative care improves symptoms and coping in patients with advanced cancers, but has not been evaluated for patients with curable solid malignancies. Because of the tremendous symptom burden and high rates of psychological distress in head and neck cancer (HNC), we evaluated feasibility and acceptability of a palliative care intervention in patients with HNC receiving curative-intent chemoradiation therapy (CRT). METHODS: This was a prospective single-arm study in HNC patients receiving CRT at a single center in the United States. The intervention entailed weekly palliative care visits integrated with oncology care with a focus on symptoms and coping. The primary outcome was feasibility, defined as a >50% enrollment rate with >70% of patients attending at least half of the visits. To assess acceptability, we collected satisfaction ratings post-intervention. We also explored symptom burden, mood, and quality of life (QOL). RESULTS: We enrolled 91% (20/22) of eligible patients. Patients attended 133 of 138 palliative care visits (96%); all 20 attended >85% of visits. Eighteen of 19 (95%) found the intervention “very helpful” and would “definitely recommend” it. QOL and symptom burden worsened from baseline to week 5, but subsequently improved at one-month post-CRT. Overall, patients valued the one-on-one format of the intervention and receipt of additional care. CONCLUSIONS: Our palliative care intervention during highly morbid CRT was feasible and acceptable with high enrollment, excellent intervention compliance, and high patient satisfaction. Future randomized studies will further explore the impact on patient-reported outcomes and health care utilization.
Published: 2021
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10. Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

Author: Karine Pemberton, Fiona Harris, Jennifer Schaible, Frank Saran, Sarah Jefferies, Agnieszka Cseh, Michael Brada, Shaun Bender, Liam Welsh, Catherine McBain, Allan James, Rao Gattamaneni, Saran, Frank [0000-0002-3448-5064], and Apollo - University of Cambridge Repository
Subjects: Oncology, Adult, Cancer Research, medicine.medical_specialty, Afatinib, ErbB, Internal medicine, Glioma, Dose-escalation, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Temozolomide, Humans, Epidermal growth factor receptor, biology, Radiotherapy, business.industry, Brain Neoplasms, medicine.disease, Dacarbazine, Regimen, Treatment Outcome, Neurology, Concomitant, biology.protein, Clinical Study, Neurology (clinical), business, Glioblastoma, medicine.drug
Abstract: Funder: Boehringer Ingelheim; doi: http://dx.doi.org/10.13039/100001003, BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).
Published: 2021

11. A Role for Prior Knowledge in Statistical Classification of the Transition from Mild Cognitive Impairment to Alzheimer’s Disease

Author: Tapabrata Maiti, Zihuan Liu, and Andrew R. Bender
Subjects: Male, Support Vector Machine, Computer science, Feature selection, Context (language use), Logistic regression, Machine learning, computer.software_genre, Machine Learning, Neuroimaging, Alzheimer Disease, Feature (machine learning), medicine, Humans, Dementia, Cognitive Dysfunction, Aged, business.industry, General Neuroscience, Brain, General Medicine, medicine.disease, Magnetic Resonance Imaging, Support vector machine, Psychiatry and Mental health, Clinical Psychology, Statistical classification, Female, Artificial intelligence, Geriatrics and Gerontology, business, computer
Abstract: Background: The transition from mild cognitive impairment (MCI) to dementia is of great interest to clinical research on Alzheimer’s disease and related dementias. This phenomenon also serves as a valuable data source for quantitative methodological researchers developing new approaches for classification. However, the growth of machine learning (ML) approaches for classification may falsely lead many clinical researchers to underestimate the value of logistic regression (LR), which often demonstrates classification accuracy equivalent or superior to other ML methods. Further, when faced with many potential features that could be used for classifying the transition, clinical researchers are often unaware of the relative value of different approaches for variable selection. Objective: The present study sought to compare different methods for statistical classification and for automated and theoretically guided feature selection techniques in the context of predicting conversion from MCI to dementia. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate different influences of automated feature preselection on LR and support vector machine (SVM) classification methods, in classifying conversion from MCI to dementia. Results: The present findings demonstrate how similar performance can be achieved using user-guided, clinically informed pre-selection versus algorithmic feature selection techniques. Conclusion: These results show that although SVM and other ML techniques are capable of relatively accurate classification, similar or higher accuracy can often be achieved by LR, mitigating SVM’s necessity or value for many clinical researchers.
Published: 2021
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12. Risk of corticosteroid treatment and hospitalization after checkpoint inhibitor and radiation therapy in patients with cancer

Author: Chin Hur, Brigham Hyde, Adam S. Faye, David Andrew Bender, Simon K. Cheng, Lawrence Koutcher, and Kate E Lee
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Cancer, Ipilimumab, Retrospective cohort study, medicine.disease, Hospitalization, Radiation therapy, Adrenal Cortex Hormones, Prednisone, Relative risk, Internal medicine, medicine, Humans, Adverse effect, business, Lung cancer, Melanoma, Retrospective Studies, medicine.drug
Abstract: BACKGROUND Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. ICIs have contributed significantly to improved survival and thereby provide more opportunity for the development of local disease symptomatology requiring palliative radiation. Radiation therapy (RT) has also recently shown benefit in the oligometastatic setting. Data on the interaction and safety of concurrent ICIs and RT are limited. METHODS In this retrospective cohort study using a large medical claims database from 2010 to 2017, the need for corticosteroid therapy and the risk of hospitalization within 180 days of treatment with an ICI were determined for patients with a diagnosis of malignant melanoma or lung cancer. Patients were stratified by the use of RT within the 30 days before and after ICI therapy. RESULTS In all, 2020 patients (218 with RT and 1802 without RT) met the inclusion criteria for prednisone analysis, whereas 3519 patients (361 with RT and 3158 without RT) met the inclusion criteria for all other analyses. In a univariable analysis, RT was not associated with the need for prednisone (relative risk [RR], 1.2; 95% confidence interval [CI], 0.8-1.9) or methylprednisolone (RR, 1.1; 95% CI, 0.7-2.0). When the end point was hospitalization, RT was significantly associated with hospitalization after ICI therapy for certain cancer/drug combinations (RR for lung cancer/programmed death 1 receptor inhibitors, 1.4; 95% CI, 1.2-1.6; P < .001; RR for melanoma/ipilimumab, 2.0; 95% CI, 1.0-3.5; P = .03). CONCLUSIONS In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring corticosteroid therapy in comparison with not receiving RT. However, RT was associated with a higher risk of hospitalization, although this finding may be a result of differences in the underlying patient illness severity or oncologic disease burden at the baseline. LAY SUMMARY Data on the interaction of immunotherapy (immune checkpoint inhibitors) and radiation therapy and the safety of combining them are limited. Using a large database, this study has found that patients treated concurrently with immune checkpoint inhibitors and radiation therapy are not at increased risk for requiring corticosteroid therapy (which is used as a proxy for immune-related adverse events). However, concurrent therapy is associated with a higher risk of hospitalization, although this finding may be due to differences in the underlying patient illness severity (sicker patients may require both immunotherapy and radiation therapy).
Published: 2021
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13. Fearful facial expressions reduce inhibition levels in the dorsolateral prefrontal cortex in subjects with specific phobia

Author: Lisa Besting, Friederike Roebruck, Lena Pokorny, Stephan Bender, and Tomasz A. Jarczok
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Prefrontal Cortex, Audiology, behavioral disciplines and activities, Specific phobia, Dorsolateral Prefrontal Cortex, mental disorders, medicine, Humans, Emotional expression, N100, Facial expression, Electroencephalography, Cognition, medicine.disease, Transcranial Magnetic Stimulation, Facial Expression, Dorsolateral prefrontal cortex, Transcranial magnetic stimulation, Psychiatry and Mental health, Clinical Psychology, medicine.anatomical_structure, Phobic Disorders, nervous system, Anxiety, Female, medicine.symptom, Psychology, psychological phenomena and processes
Abstract: Background Specific phobias have the highest prevalence among anxiety disorders. Cognitive control involving the dorsolateral prefrontal cortex (DLPFC) is crucial for coping abilities in anxiety disorders. However, there is little research on the DLPFC in specific phobia. Methods Using transcranial magnetic stimulation (TMS), we investigated the TMS-evoked potential component N100 in the DLPFC at rest and while watching emotional expressions. The TMS-evoked N100 provides a parameter for gamma-aminobutyric acid (GABA)-B-mediated cortical inhibition. Twenty-two drug-free subjects with specific phobia (21 females and 1 male) were compared with 26 control subjects (23 females and 3 males) regarding N100 in the DLPFC at rest and during an emotional 1-back task with fearful, angry, and neutral facial expressions. Results At rest, we found reduced N100 amplitudes in the specific phobia compared with the control group. Furthermore, the specific phobia group showed a further reduction in N100 amplitude when memorizing fearful compared with neutral facial expressions. Conclusion There appears to be a decrease in GABA-B-mediated inhibition in the DLPFC in subjects with a specific phobia at rest. This decrease was more pronounced under emotional activation by exposure to fearful facial expressions, pointing towards additional state effects of emotional processing on inhibitory function in the DLPFC.
Published: 2021
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14. Combined Pipeline Embolization Device with Endoscopic Endonasal Fascia Lata/Muscle Graft Repair as a Salvage Technique for Treatment of Iatrogenic Carotid Artery Pseudoaneurysm

Author: Ann Liu, Nyall R. London, Alexander L. Coon, Douglas D. Reh, Cameron G. McDougall, Anthony P. Tufaro, Gary L. Gallia, Jordina Rincon-Torroella, and Matthew T. Bender
Subjects: endoscopic endonasal, medicine.medical_specialty, RD1-811, Pipeline (computing), medicine.medical_treatment, Carotid arteries, pituitary adenoma, Pseudoaneurysm, iatrogenic carotid injury, Fascia lata, medicine, Muscle graft, pipeline embolization, Embolization, RC346-429, business.industry, pseudoaneurysm, medicine.disease, Surgery, medicine.anatomical_structure, fascia lata, cardiovascular system, Original Article, Neurology. Diseases of the nervous system, Neurology (clinical), business, muscle graft
Abstract: The incidence of internal carotid artery (ICA) injury associated with endoscopic endonasal approaches to the pituitary is less than 1%. While parent vessel sacrifice has historically been the choice of treatment, vessel-preserving endovascular techniques have been reported. Although flow diversion offers endoluminal reconstruction, its major limitation is the delay in obtaining complete occlusion. We describe the use of a combined Pipeline embolization device (PED) with endoscopic endonasal repair using a fascia lata/muscle graft to treat an iatrogenic ICA pseudoaneurysm and report long-term radiographic follow-up. Further investigation into the utility of directed endoscopic endonasal repair of iatrogenic pseudoaneurysms initially treated with PED is necessary, especially given the need of post-PED anticoagulation and the rate of permanent neurological deficit after ICA sacrifice.
Published: 2021
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15. Variation in Early Management Practices in Moderate-to-Severe ARDS in the United States

Author: Nida Qadir, Raquel R. Bartz, Mary L. Cooter, Catherine L. Hough, Michael J. Lanspa, Valerie M. Banner-Goodspeed, Jen-Ting Chen, Shewit Giovanni, Dina Gomaa, Michael W. Sjoding, Negin Hajizadeh, Jordan Komisarow, Abhijit Duggal, Ashish K. Khanna, Rahul Kashyap, Akram Khan, Steven Y. Chang, Joseph E. Tonna, Harry L. Anderson, Janice M. Liebler, Jarrod M. Mosier, Peter E. Morris, Alissa Genthon, Irene K. Louh, Mark Tidswell, R. Scott Stephens, Annette M. Esper, David J. Dries, Anthony Martinez, Kraftin E. Schreyer, William Bender, Anupama Tiwari, Pramod K. Guru, Sinan Hanna, Michelle N. Gong, Pauline K. Park, Jay S. Steingrub, Kristin Brierley, Julia L. Larson, Ariel Mueller, Tereza Pinkhasova, Daniel Talmor, Imoigele Aisiku, Rebecca Baron, Lauren Fredenburgh, Peter Hou, Anthony Massaro, Raghu Seethala, Duncan Hite, Daniel Brodie, Briana Short, Raquel Bartz, Jordan C. Komisarow, James Blum, Annette Esper, Greg S. Martin, Eileen Bulger, Anna Ungar, Samuel M. Brown, Colin K. Grissom, Eliotte L. Hirshberg, Ithan D. Peltan, Roy G. Brower, Sarina K. Sahetya, R Scott Stephens, John K. Bohman, Hongchuan Coville, Ognjen Gajic, John C. O’Horo, Jorge-Bleik Ataucuri-Vargas, Fiore Mastroianni, Jamie Hirsch, Michael Qui, Molly Stewart, Ebaad Haq, Makrina Kamel, Olivia Krol, Kimberly Lerner, John Marini, Valentina Chiara Bistolfi Amaral, Jill Brown, Michael Brozik, Heidi Kemmer, Janet Obear, Nina Gentile, Kraftin E. Shreyer, Charles Cairns, Cameron Hypes, Josh Malo, Jarrod Mosier, Bhupinder Natt, Scott Hu, Ishan Mehta, Richard Branson, Betty Tsuei, Sanjay Dhar, Ashley Montgomery-Yates, Peter Morris, Tina Chen, Alfredo Lee Chang, Perren Cobb, Estelle Harris, Nate Hatton, Gia Lewis, Stephen McKellar, Sanjeev Raman, Joseph Tonna, Ellen Caldwell, and Sarah Dean
Subjects: Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, business.industry, Mortality rate, Peak inspiratory pressure, Critical Care and Intensive Care Medicine, medicine.disease, End stage renal disease, 03 medical and health sciences, 0302 clinical medicine, Standardized mortality ratio, 030228 respiratory system, Interquartile range, Emergency medicine, medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Tidal volume, Cohort study
Abstract: Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov
Published: 2021
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16. Robin sequence without cleft palate: Genetic diagnoses and management implications

Author: Stephanie A. Balow, Robert J. Hopkin, Sara Hopkin, K. Nicole Weaver, Howard M. Saal, Rolf W. Stottmann, Xue Zhang, Patricia L. Bender, Brian S. Pan, Bonnie Sullivan, and Barbara A. Chini
Subjects: Pediatrics, medicine.medical_specialty, Robin Sequence, Pierre Robin Syndrome, Respiratory distress, business.industry, Micrognathism, Glossoptosis, Infant, Newborn, Airway obstruction, medicine.disease, Feeding difficulty, Airway Obstruction, Cleft Palate, Management implications, Genetics, medicine, Humans, Medical diagnosis, medicine.symptom, Child, business, Genetics (clinical), Retrospective Studies
Abstract: Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases ("syndromic" RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.
Published: 2021
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17. Women's experiences of early pregnancy assessment unit services: a qualitative investigation

Author: Ruth Bender-Atik, Maria Memtsa, Sergio A. Silverio, Davor Jurkovic, Geraldine Barrett, Jennifer Hall, Judith Stephenson, and Venetia Goodhart
Subjects: Adult, medicine.medical_specialty, Early pregnancy factor, Sample (statistics), Health Services Accessibility, Unit (housing), Interviews as Topic, Young Adult, Clinical pathway, Pregnancy, Humans, Medicine, Maternal Health Services, Qualitative Research, Service (business), biology, business.industry, Qualitative interviews, Obstetrics and Gynecology, Abortion, Induced, medicine.disease, United Kingdom, Abortion, Spontaneous, Patient Satisfaction, Family medicine, biology.protein, Female, Pregnant Women, business, Qualitative research
Abstract: OBJECTIVE To explore the experiences of women who had used an Early Pregnancy Assessment Unit (EPAU) service in the UK and make recommendations for their improvement. DESIGN Qualitative interview study. SETTING Early Pregnancy Assessment Units in the UK. SAMPLE A maximum variation sample of women who had consented to be interviewed having attended one of 26 EPAUs involved in the VESPA study in 2018. METHODS In-depth telephone interviews with 38 women. A thematic framework analysis was conducted, with a focus on how experiences varied according to EPAU service configuration and clinical pathway. MAIN OUTCOME MEASURES Women's experiences of EPAU services. RESULTS We found that EPAUs are highly valued, and women's experiences were generally positive. However, women reported a range of issues that negatively affected their experience. These included difficulties accessing the service, insensitive management of the investigation and treatment options of pregnancy loss, poor communication, insufficient information and a lack of support for their psychological health. These issues were not strongly associated with EPAU configuration or clinical pathway. CONCLUSIONS Recommendations to improve women's experiences include the separation of EPAUs from general maternity services, and we make suggestions on how to remove barriers to access by reviewing opening hours, how to provide sensitive patient management, such as automatically cancelling appointments and scans following pregnancy loss, and how to improve communication, both with women and their partners as well as with other parts of the health service. TWEETABLE ABSTRACT Early Pregnancy Assessment Units are highly valued by women but aspects of their care experiences, particularly around sensitive management of pregnancy loss, could be improved.
Published: 2021
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18. Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits

Author: Thomas D. Barbour, Piers Blombery, Guy Touchard, Christophe Sirac, Lucy C. Fox, Moira Finlay, Adam G. Steinberg, Ahida Batrouney, Sébastien Bender, Surender Juneja, and Frank Bridoux
Subjects: business.industry, 030232 urology & nephrology, Glomerulonephritis, Immunoglobulin light chain, Fibril, medicine.disease, Molecular biology, Complement system, 03 medical and health sciences, 0302 clinical medicine, Nephrology, Monoclonal, Alternative complement pathway, Medicine, 030212 general & internal medicine, business, Nephrotic syndrome, Multiple myeloma
Abstract: There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.
Published: 2021
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19. Peroxisomal L-bifunctional Protein Deficiency Causes Male-specific Kidney Hypertrophy and Proximal Tubular Injury in Mice

Author: Sander M. Houten, Aaron Bender, Carmen Argmann, Pablo Ranea-Robles, Kensey Portman, John Cijiang He, David J. Mulholland, and Kyung Lee
Subjects: Male, medicine.medical_specialty, Renal function, Mitochondrion, Kidney, Article, Transcriptome, Mice, Internal medicine, Peroxisomes, medicine, Animals, Orchiectomy, Mice, Knockout, urogenital system, business.industry, Acute kidney injury, Hypertrophy, General Medicine, Peroxisome, medicine.disease, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, Renal physiology, business
Abstract: Background Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. Methods We studied kidneys of WT and Ehhadh KO mice on a C57BL/6N background using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, and metabolomics. To assess the role of androgens in the kidney phenotype of Ehhadh KO mice, mice underwent orchiectomy. Results We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipid levels. Orchiectomy of Ehhadh KO mice decreased the number of KIM-1 positive cells to WT levels. We revealed a pronounced sexual dimorphism in the expression of peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. Conclusions Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.
Published: 2021
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20. Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

Author: Menden M, Wang D, Mason M, Szalai B, Bulusu K, Guan Y, Yu T, Kang J, Jeon M, Wolfinger R, Nguyen T, Zaslavskiy M, Jang I, Ghazoui Z, Ahsen M, Vogel R, Neto E, Norman T, Tang E, Garnett M, Di Veroli G, Fawell S, Stolovitzky G, Guinney J, Dry J, Saez-Rodriguez J, Abante J, Abecassis B, Aben N, Aghamirzaie D, Aittokallio T, Akhtari F, Al-lazikani B, Alam T, Allam A, Allen C, de Almeida M, Altarawy D, Alves V, Amadoz A, Anchang B, Antolin A, Ash J, Aznar V, Ba-alawi W, Bagheri M, Bajic V, Ball G, Ballester P, Baptista D, Bare C, Bateson M, Bender A, Bertrand D, Wijayawardena B, Boroevich K, Bosdriesz E, Bougouffa S, Bounova G, Brouwer T, Bryant B, Calaza M, Calderone A, Calza S, Capuzzi S, Carbonell-Caballero J, Carlin D, Carter H, Castagnoli L, Celebi R, Cesareni G, Chang H, Chen G, Chen H, Cheng L, Chernomoretz A, Chicco D, Cho K, Cho S, Choi D, Choi J, Choi K, Choi M, De Cock M, Coker E, Cortes-Ciriano I, Cserzo M, Cubuk C, Curtis C, Van Daele D, Dang C, Dijkstra T, Dopazo J, Draghici S, Drosou A, Dumontier M, Ehrhart F, Eid F, ElHefnawi M, Elmarakeby H, van Engelen B, Engin H, de Esch I, Evelo C, Falcao A, Farag S, Fernandez-Lozano C, Fisch K, Flobak A, Fornari C, Foroushani A, Fotso D, Fourches D, Friend S, Frigessi A, Gao F, Gao X, Gerold J, Gestraud P, Ghosh S, Gillberg J, Godoy-Lorite A, Godynyuk L, Godzik A, Goldenberg A, Gomez-Cabrero D, Gonen M, de Graaf C, Gray H, Grechkin M, Guimera R, Guney E, Haibe-Kains B, Han Y, Hase T, He D, He L, Heath L, Hellton K, Helmer-Citterich M, Hidalgo M, Hidru D, Hill S, Hochreiter S, Hong S, Hovig E, Hsueh Y, Hu Z, Huang J, Huang R, Hunyady L, Hwang J, Hwang T, Hwang W, Hwang Y, Isayev O, Walk O, Jack J, Jahandideh S, Ji J, Jo Y, Kamola P, Kanev G, Karacosta L, Karimi M, Kaski S, Kazanov M, Khamis A, Khan S, Kiani N, Kim A, Kim J, Kim K, Kim S, Kim Y, Kirk P, Kitano H, Klambauer G, Knowles D, Ko M, Kohn-Luque A, Kooistra A, Kuenemann M, Kuiper M, Kurz C, Kwon M, van Laarhoven T, Laegreid A, Lederer S, Lee H, Lee J, Lee Y, Leppaho E, Lewis R, Li J, Li L, Liley J, Lim W, Lin C, Liu Y, Lopez Y, Low J, Lysenko A, Machado D, Madhukar N, De Maeyer D, Malpartida A, Mamitsuka H, Marabita F, Marchal K, Marttinen P, Mason D, Mazaheri A, Mehmood A, Mehreen A, Michaut M, Miller R, Mitsopoulos C, Modos D, Van Moerbeke M, Moo K, Motsinger-Reif A, Movva R, Muraru S, Muratov E, Mushthofa M, Nagarajan N, Nakken S, Nath A, Neuvial P, Newton R, Ning Z, De Niz C, Oliva B, Olsen C, Palmeri A, Panesar B, Papadopoulos S, Park J, Park S, Pawitan Y, Peluso D, Pendyala S, Peng J, Perfetto L, Pirro S, Plevritis S, Politi R, Poon H, Porta E, Prellner I, Preuer K, Pujana M, Ramnarine R, Reid J, Reyal F, Richardson S, Ricketts C, Rieswijk L, Rocha M, Rodriguez-Gonzalvez C, Roell K, Rotroff D, de Ruiter J, Rukawa P, Sadacca B, Safikhani Z, Safitri F, Sales-Pardo M, Sauer S, Schlichting M, Seoane J, Serra J, Shang M, Sharma A, Sharma H, Shen Y, Shiga M, Shin M, Shkedy Z, Shopsowitz K, Sinai S, Skola D, Smirnov P, Soerensen I, Soerensen P, Song J, Song S, Soufan O, Spitzmueller A, Steipe B, Suphavilai C, Tamayo S, Tamborero D, Tang J, Tanoli Z, Tarres-Deulofeu M, Tegner J, Thommesen L, Tonekaboni S, Tran H, De Troyer E, Truong A, Tsunoda T, Turu G, Tzeng G, Verbeke L, Videla S, Vis D, Voronkov A, Votis K, Wang A, Wang H, Wang P, Wang S, Wang W, Wang X, Wennerberg K, Wernisch L, Wessels L, van Westen G, Westerman B, White S, Willighagen E, Wurdinger T, Xie L, Xie S, Xu H, Yadav B, Yau C, Yeerna H, Yin J, Yu M, Yun S, Zakharov A, Zamichos A, Zanin M, Zeng L, Zenil H, Zhang F, Zhang P, Zhang W, Zhao H, Zhao L, Zheng W, Zoufir A, Zucknick M, AstraZeneca-Sanger Drug Combinatio, Ege Üniversitesi, Gönen, Mehmet (ORCID 0000-0002-2483-075X & YÖK ID 237468), Menden, Michael P., Wang, Dennis, Mason, Mike J., Szalai, Bence, Bulusu, Krishna C., Guan, Yuanfang, Yu, Thomas, Kang, Jaewoo, Jeon, Minji, Wolfinger, Russ, Nguyen, Tin, Zaslavskiy, Mikhail, Jang, In Sock, Ghazoui, Zara, Ahsen, Mehmet Eren, Vogel, Robert, Neto, Elias Chaibub, Norman, Thea, Tang, Eric K. Y., Garnett, Mathew J., Di Veroli, Giovanni Y., Fawell, Stephen, Stolovitzky, Gustavo, Guinney, Justin, Dry, Jonathan R., Saez-Rodriguez, Julio, Abante, Jordi, Abecassis, Barbara Schmitz, Aben, Nanne, Aghamirzaie, Delasa, Aittokallio, Tero, Akhtari, Farida S., Al-lazikani, Bissan, Alam, Tanvir, Allam, Amin, Allen, Chad, de Almeida, Mariana Pelicano, Altarawy, Doaa, Alves, Vinicius, Amadoz, Alicia, Anchang, Benedict, Antolin, Albert A., Ash, Jeremy R., Romeo Aznar, Victoria, Ba-alawi, Wail, Bagheri, Moeen, Bajic, Vladimir, Ball, Gordon, Ballester, Pedro J., Baptista, Delora, Bare, Christopher, Bateson, Mathilde, Bender, Andreas, Bertrand, Denis, Wijayawardena, Bhagya, Boroevich, Keith A., Bosdriesz, Evert, Bougouffa, Salim, Bounova, Gergana, Brouwer, Thomas, Bryant, Barbara, Calaza, Manuel, Calderone, Alberto, Calza, Stefano, Capuzzi, Stephen, Carbonell-Caballero, Jose, Carlin, Daniel, Carter, Hannah, Castagnoli, Luisa, Celebi, Remzi, Cesareni, Gianni, Chang, Hyeokyoon, Chen, Guocai, Chen, Haoran, Chen, Huiyuan, Cheng, Lijun, Chernomoretz, Ariel, Chicco, Davide, Cho, Kwang-Hyun, Cho, Sunghwan, Choi, Daeseon, Choi, Jaejoon, Choi, Kwanghun, Choi, Minsoo, De Cock, Martine, Coker, Elizabeth, Cortes-Ciriano, Isidro, Cserzo, Miklos, Cubuk, Cankut, Curtis, Christina, Van Daele, Dries, Dang, Cuong C., Dijkstra, Tjeerd, Dopazo, Joaquin, Draghici, Sorin, Drosou, Anastasios, Dumontier, Michel, Ehrhart, Friederike, Eid, Fatma-Elzahraa, ElHefnawi, Mahmoud, Elmarakeby, Haitham, van Engelen, Bo, Engin, Hatice Billur, de Esch, Iwan, Evelo, Chris, Falcao, Andre O., Farag, Sherif, Fernandez-Lozano, Carlos, Fisch, Kathleen, Flobak, Asmund, Fornari, Chiara, Foroushani, Amir B. K., Fotso, Donatien Chedom, Fourches, Denis, Friend, Stephen, Frigessi, Arnoldo, Gao, Feng, Gao, Xiaoting, Gerold, Jeffrey M., Gestraud, Pierre, Ghosh, Samik, Gillberg, Jussi, Godoy-Lorite, Antonia, Godynyuk, Lizzy, Godzik, Adam, Goldenberg, Anna, Gomez-Cabrero, David, de Graaf, Chris, Gray, Harry, Grechkin, Maxim, Guimera, Roger, Guney, Emre, Haibe-Kains, Benjamin, Han, Younghyun, Hase, Takeshi, He, Di, He, Liye, Heath, Lenwood S., Hellton, Kristoffer H., Helmer-Citterich, Manuela, Hidalgo, Marta R., Hidru, Daniel, Hill, Steven M., Hochreiter, Sepp, Hong, Seungpyo, Hovig, Eivind, Hsueh, Ya-Chih, Hu, Zhiyuan, Huang, Justin K., Huang, R. Stephanie, Hunyady, Laszlo, Hwang, Jinseub, Hwang, Tae Hyun, Hwang, Woochang, Hwang, Yongdeuk, Isayev, Olexandr, Walk, Oliver Bear Don't, Jack, John, Jahandideh, Samad, Ji, Jiadong, Jo, Yousang, Kamola, Piotr J., Kanev, Georgi K., Karacosta, Loukia, Karimi, Mostafa, Kaski, Samuel, Kazanov, Marat, Khamis, Abdullah M., Khan, Suleiman Ali, Kiani, Narsis A., Kim, Allen, Kim, Jinhan, Kim, Juntae, Kim, Kiseong, Kim, Kyung, Kim, Sunkyu, Kim, Yongsoo, Kim, Yunseong, Kirk, Paul D. W., Kitano, Hiroaki, Klambauer, Gunter, Knowles, David, Ko, Melissa, Kohn-Luque, Alvaro, Kooistra, Albert J., Kuenemann, Melaine A., Kuiper, Martin, Kurz, Christoph, Kwon, Mijin, van Laarhoven, Twan, Laegreid, Astrid, Lederer, Simone, Lee, Heewon, Lee, Jeon, Lee, Yun Woo, Leppaho, Eemeli, Lewis, Richard, Li, Jing, Li, Lang, Liley, James, Lim, Weng Khong, Lin, Chieh, Liu, Yiyi, Lopez, Yosvany, Low, Joshua, Lysenko, Artem, Machado, Daniel, Madhukar, Neel, De Maeyer, Dries, Malpartida, Ana Belen, Mamitsuka, Hiroshi, Marabita, Francesco, Marchal, Kathleen, Marttinen, Pekka, Mason, Daniel, Mazaheri, Alireza, Mehmood, Arfa, Mehreen, Ali, Michaut, Magali, Miller, Ryan A., Mitsopoulos, Costas, Modos, Dezso, Van Moerbeke, Marijke, Moo, Keagan, Motsinger-Reif, Alison, Movva, Rajiv, Muraru, Sebastian, Muratov, Eugene, Mushthofa, Mushthofa, Nagarajan, Niranjan, Nakken, Sigve, Nath, Aritro, Neuvial, Pierre, Newton, Richard, Ning, Zheng, De Niz, Carlos, Oliva, Baldo, Olsen, Catharina, Palmeri, Antonio, Panesar, Bhawan, Papadopoulos, Stavros, Park, Jaesub, Park, Seonyeong, Park, Sungjoon, Pawitan, Yudi, Peluso, Daniele, Pendyala, Sriram, Peng, Jian, Perfetto, Livia, Pirro, Stefano, Plevritis, Sylvia, Politi, Regina, Poon, Hoifung, Porta, Eduard, Prellner, Isak, Preuer, Kristina, Angel Pujana, Miguel, Ramnarine, Ricardo, Reid, John E., Reyal, Fabien, Richardson, Sylvia, Ricketts, Camir, Rieswijk, Linda, Rocha, Miguel, Rodriguez-Gonzalvez, Carmen, Roell, Kyle, Rotroff, Daniel, de Ruiter, Julian R., Rukawa, Ploy, Sadacca, Benjamin, Safikhani, Zhaleh, Safitri, Fita, Sales-Pardo, Marta, Sauer, Sebastian, Schlichting, Moritz, Seoane, Jose A., Serra, Jordi, Shang, Ming-Mei, Sharma, Alok, Sharma, Hari, Shen, Yang, Shiga, Motoki, Shin, Moonshik, Shkedy, Ziv, Shopsowitz, Kevin, Sinai, Sam, Skola, Dylan, Smirnov, Petr, Soerensen, Izel Fourie, Soerensen, Peter, Song, Je-Hoon, Song, Sang Ok, Soufan, Othman, Spitzmueller, Andreas, Steipe, Boris, Suphavilai, Chayaporn, Tamayo, Sergio Pulido, Tamborero, David, Tang, Jing, Tanoli, Zia-ur-Rehman, Tarres-Deulofeu, Marc, Tegner, Jesper, Thommesen, Liv, Tonekaboni, Seyed Ali Madani, Tran, Hong, De Troyer, Ewoud, Truong, Amy, Tsunoda, Tatsuhiko, Turu, Gabor, Tzeng, Guang-Yo, Verbeke, Lieven, Videla, Santiago, Vis, Daniel, Voronkov, Andrey, Votis, Konstantinos, Wang, Ashley, Wang, Hong-Qiang Horace, Wang, Po-Wei, Wang, Sheng, Wang, Wei, Wang, Xiaochen, Wang, Xin, Wennerberg, Krister, Wernisch, Lorenz, Wessels, Lodewyk, van Westen, Gerard J. P., Westerman, Bart A., White, Simon Richard, Willighagen, Egon, Wurdinger, Tom, Xie, Lei, Xie, Shuilian, Xu, Hua, Yadav, Bhagwan, Yau, Christopher, Yeerna, Huwate, Yin, Jia Wei, Yu, Michael, Yu, MinHwan, Yun, So Jeong, Zakharov, Alexey, Zamichos, Alexandros, Zanin, Massimiliano, Zeng, Li, Zenil, Hector, Zhang, Frederick, Zhang, Pengyue, Zhang, Wei, Zhao, Hongyu, Zhao, Lan, Zheng, Wenjin, Zoufir, Azedine, Zucknick, Manuela, College of Engineering, Department of Industrial Engineering, Institute of Data Science, RS: FSE DACS IDS, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: FHML MaCSBio, Promovendi NTM, Tero Aittokallio / Principal Investigator, Bioinformatics, Institute for Molecular Medicine Finland, Hu, Z, Fotso, DC, Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, Bosdriesz, E, Bougouffa, S, Bounova, G, Brouwer, T, Bryant, B, Calaza, M, Calderone, A, Calza, S, Capuzzi, S, Carbonell-Caballero, J, Carlin, D, Carter, H, Castagnoli, L, Celebi, R, Cesareni, G, Chang, H, Chen, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, Gestraud, P, Ghosh, S, Gillberg, J, Godoy-Lorite, A, Godynyuk, L, Godzik, A, Goldenberg, A, Gomez-Cabrero, D, Gonen, M, de Graaf, C, Gray, H, Grechkin, M, Guimera, R, Guney, E, Haibe-Kains, B, Han, Y, Hase, T, He, D, He, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, Moerbeke, M, Moo, K, Motsinger-Reif, A, Movva, R, Muraru, S, Muratov, E, Mushthofa, M, Nagarajan, N, Nakken, S, Nath, A, Neuvial, P, Newton, R, Ning, Z, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, Park, S, Pawitan, Y, Peluso, D, Pendyala, S, Peng, J, Perfetto, L, Pirro, S, Plevritis, S, Politi, R, Poon, H, Porta, E, Prellner, I, Preuer, K, Pujana, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden, Michael P. [0000-0003-0267-5792], Mason, Mike J. [0000-0002-5652-7739], Yu, Thomas [0000-0002-5841-0198], Kang, Jaewoo [0000-0001-6798-9106], Nguyen, Tin [0000-0001-8001-9470], Ahsen, Mehmet Eren [0000-0002-4907-0427], Stolovitzky, Gustavo [0000-0002-9618-2819], Guinney, Justin [0000-0003-1477-1888], Saez-Rodriguez, Julio [0000-0002-8552-8976], Apollo - University of Cambridge Repository, Menden, Michael P [0000-0003-0267-5792], Mason, Mike J [0000-0002-5652-7739], Pathology, CCA - Cancer biology and immunology, Medical oncology laboratory, Neurosurgery, Chemistry and Pharmaceutical Sciences, AIMMS, Medicinal chemistry, Universidade do Minho, Department of Computer Science, Professorship Marttinen P., Aalto-yliopisto, and Aalto University
Subjects: Drug Resistance, 02 engineering and technology, 13, PATHWAY, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Càncer, lcsh:Science, media_common, Cancer, Tumor, Settore BIO/18, Settore BIO/11, Drug combinations, High-throughput screening, Drug Synergism, purl.org/becyt/ford/1.2 [https], Genomics, Machine Learning, predictions, 3. Good health, ddc, Technologie de l'environnement, contrôle de la pollution, Benchmarking, 5.1 Pharmaceuticals, Cancer treatment, Farmacogenètica, Science & Technology - Other Topics, Development of treatments and therapeutic interventions, 0210 nano-technology, Human, Drug, media_common.quotation_subject, Science, 49/23, ADAM17 Protein, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Machine learning, Genetics, Chimie, Humans, BREAST-CANCER, CELL, 49/98, Science & Technology, Antineoplastic Combined Chemotherapy Protocol, 45, MUTATIONS, Computational Biology, Androgen receptor, Breast-cancer, Gene, Cell, Inhibition, Resistance, Pathway, Mutations, Landscape, Resource, 631/114/1305, medicine.disease, Drug synergy, 49, 030104 developmental biology, Pharmacogenetics, Mutation, Ciências Médicas::Biotecnologia Médica, lcsh:Q, 631/154/1435/2163, Biomarkers, RESISTANCE, 0301 basic medicine, ING-INF/06 - BIOINGEGNERIA ELETTRONICA E INFORMATICA, Statistical methods, Computer science, General Physics and Astronomy, Datasets as Topic, Drug resistance, purl.org/becyt/ford/1 [https], Phosphatidylinositol 3-Kinases, Biotecnologia Médica [Ciências Médicas], Neoplasms, Science and technology, Phosphoinositide-3 Kinase Inhibitors, Multidisciplinary, Biomarkers, Tumor, Cell Line, Tumor, Drug Antagonism, Drug Resistance, Neoplasm, Treatment Outcome, Pharmacogenetic, article, ANDROGEN RECEPTOR, 49/39, 631/114/2415, 021001 nanoscience & nanotechnology, 692/4028/67, Multidisciplinary Sciences, 317 Pharmacy, Patient Safety, Systems biology, 3122 Cancers, INHIBITION, Computational biology, Cell Line, medicine, LANDSCAPE, Physique, Human Genome, Data Science, General Chemistry, AstraZeneca-Sanger Drug Combination DREAM Consortium, Astronomie, GENE, Good Health and Well Being, Pharmacogenomics, Genomic, Neoplasm, 631/553, Phosphatidylinositol 3-Kinase
Abstract: PubMed: 31209238, The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. © 2019, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.
Published: 2019
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21. An online Sexual Health and Rehabilitation eClinic (TrueNTH SHAReClinic) for prostate cancer patients: a feasibility study

Author: Gerald B. Brock, Deborah McLeod, Antonio Finelli, L Jamnicky, S Elliott, Z G Yang, John W. Robinson, Jackie Bender, Lauren M. Walker, Keith Jarvi, Janet Ellis, Lianne Trachtenberg, Neil Fleshner, Richard J. Wassersug, Rajiv K. Singal, A. Petrella, Andrew Matthew, and Dean Elterman
Subjects: Male, Canada, medicine.medical_specialty, Sexual Behavior, medicine.medical_treatment, Intervention, Single item, Sexual recovery, Prostate cancer, Intervention (counseling), Humans, Medicine, Reproductive health, Rehabilitation, business.industry, Nursing research, Prostatic Neoplasms, Feasibility, medicine.disease, Oncology, Analytics, Family medicine, Feasibility Studies, Original Article, Web-based, Sexual Health, business, Rehabilitation interventions
Abstract: Purpose The primary objective was to determine the feasibility of implementing the TrueNTH SHAReClinic as a pan-Canadian sexual health and rehabilitation intervention for patients treated for localized prostate cancer. Methods The feasibility study was designed to evaluate the accessibility and acceptability of the intervention. Participants from five institutions across Canada were enrolled to attend one pre-treatment and five follow-up online clinic visits over 1 year following their prostate cancer (PC) treatment. Results Sixty-five patients were enrolled in the intervention. Website analytics revealed that 71% completed the intervention in its entirety, including the educational modules, with an additional 10% completing more than half of the intervention. Five thousand eighty-three views of the educational modules were made along with 654 views of the health library items. Over 1500 messages were exchanged between participants and their sexual health coaches. At 12 months, the intervention received an overall average participant rating of 4.1 out of 5 on a single item satisfaction measure. Conclusion Results support the TrueNTH SHAReClinic as highly acceptable to participants as defined by intervention adherence and engagement. The TrueNTH SHAReClinic demonstrated promise for being a feasible and potentially resource-efficient approach to effectively improving the sexual well-being of patients after PC treatment.
Published: 2021
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22. Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL

Author: B. Dharmaveer Shetty, Konrad J. Cios, Kallesh Danappa Jayappa, Vicki L. Gordon, Craig A. Portell, Michael J. Weber, Briana Wilson, Krista Isaac, Michael E. Williams, Puja C. Arora, Timothy P. Bender, Christopher Morris, and Shekhar Saha
Subjects: Lymphoid Neoplasia, medicine.diagnostic_test, Chemistry, Venetoclax, Chronic lymphocytic leukemia, Cell, Apoptosis, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Minimal residual disease, Flow cytometry, Multiple drug resistance, chemistry.chemical_compound, Phenotype, medicine.anatomical_structure, Drug Resistance, Neoplasm, In vivo, Leukocytes, Mononuclear, Tumor Microenvironment, medicine, Cancer research, Humans, Ex vivo
Abstract: The Bcl-2 inhibitor venetoclax has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional proapoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling antiapoptotic proteins using flow cytometry, we find that leukemic B cells that recently emigrated from the lymph node (CD69+/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple antiapoptotic proteins (Mcl-1High/Bcl-xLHigh/Bcl-2High) in both treated and treatment-naive CLL patients. These cells exhibited antiapoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry–based functional assay. Antiapoptotic multidrug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving “persister” cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally induced multidrug resistance. Overcoming this resistance required simultaneous inhibition of multiple antiapoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient peripheral blood mononuclear cells cultured in an ex vivo microenvironment model, we identify novel venetoclax drug combinations that induce selective cytotoxicity in multidrug-resistant CLL cells. Thus, we demonstrate that antiapoptotic multidrug-resistant CLL cells exist in patients de novo and show that these cells persist during proapoptotic treatment, such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.
Published: 2021
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23. Jaundice in patients with <scp>COVID</scp> ‐19

Author: Howard J. Worman and Joshua M. Bender
Subjects: medicine.medical_specialty, Bilirubin, RC799-869, liver, medicine.disease_cause, Gastroenterology, jaundice, law.invention, Sepsis, chemistry.chemical_compound, Ischemic hepatitis, COVID‐19, law, Internal medicine, medicine, Leukocytosis, Liver injury, Hepatology, business.industry, Original Articles, Diseases of the digestive system. Gastroenterology, Jaundice, medicine.disease, Intensive care unit, Elevated serum creatinine, chemistry, Original Article, bilirubin, medicine.symptom, business, liver injury, severe acute respiratory syndrome coronavirus 2
Abstract: Background and Aim While many studies have reported on liver injury in patients with coronavirus disease 2019 (COVID‐19), none have specifically addressed the significance of hepatic jaundice. We aimed to determine the clinical consequences and etiologies of jaundice in patients with COVID‐19. Methods We retrospectively analyzed clinical features, laboratory abnormalities, and rates of survival and intensive care unit admission in 551 patients with COVID‐19, hospitalized between 1 March 2020, and 31 May 2020 at a tertiary care academic medical center. Hepatic jaundice was defined as a serum total bilirubin concentration >2.5 mg/dL and a direct bilirubin concentration >0.3 mg/dL that was >25% of the total. Liver injury was characterized as cholestatic, mixed, or hepatocellular at the time of peak serum total bilirubin concentration by calculating the R factor. Results Hepatic jaundice was present in 49 (8.9%) patients and associated with a mortality rate of 40.8% and intensive care unit admission rate of 69.4%, both significantly higher than for patients without jaundice. Jaundiced patients had an increased frequency of fever, leukopenia, leukocytosis, thrombocytopenia, hypotension, hypoxemia, elevated serum creatinine concentration, elevated serum procalcitonin concentration, and sepsis. Nine jaundiced patients had isolated hyperbilirubinemia. Of the 40 patients with abnormally elevated serum alanine aminotransferase or alkaline phosphatase activities, 62.5% had a cholestatic, 20.0% mixed, and 17.5% hepatocellular pattern of liver injury. Conclusion Hepatic jaundice in patients with COVID‐19 is associated with high mortality. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis., Jaundice is a hallmark of liver dysfunction. We show that hepatic jaundice in patients with COVID‐19 is associated with high mortality, similar to that observed with invasive mechanical ventilation. The main etiologies of liver dysfunction leading to jaundice appear to be sepsis, severe systemic inflammation, and hypoxic/ischemic hepatitis.
Published: 2021
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24. Impact of 18F-FET PET/MRI on Clinical Management of Brain Tumor Patients

Author: Ulrike Ernemann, Caroline Maier, Ghazaleh Tabatabai, Jens Schittenhelm, Salvador Castaneda-Vega, Frank Paulsen, Christian la Fougère, Mirjam Renovanz, Benjamin Bender, Cornelia Brendle, and Constantin Roder
Subjects: medicine.medical_specialty, Contrast enhancement, business.industry, Clinical course, Brain tumor, medicine.disease, Malignancy, New diagnosis, Patient management, Functional brain, Tumor progression, Medicine, Radiology, Nuclear Medicine and imaging, Radiology, business
Abstract: Multiparametric PET-MRI with the amino-acid analog 18F-FET enables the simultaneous assessment of molecular, morphologic, and functional brain tumor characteristics. Although it is considered the most accurate non-invasive approach in brain tumors, its relevance for patient management is still under debate. Here we report the diagnostic performance of 18F-FET PET/MR and its impact on clinical management in a retrospective patient cohort. Methods: We retrospectively analyzed brain tumor patients who underwent 18F-FET PET/MR between 2017 and 2018. 18F-FET PET/MR examinations were indicated clinically due to equivocal standard imaging or clinical course. Histological confirmation or clinical and standard imaging follow-up served as the reference standard. We evaluated 18F-FET PET/MR accuracy in identifying malignancy in untreated suspect lesions (category new diagnosis) and true progression during adjuvant treatment (category detection of progression) in a clinical setting. Using multiple regression, we also estimated the contribution of single modalities to produce an optimal PET/MRI outcome. We assessed the recommended and applied therapies before and after 18F-FET PET/MR and noted if the treatment changed based on the 18F-FET PET/MR outcome. Results: We included 189 cases in the study. 18F-FET PET/MR allowed the identification of malignancy at new diagnosis with an accuracy of 85% and identified true progression with an accuracy of 93%. Contrast enhancement, 18F-FET PET uptake, and tracer kinetics were the major contributors to an optimal PET/MR outcome. In the previously equivocal patients, 18F-FET PET/MR changed the clinical management in 33% of the untreated lesions and 53% of the tumor progressions. Conclusion: Our results suggest that 18F-FET PET/MR helps clarify equivocal conditions and profoundly supports brain tumor patients' clinical management. The optimal modality setting of 18F-FET PET/MR and the clinical value of a simultaneous examination need further exploration. At a new diagnosis, multiparametric 18F-FET PET/MR might help prevent unnecessary invasive procedures by ruling out malignancy; however, adding static 18F-FET PET to an already existing MR examination seems to be of equal value. At detection of progression, multiparametric 18F-FET PET/MR may increase therapy effectiveness by distinguishing between tumor progression and therapy-related imaging alterations.
Published: 2021
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25. Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist

Author: Sichen Chang, Jonathan W. Dickerson, Baker Logan A, Thomas M. Bridges, Craig W. Lindsley, Darren W. Engers, Aidong Qi, Jerri M. Rook, Aaron M. Bender, P. Jeffrey Conn, Katrina A. Bollinger, Colleen M. Niswender, Changho Han, Alice L. Rodriguez, Trever R Carter, Li Peng, Julie L. Engers, Jordan C. O’Neill, Matthew Spock, and Katherine J. Watson
Subjects: Dystonia, Movement disorders, Chemistry, Organic Chemistry, Antagonist, Pharmacology, medicine.disease, Highly selective, Biochemistry, In vitro, Bioavailability, In vivo, Drug Discovery, Muscarinic acetylcholine receptor, medicine, medicine.symptom
Abstract: [Image: see text] Herein, we report the SAR leading to the discovery of VU6028418, a potent M(4) mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.
Published: 2021
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26. Discovery of the First Selective M4 Muscarinic Acetylcholine Receptor Antagonists with in Vivo Antiparkinsonian and Antidystonic Efficacy

Author: Jerri M. Rook, Aaron M. Bender, Colleen M. Niswender, Yuping Donsante, P. Jeffrey Conn, Hyekyung P. Cho, Li Peng, Julie L. Engers, Jonathan W. Dickerson, Thomas M. Bridges, Craig W. Lindsley, Ellen J. Hess, Sichen Chang, Aidong Qi, Weimin Peng, Mark S. Moehle, Jordan C. O’Neill, Daniel J. Foster, Alice L. Rodriguez, Zoey Bryant, Katherine J. Watson, and Kaylee J. Stillwell
Subjects: Pharmacology, Dystonia, Movement disorders, business.industry, Central nervous system, medicine.disease, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Tolerability, In vivo, Muscarinic acetylcholine receptor, Genetic model, Medicine, Pharmacology (medical), medicine.symptom, business, Neurotransmitter
Abstract: Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.
Published: 2021
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27. Malignancy-associated Sweet syndrome presenting with simultaneous histopathologic and morphologic variants

Author: Kiran Motaparthi, Nathan Burke, Nicole R. Bender, and Sami K Saikaly
Subjects: Pathology, medicine.medical_specialty, subcutaneous Sweet syndrome, ND, neutrophilic dermatoses, MPO, myeloperoxidase, Case Report, Dermatology, Malignancy, HSS, histiocytoid Sweet syndrome, histiocytoid Sweet syndrome, pulmonary Sweet syndrome, medicine, multiple clinical variants, MSS, malignancy-associated Sweet syndrome, biology, business.industry, multiple histopathologic variants, Sweet Syndrome, Sweet syndrome, SS, Sweet syndrome, medicine.disease, SSS, malignancy-associated Sweet syndrome, RL1-803, Myeloperoxidase, biology.protein, acute myelocytic leukemia, business, SSS, subcutaneous Sweet syndrome
Published: 2021
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28. Adaptive Cardiac Resynchronization Therapy Effect on Electrical Dyssynchrony (aCRT-ELSYNC): A randomized controlled trial

Author: Jason Thomas, Ashley Wirth, Merritt H. Raitt, Khidir Dalouk, Maros Ferencik, Cristina Fuss, Ryle Przybylowicz, Katherine J. Lutz, Peter M. Jessel, Ignatius Gerardo E. Zarraga, Thomas A. Dewland, Larisa G. Tereshchenko, Charles A. Henrikson, Bassel Beitinjaneh, Nichole M. Rogovoy, Christopher Hamilton, Karen S. MacMurdy, Aron Bender, David M. German, Kazi T. Haq, Babak Nazer, Peter M. van Dam, and Eric C. Stecker
Subjects: medicine.medical_specialty, medicine.medical_treatment, Cardiac resynchronization therapy, Heart failure, Noninvasive mapping, AV optimization, QRS complex, Clinical, Interquartile range, Internal medicine, medicine, Diseases of the circulatory (Cardiovascular) system, cardiovascular diseases, Implantable Devices, Ischemic cardiomyopathy, Ejection fraction, Bundle branch block, Left bundle branch block, business.industry, Electrocardiographic imaging, medicine.disease, Ventricular conduction abnormalities, Dyssynchrony, Randomized controlled trial, RC666-701, Cardiology, cardiovascular system, CRT, ECGI, business
Abstract: Background Adaptive cardiac resynchronization therapy (aCRT) is known to have clinical benefits over conventional CRT, but the mechanisms are unclear. Objective Compare effects of aCRT and conventional CRT on electrical dyssynchrony. Methods A prospective, double-blind, 1:1 parallel-group assignment randomized controlled trial in patients receiving CRT for routine clinical indications. Participants underwent cardiac computed tomography and 128-electrode body surface mapping. The primary outcome was change in electrical dyssynchrony measured on the epicardial surface using noninvasive electrocardiographic imaging before and 6 months post-CRT. Ventricular electrical uncoupling (VEU) was calculated as the difference between the mean left ventricular (LV) and right ventricular (RV) activation times. An electrical dyssynchrony index (EDI) was computed as the standard deviation of local epicardial activation times. Results We randomized 27 participants (aged 64 ± 12 years; 34% female; 53% ischemic cardiomyopathy; LV ejection fraction 28% ± 8%; QRS duration 155 ± 21 ms; typical left bundle branch block [LBBB] in 13%) to conventional CRT (n = 15) vs aCRT (n = 12). In atypical LBBB (n = 11; 41%) with S waves in V5-V6, conduction block occurred in the anterior RV, as opposed to the interventricular groove in strict LBBB. As compared to baseline, VEU reduced post-CRT in the aCRT (median reduction 18.9 [interquartile range 4.3–29.2 ms; P = .034]), but not in the conventional CRT (21.4 [-30.0 to 49.9 ms; P = .525]) group. There were no differences in the degree of change in VEU and EDI indices between treatment groups. Conclusion The effect of aCRT and conventional CRT on electrical dyssynchrony is largely similar, but only aCRT harmoniously reduced interventricular dyssynchrony by reducing RV uncoupling., Graphical abstract
Published: 2021

29. Adverse device‐device interaction between pacemaker and subcutaneous implantable cardiac defibrillator

Author: Seshadri Balaji, Nicholas James Abbott, Babak Nazer, Charles A. Henrikson, Jared Miller, and Aron Bender
Subjects: Adult, Male, Pacemaker, Artificial, medicine.medical_specialty, Heart block, Defibrillation, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, Ebstein's anomaly, Internal medicine, medicine, Humans, In patient, Prior Surgery, business.industry, General Medicine, medicine.disease, Defibrillators, Implantable, Heart Block, Shock (circulatory), Ventricular fibrillation, Cardiology, medicine.symptom, Electrophysiologic Techniques, Cardiac, Cardiology and Cardiovascular Medicine, business
Abstract: A 26-year-old patient with prior surgery for Ebstein's anomaly and a pacemaker (placed for post-surgical heart block and poor underlying rhythm) underwent SICD was placement. During defibrillation testing, device-device interaction led to undersensing of ventricular fibrillation with failure to shock. Increasing the pacemaker sensitivity resolved the problem but post shock pacing was unable to capture the heart after both shocks. The patient underwent removal of both the pacemaker and the SICD and placement of a transvenous ICD. Complex device-device interactions can occur in patients who are pacemaker dependent and undergo placement of a SICD.
Published: 2021
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30. Perceived impact of the COVID-19 pandemic on child and adolescent psychiatric services after 1 year (February/March 2021): ESCAP CovCAP survey

Author: Revet, Alexis, Hebebrand, Johannes, Anagnostopoulos, Dimitris, Kehoe, Laura A., Gradl-Dietsch, Gertraud, Anderluh, Marija, Armando, Marco, Askenazy, Florence, Banaschewski, Tobias, Bender, Stephan, Bernardon, Angelo, Brunner, Romuald, Cortese, Samuele, Delorme, Richard, Deschamps, Peter, Dodig-Ćurković, Katarina, Drobnic Radobuljac, Maja, Dubicka, Bernadka, Falkenberg Krantz, Mette, Fernandez, Arnaud, Fonseca Pinto, Vanessa, Franic, Tomislav, Fricke, Oliver, Gerardin, Priscille, Gindt, Morgane, Kumperščak, Hojka Gregorič, Goldschmidt, Teresa, Herpertz-Dahlmann, Beate, Kapp, Carole, Kotsis, Konstantinos, Lázaro, Luisa, Margari, Lucia, Margari, Francesco, Mazzone, Luigi, Mira Coelho, Alda, Möhler, Eva, Ozyurt, Gonca, Pamias Massana, Montserrat, Pastore, Adriana, Pàszthy, Bea, Pereira da Rocha, Ana Sofia, Pinho, Carla, Plener, Paul, Podlipny, Jiri, Polnareva, Nadia, Poustka, Luise, Purper-Ouakil, Diane, Rapado-Castro, Marta, Seker, Asilay, Serdari, Aspasia, Skrypnyk, Tetiana, Torres, Paloma, Trebaticka, Jana, von Plessen, Kerstin, Walitza, Susanne, Yurteri, Nihal, Zepf, Florian Daniel, and Klauser, Paul
Subjects: medicine.medical_specialty, Telemedicine, Service delivery framework, Medizin, Adolescents, Pandemic, Developmental and Educational Psychology, medicine, Child and adolescent psychiatry, Psychiatry, Children, business.industry, COVID-19, Original Contribution, General Medicine, medicine.disease, Mental health, Europe, Psychiatry and Mental health, Eating disorders, Pediatrics, Perinatology and Child Health, Anxiety, medicine.symptom, business, Psychopathology
Abstract: In April 2020, the European Society for Child and Adolescent Psychiatry (ESCAP) Research Academy and the ESCAP Board launched the first questionnaire of the CovCAP longitudinal survey to estimate the impact of COVID-19 on child and adolescent psychiatry (CAP) services in Europe. In this brief report, we present the main findings from the second questionnaire of the survey, one year after the COVID-19 pandemic began to hit Europe (i.e., February/March 2021). While service delivery to patients and their families was affected in a major way (reported by 68%) at the beginning of the pandemic, the majority of respondents (59%) in this second survey only reported a minor impact on care delivery. The use of telemedicine remained widespread (91%) but the proportion of CAP services partially closed or transformed to accommodate COVID-19 patients (59% in 2020) dropped to 20%. On the other hand, the perceived impact on the mental health and psychopathology of children and adolescents dramatically increased from “medium” (> 50%) in 2020 to “strong” or “extreme” (80%) in 2021. Four nosographic entities were particularly impacted: suicidal crises, anxiety disorders, eating disorders and major depressive episodes. Accordingly, this was associated with a substantial increase in the number of referrals or requests for assessments (91% reported an increase in 2021 while 61% reported a decrease in 2020). Finally, heads of the CAP departments expressed strong concerns regarding the management of the long-term consequences of this crisis, especially regarding the provision of care in light of the perceived increase in referrals. Supplementary Information The online version contains supplementary material available at 10.1007/s00787-021-01851-1.
Published: 2021
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31. Synergism between Rifampicin and Cationic Polyurethanes Overcomes Intrinsic Resistance of Escherichia coli

Author: Francis Dang, Chinnapatch Tantisuwanno, Matthew E Jennings, Kristin Bender, Hazel A. Barton, Abraham Joy, and John David Spencer
Subjects: Gram-negative bacteria, Polymers and Plastics, medicine.drug_class, Antibiotics, Bioengineering, 02 engineering and technology, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, Microbiology, Biomaterials, Polyketide, Materials Chemistry, medicine, Escherichia coli, biology, Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, biology.organism_classification, Hemolysis, 0104 chemical sciences, 0210 nano-technology, Bacterial outer membrane, Bacteria, Rifampicin, medicine.drug
Abstract: Antibiotic-resistant Gram-negative bacteria are emergent pathogens, causing millions of infections worldwide. While there are several classes of antibiotics that are effective against Gram-positive bacteria, the outer membrane (OM) of Gram-negative bacteria excludes high-molecular-weight hydrophobic antibiotics, making these species intrinsically resistant to several classes of antibiotics, including polyketides, aminocoumarins, and macrolides. The overuse of antibiotics such as β-lactams has also promoted the spread of resistance genes throughout Gram-negative bacteria, including the production of extended spectrum β-lactamases (ESBLs). The combination of innate and acquired resistance makes it extremely challenging to identify antibiotics that are effective against Gram-negative bacteria. In this study, we have demonstrated the synergistic effect of outer membrane-permeable cationic polyurethanes with rifampicin, a polyketide that would otherwise be excluded by the OM, on different strains of E. coli, including a clinically isolated uropathogenic multidrug-resistant (MDR) E. coli. Rifampicin combined with a low-dose treatment of a cationic polyurethane reduced the MIC in E. coli of rifampicin by up to 64-fold. The compositions of cationic polyurethanes were designed to have low hemolysis and low cell cytotoxicity while maintaining high antibacterial activity. Our results demonstrate the potential to rescue the large number of available OM-excluded antibiotics to target normally resistant Gram-negative bacteria via synergistic action with these cationic polyurethanes, acting as a novel antibiotic adjuvant class.
Published: 2021
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32. Abstract Anne H Berman – incoming ISBM president

Author: Keith Bender, Rebecca Beeken, Janice Thompson, Kathryn Burns Cunningham, Susan Michie, Helle Terkildsen Maindal, Ian Boardley, Nicole Andelic, Dorothy Currie, Juliane Traxler, Ingelise Andersen, Gozde Ozakinci, Peter Murchie, Jet Veldhuijzen van Zanten, Mary Barker, Olga Khavjou, Joanna Inchley, Sharon Carstairs, Finn Diderichsen, Susana Torres, Victoria Goodyear, Danielle Schoenaker, Julia Allan, and Jimmi Mathisen
Subjects: medicine.medical_specialty, business.industry, Self, Physical therapy, Chronic pain, Medicine, Smartphone application, business, medicine.disease, Applied Psychology
Published: 2021
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33. Necrotizing Escherichia coli skin and soft tissue infection with malakoplakia-like features mimicking pyoderma gangrenosum

Author: Nicole R. Bender, Kerrie G. Satcher, Alexander M. Hammond, Jennifer J. Schoch, and Kiran Motaparthi
Subjects: Pathology, medicine.medical_specialty, malakoplakia, business.industry, Malakoplakia, Dermatology, medicine.disease, medicine.disease_cause, RL1-803, medicine, Soft tissue infection, business, Escherichia coli, Pyoderma gangrenosum, pyoderma gangrenosum
Published: 2021

34. Competing risks in patients with primary prevention implantable cardioverter-defibrillators: Global Electrical Heterogeneity and Clinical Outcomes study

Author: Jonathan W. Waks, Ashkan Ehdaie, Khidir Dalouk, Merritt H. Raitt, Stacey J. Howell, Christine Tompkins, Albert J. Rogers, Sanjiv M. Narayan, Kazi T. Haq, Jessica Minnier, Aron Bender, Achille Peiris, Larisa G. Tereshchenko, and Sumeet S. Chugh
Subjects: Male, medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Risk Assessment, Article, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Physiology (medical), Internal medicine, medicine, Humans, 030212 general & internal medicine, education, Retrospective Studies, education.field_of_study, Ejection fraction, business.industry, Hazard ratio, Retrospective cohort study, Middle Aged, medicine.disease, Survival Analysis, United States, Confidence interval, Defibrillators, Implantable, Primary Prevention, Survival Rate, Death, Sudden, Cardiac, Heart failure, Ventricular fibrillation, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Heart Failure, Systolic
Abstract: Global electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear.The purpose of this study was to investigate whether GEH is associated with sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies in patients with heart failure and PP ICDs.We conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral on preimplant 12-lead electrocardiograms. Survival analysis using cause-specific hazard functions compared the strength of associations with 2 competing outcomes: sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies.We analyzed 2668 patients (mean age 63 ± 12 years; 624 (23%) female; 78% white; 43% nonischemic cardiomyopathy; left ventricular ejection fraction 28% ± 11% from 6 academic medical centers). After adjustment for demographic, clinical, device, and traditional electrocardiographic characteristics, SVG elevation (hazard ratio [HR] per 1SD 1.14; 95% confidence interval [CI] 1.04-1.25; P = .004), SVG azimuth (HR per 1SD 1.12; 95% CI 1.01-1.24; P = .039), SVG magnitude (HR per 1SD 0.75; 95% CI 0.66-0.85; P.0001), and QRS-T angle (HR per 1SD 1.21; 95% CI 1.08-1.36; P = .001) were associated with appropriate ICD therapies. Sum absolute QRST integral had different associations in infarct-related cardiomyopathy (HR 1.29; 95% CI 1.04-1.60) and nonischemic cardiomyopathy (HR 0.78; 95% CI 0.62-0.96) (PIn patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with 2 competing outcomes.
Published: 2021
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35. A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers

Author: Yolande A.L. Pijnenburg, Alessandro Padovani, Lieke H.H. Meeter, Rita Guerreiro, Mathieu Vandenbulcke, Rose Bruffaerts, Sonja Schönecker, Sofia Bergström, Florence Pasquier, Mikel Tainta, Beatriz Santiago, Roberto Gasparotti, Maria Rosário Almeida, Núria Bargalló, Abbe Ullgren, Martina Bocchetta, James B. Rowe, Pietro Tiraboschi, Robart Bartha, Rachelle Shafei, Benjamin Bender, Anna Månberg, Enrico Premi, Sergi Borrego-Écija, Sandro Sorbi, Christopher C Butler, Rick van Minkelen, Alberto Benussi, Marta Cañada, Carlo Wilke, Christin Andersson, Caroline Graff, Isabel Santana, Elisa Semler, Valentina Bessi, Miren Zulaica, Benedetta Nacmias, Tobias Langheinrich, Christen Shoesmith, Philip Van Damme, Camilla Ferrari, Martin Rosser, Pedro Rosa-Neto, Alexandre de Mendonça, Jennifer M. Nicholas, Catharina Prix, Sebastien Ourselin, Michele Veldsman, Jessica L. Panman, Håkan Thonberg, Jennie Olofsson, Paul M. Thompson, Ana Gorostidi, Andrea Arighi, Raquel Sánchez-Valle, Anna Antonell, Vesna Jelic, Ana Verdelho, Sara Mitchell, Janne M. Papma, Alina Díez, Giuliano Binetti, Rhian S Convery, Silvana Archetti, Ekaterina Rogaeva, Michela Pievani, C. Ferreira, Hans-Otto Karnath, Veronica Redaelli, Giuseppe Di Fede, Giovanni B. Frisoni, Carolina Maruta, Giacomina Rossi, Jaume Olives, Simon Ducharme, Roberta Ghidoni, Alexander Gerhard, Ron Keren, Johannes Levin, Sandra V. Loosli, Jose Bras, Isabelle Le Ber, Emily Todd, Robert Laforce, Sónia Afonso, Matthis Synofzik, Alazne Gabilondo, Elizabeth Finger, Thomas E. Cope, Paola Caroppo, Jorge Villanua, Diana Duro, Georgia Peakman, Giorgio G. Fumagalli, Serge Gauthier, Mario Masellis, Markus Otto, Caroline V. Greaves, Carolyn Timberlake, Harro Seelaar, Ione O.C. Woollacott, Sara Prioni, Jason D. Warren, Cristina Polito, Miguel Tábuas-Pereira, David F. Tang-Wai, Carmela Tartaglia, Linn Öijerstedt, Luisa Benussi, Barbara Borroni, Ricardo Taipa, Albert Lladó, Mircea Balasa, Rosa Rademakers, Lize C. Jiskoot, Miguel Castelo-Branco, Julia Remnestål, Fabrizio Tagliavini, Giorgio Giaccone, Maria João Leitão, Henrik Zetterberg, Valentina Cantoni, Daniela Galimberti, Sarah Anderl-Straub, Simon Mead, Myriam Barandiaran, Adrian Danek, Timothy Rittman, Chiara Fenoglio, Katrina M. Moore, David M. Cash, Rik Vandenberghe, Peter Nilsson, Elisabeth Wlasich, John C. van Swieten, Morris Freedman, Sandra E. Black, Carolin Heller, Stefano Gazzina, Gabriel Miltenberger, Fermin Moreno, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Begoña Indakoetxea, Tobias Hoegen, Gemma Lombardi, Elio Scarpini, Bergström, Sofia [0000-0003-2910-4754], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, Genetic Frontotemporal Dementia Initiative (GENFI), Jiskoot, Lize (Beitragende*r), Rowe, James B. (Beitragende*r), de Mendonça, Alexandre (Beitragende*r), Tagliavini, Fabrizio (Beitragende*r), Santana, Isabel (Beitragende*r), Le Ber, Isabelle (Beitragende*r), Levin, Johannes (Beitragende*r), Danek, Adrian (Beitragende*r), Otto, Markus (Beitragende*r), Frisoni, Giovanni (Beitragende*r), Ghidoni, Roberta (Beitragende*r), Sorbi, Sandro (Beitragende*r), Pasquier, Florence (Beitragende*r), Jelic, Vesna (Beitragende*r), Andersson, Christin (Beitragende*r), Afonso, Sónia (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Antonell, Anna (Beitragende*r), Archetti, Silvana (Beitragende*r), Arighi, Andrea (Beitragende*r), Balasa, Mircea (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Bargalló, Nuria (Beitragende*r), Bartha, Robart (Beitragende*r), Bender, Benjamin (Beitragende*r), Benussi, Alberto (Beitragende*r), Benussi, Luisa (Beitragende*r), Bessi, Valentina (Beitragende*r), Binetti, Giuliano (Beitragende*r), Black, Sandra (Beitragende*r), Bocchetta, Martina (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Bras, Jose (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Cañada, Marta (Beitragende*r), Cantoni, Valentina (Beitragende*r), Caroppo, Paola (Beitragende*r), Cash, David (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Convery, Rhian (Beitragende*r), Cope, Thomas (Beitragende*r), Di Fede, Giuseppe (Beitragende*r), Díez, Alina (Beitragende*r), Duro, Diana (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Ferrari, Camilla (Beitragende*r), Ferreira, Catarina B. (Beitragende*r), Fox, Nick (Beitragende*r), Freedman, Morris (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Gauthier, Serge (Beitragende*r), Gazzina, Stefano (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Gorostidi, Ana (Beitragende*r), Greaves, Caroline (Beitragende*r), Guerreiro, Rita (Beitragende*r), Heller, Carolin (Beitragende*r), Hoegen, Tobias (Beitragende*r), Indakoetxea, Begoña (Beitragende*r), Karnath, Hans-Otto (Beitragende*r), Keren, Ron (Beitragende*r), Langheinrich, Tobias (Beitragende*r), Leitão, Maria João (Beitragende*r), Lladó, Albert (Beitragende*r), Lombardi, Gemma (Beitragende*r), Loosli, Sandra (Beitragende*r), Maruta, Carolina (Beitragende*r), Mead, Simon (Beitragende*r), Meeter, Lieke (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), van Minkelen, Rick (Beitragende*r), Mitchell, Sara (Beitragende*r), Moore, Katrina (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Olives, Jaume (Beitragende*r), Ourselin, Sebastien (Beitragende*r), Padovani, Alessandro (Beitragende*r), Panman, Jessica (Beitragende*r), Papma, Janne M. (Beitragende*r), Peakman, Georgia (Beitragende*r), Pievani, Michela (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Polito, Cristina (Beitragende*r), Premi, Enrico (Beitragende*r), Prioni, Sara (Beitragende*r), Prix, Catharina (Beitragende*r), Rademakers, Rosa (Beitragende*r), Redaelli, Veronica (Beitragende*r), Rittman, Tim (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Rossi, Giacomina (Beitragende*r), Rosser, Martin (Beitragende*r), Santiago, Beatriz (Beitragende*r), Scarpini, Elio (Beitragende*r), Schönecker, Sonja (Beitragende*r), Semler, Elisa (Beitragende*r), Shafei, Rachelle (Beitragende*r), Shoesmith, Christen (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Tainta, Mikel (Beitragende*r), Taipa, Ricardo (Beitragende*r), Tang-Wai, David (Beitragende*r), Thomas, David L. (Beitragende*r), Thompson, Paul (Beitragende*r), Thonberg, Håkan (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Tiraboschi, Pietro (Beitragende*r), Todd, Emily (Beitragende*r), Van Damme, Philip (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Veldsman, Michele (Beitragende*r), Verdelho, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Warren, Jason (Beitragende*r), Wilke, Carlo (Beitragende*r), Woollacott, Ione (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Zetterberg, Henrik (Beitragende*r), and Zulaica, Miren (Beitragende*r)
Subjects: medicine.medical_specialty, Neurology, NEFM, Medizin, genetics [Mutation], LASSO, Biology, Aquaporin 4 (AQP4), Neurosecretory protein VGF (VGF), DISEASE, genetics [Progranulins], Cellular and Molecular Neuroscience, Progranulins, CEREBROSPINAL-FLUID, C9orf72, ddc:570, medicine, CRITERIA, Humans, Neuronal pentraxin 2 (NPTX2), RC346-429, genetics [Frontotemporal Dementia], Molecular Biology, Pathological, Genetics, Science & Technology, Neurosciences, RC952-954.6, Brain, Neurofilament medium polypeptide (NEFM), medicine.disease, Molecular medicine, Cerebrospinal fluid, Aquaporin 4, Geriatrics, Suspension bead array, Frontotemporal Dementia, Mutation, Mutation (genetic algorithm), Neurosciences & Neurology, Neurology. Diseases of the nervous system, Neurology (clinical), Life Sciences & Biomedicine, Random forest, Biomarkers, Research Article, Frontotemporal dementia
Abstract: Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.
Published: 2021
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36. Quantitative standardization of resident mouse behavior for studies of aggression and social defeat

Author: Ken Moon, Isabella Ndlebe, Sam A. Golden, Andrew R. Bender, Christine C. Kwiatkowski, Andrew L. Eagle, Hope O. Akaeze, Alfred J. Robison, and Nastacia L. Goodwin
Subjects: Male, Research groups, Standardization, Individuality, Article, Structural equation modeling, Social Defeat, Correlation, Social defeat, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Generalizability theory, Social Behavior, Pharmacology, Behavior, Animal, Aggression, Reference Standards, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Mood disorders, medicine.symptom, Stress, Psychological, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.
Published: 2021
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37. A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Author: Friedemann Bender, Tobias B. Haack, Alejandra Leyva-Gutiérrez, Stefan Hauser, Selina Reich, Matthis Synofzik, Andreas Traschütz, and David Mengel
Subjects: Adult, 0301 basic medicine, Spastic gait, Ataxia, Cerebellar Ataxia, Ubiquitin-Protein Ligases, Early-onset ataxia, Disease, 030105 genetics & heredity, Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, SCA48, medicine, Humans, Spinocerebellar Ataxias, Dominant, ddc:610, Index case, Exome sequencing, genetics [Ubiquitin-Protein Ligases], Genetics, Sanger sequencing, Original Communication, CHIP, genetics [Ataxia], medicine.disease, Phenotype, Pedigree, Neurology, symbols, Neurology (clinical), medicine.symptom, STUB1, Myoclonus, 030217 neurology & neurosurgery
Abstract: Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.
Published: 2021
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38. Sport-related femoral artery occlusion detected by near-infrared spectroscopy and pedal power measurements: a case report

Author: Marc R.M. Scheltinga, Martijn van Hooff, Mart Bender, Goof Schep, Hans H.C.M. Savelberg, Nutrition and Movement Sciences, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, and RS: SHE - R1 - Research (OvO)
Subjects: Male, medicine.medical_specialty, near-infrared spectroscopy, Flow limitation, Physical Therapy, Sports Therapy and Rehabilitation, Femoral artery occlusion, pedal power measurements, Peripheral Arterial Disease, Internal medicine, Case report, Humans, Medicine, Ankle Brachial Index, Orthopedics and Sports Medicine, disease, exercise testing, Spectroscopy, Near-Infrared, biology, Foot, business.industry, Vascular disease, Athletes, medicine.disease, biology.organism_classification, Arterial occlusion, Femoral Artery, Cardiology, business, arterial occlusion
Abstract: Approximately one in five professional cycling athletes will eventually develop a sport-related vascular problem. However, detecting such flow limitation is a diagnostic challenge as the sensitivity of the currently available standard diagnostic tools is limited.Here we present an athlete with exercise-induced pain and weakness of the left leg. During the physical examination, pulsations of the femoral artery were palpable but less prominent. He was analyzed in an ongoing research project aimed at improving methods detecting sport-related leg flow limitations.During functional testing, the ankle-brachial index of the left leg was moderately lowered. However, results of near-infrared spectroscopy and pedal power measurements were largely abnormal suggesting a severe flow limitation.Combining post-exercise ankle-brachial index, near-infrared spectroscopy, and pedal power measurements as routine diagnostic functional testing suggested a severe arterial flow inflow limitation. Conventional diagnostics encompassing duplex-Doppler echography and magnetic resonance angiography confirmed a femoral artery occlusion.https://www.trialregister.nl/ identifier is Trial NL8557.
Published: 2021
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39. Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

Author: Rebecca E. Tweedell, Rhoel R. Dinglasan, Abhai K. Tripathi, Prachi Khare, Dustin Miller, Juan José Martínez, Ronald R. Cobb, Timothy Hamerly, Nicole G Bender, Borja López-Gutiérrez, Matthias Harbers, Sandrine E. Nsango, Randall F. Howard, Eric M. Vela, Ryan R. Davis, and Vincent O. Nyasembe
Subjects: 0301 basic medicine, Protein vaccines, medicine.medical_treatment, Immunology, Biology, Article, Epitope, 03 medical and health sciences, 0302 clinical medicine, Antigen, parasitic diseases, medicine, Pharmacology (medical), 030212 general & internal medicine, RC254-282, Pharmacology, Vaccines, Immunogenicity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC581-607, medicine.disease, QS21, Virology, Malaria, 030104 developmental biology, Infectious Diseases, Humoral immunity, biology.protein, Antibody, Immunologic diseases. Allergy, Adjuvant
Abstract: Malaria transmission-blocking vaccines (TBVs) prevent the completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen. Structure-function studies identified two Class II epitopes that can induce potent transmission-blocking (T-B) antibodies, informing the design of the next-generation AnAPN1. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We then established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ effectively immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity, underscoring UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.
Published: 2021

40. Comprehensive Preclinical Assessment of ADVM-022, an Intravitreal Anti-VEGF Gene Therapy for the Treatment of Neovascular AMD and Diabetic Macular Edema

Author: Ruslan Grishanin, Pallavi Sharma, Szilard Kiss, Mehdi Gasmi, Claire M. Gelfman, Judith Greengard, Julio Nieves, Aivan Nguyen, and Kristina Oresic Bender
Subjects: 0301 basic medicine, medicine.medical_specialty, intravitreal, genetic structures, medicine.medical_treatment, neovascular AMD, Vitrectomy, adeno-associated virus, Macular Edema, 03 medical and health sciences, chemistry.chemical_compound, Macular Degeneration, 0302 clinical medicine, Ophthalmology, Diabetes Mellitus, Medicine, Pharmacology (medical), Aflibercept, Pharmacology, medicine.diagnostic_test, business.industry, Vascular Endothelial Growth Factors, Intravitreal administration, Original Articles, Genetic Therapy, Macular degeneration, Dependovirus, medicine.disease, gene therapy, eye diseases, Choroidal Neovascularization, Vascular endothelial growth factor, Clinical trial, 030104 developmental biology, Choroidal neovascularization, chemistry, anti-VEGF, 030221 ophthalmology & optometry, sense organs, medicine.symptom, business, medicine.drug, Electroretinography
Abstract: Inhibition of vascular endothelial growth factor is the mode of action for several approved therapies, including aflibercept, for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Lack of compliance due to the frequent intravitreal dosing requirements may result in inadequately treated disease, leading to irreversible vision impairment. To date, the majority of gene therapy clinical trials providing sustained anti-VEGF levels in the retina have been limited to subretinal injections requiring a vitrectomy. A single intravitreal injection of a gene therapy product could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, has been optimized for intravitreal delivery and strong protein expression. Long-term expression and efficacy of ADVM-022-derived aflibercept were evaluated in a laser-induced choroidal neovascularization (CNV) model in non-human primates. Ocular safety was evaluated following long-term suppression of VEGF by clinical scoring (inflammatory parameters) as well as optical coherence tomography (OCT) and electroretinography (ERG). Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels in ocular tissues. In addition, ADVM-022 administration 13 months before laser-induced CNV prevented the occurrence of clinically relevant CNV lesions, to the same degree as a bolus of aflibercept delivered at the time of laser. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for nAMD and DME, and may ultimately improve patients' visual outcomes. Clinical trials are currently underway, evaluating safety and efficacy following a single intravitreal injection of ADVM-022.
Published: 2021

41. Patterns of Translocation Testing in Patients Enrolling in a Cooperative Group Trial for Newly Diagnosed Metastatic Ewing Sarcoma

Author: Steven G. DuBois, Dinesh Rakheja, Allen Buxton, Lisa A. Teot, Julia Glade-Bender, Katherine A. Janeway, Mark Krailo, Richard Gorlick, Stephen L. Lessnick, and Brian D. Crompton
Subjects: Oncology, medicine.medical_specialty, Oncogene Proteins, Fusion, Bone Neoplasms, Context (language use), Chromosomal translocation, Sarcoma, Ewing, Translocation, Genetic, Article, Pathology and Forensic Medicine, law.invention, Randomized controlled trial, law, Internal medicine, Humans, Medicine, Neuroectodermal Tumors, Primitive, Peripheral, Pathology, Molecular, Child, In Situ Hybridization, Fluorescence, medicine.diagnostic_test, business.industry, General Medicine, medicine.disease, Molecular diagnostics, Primary tumor, Medical Laboratory Technology, Metastatic Ewing Sarcoma, Sarcoma, RNA-Binding Protein EWS, business, Fluorescence in situ hybridization
Abstract: Context.— Molecular diagnostics play an increasing role in the diagnosis of Ewing sarcoma. The type of molecular testing used in clinical practice has been poorly described. Objective.— To describe patterns of translocation testing for newly diagnosed Ewing sarcoma. Design.— Children's Oncology Group (COG) trial AEWS1221 was a phase III randomized trial enrolling patients with newly diagnosed metastatic Ewing sarcoma from 2014 to 2019. Patients were required to have a histologic diagnosis of Ewing sarcoma, but translocation testing was not required. Sites provided types and results of any molecular diagnostics performed. Results.— Data from 305 enrolled patients were available. The most common type of molecular testing was fluorescence in situ hybridization (FISH) performed on the primary tumor (236 of 305 patients; 77.4%), with positive testing for an EWSR1 or FUS translocation in 211 (89.4%). Reverse transcription–polymerase chain reaction (RT-PCR) on the primary tumor was performed in 61 of 305 patients (20%), with positive results in 48 of 61 patients (78.7%). Next-generation sequencing was reported in 7 patients for the primary tumor and in 3 patients for metastatic sites. For all types of testing on either primary or metastatic tumor, 16 of 305 patients (5.2%) had no reported translocation testing. When evaluating all results from all testing, 44 of 305 patients (14.4%) lacked documentation of an abnormality consistent with a molecular diagnosis of Ewing sarcoma. Conclusions.— COG sites enrolling in a Ewing sarcoma trial have high rates of testing by FISH or PCR. A small proportion of patients have no translocation testing on either primary or metastatic sites. Next-generation sequencing techniques are not yet commonly used in this context.
Published: 2021
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42. Next of kin’s Reactions to Results of Functional Neurodiagnostics of Disorders of Consciousness: a Question of Information Delivery or of Differing Epistemic Beliefs?

Author: Katja Kuehlmeyer, Leah Schembs, Andreas Bender, Ralf J. Jox, Maria Ruhfass, and Eric Racine
Subjects: Next of kin, Family caregivers, Health Policy, Judgement, Neuropsychology, Disorders of consciousness, medicine.disease, Psychiatry and Mental health, Neurology, Functional neuroimaging, medicine, Neuroethics, Psychology, Qualitative research, Cognitive psychology
Abstract: Our recent publication in Neuroethics re-constructed the perspectives of family caregivers of patients with disorders of consciousness (DOC) on functional neurodiagnostics (Schembs et al., Neuroethics, 2020). Two papers criticized some of our methodological decisions (Peterson, Neuroethics, 2020; Andersen et al., Neuroethics, 2020) and commented on some conclusions. In this commentary, we would like to further explain our methodological decisions. Despite the limitations of our findings, which we readily acknowledged, we continue to think they entail valid hypotheses that need further investigation. We conclude that some caregivers with high hopes for the recovery of their loved ones with DOC will most likely not consider results of functional neuroimaging as guiding information for treatment decisions, despite efforts taken to deliver information to them. Caregivers of that type might argue that such test-results are not a reliable source of information for the judgement of whether their loved one is likely going to recover or not (prognosis). We introduce the concept of epistemic beliefs to formulate this hypothesis and suggest that future qualitative studies in this area should be aware of such beliefs when investigating the effects of functional neurodiagnostics on knowledge communication and shared decision making for patients with DOC.
Published: 2021
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43. Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma

Author: Jennifer Bordeaux, Dustin McCurry, Arivarasan Karunamurthy, Lisa H. Butterfield, Rogerio I. Neves, Anil Pahuja, Matthew P. Holtzman, Beiru Chen, Jehovana Orozco Bender, Ahmad A. Tarhini, Yan Zang, Ju Young Kim, John M. Kirkwood, Yan Lin, Cindy Sander, Joseph J. Skitzki, IlaSri B. Summit, Marc S. Ernstoff, Christian Laing, Joseph J. Drabick, Yana G. Najjar, Huang Lin, Jennifer Tsau, Ghanashyam Sarikonda, Igor Puzanov, Hassane M. Zarour, Zeni Alfonso, Amy Rose, James F. Pingpank, and Diwakar Davar
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Oncology and Carcinogenesis, Antineoplastic Agents, Pembrolizumab, Interferon alpha-2, Antibodies, Monoclonal, Humanized, Antibodies, Drug Therapy, Clinical Research, Internal medicine, Monoclonal, 80 and over, medicine, Clinical endpoint, Humans, Oncology & Carcinogenesis, Stage (cooking), Melanoma, Humanized, Neoplasm Staging, Aged, Cancer, Aged, 80 and over, business.industry, Evaluation of treatments and therapeutic interventions, Immunotherapy, Middle Aged, medicine.disease, Neoadjuvant Therapy, Confidence interval, Discontinuation, 6.1 Pharmaceuticals, Combination, Drug Therapy, Combination, Female, Immunization, business, Adjuvant
Abstract: Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133
Published: 2021
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44. Stepwise Strategic Mitigation Planning in a Pediatric Oncology Center During the COVID-19 Pandemic

Author: Cassie Martinez, Stephen Gilheeney, Andrew L. Kung, Victoria Szenes, James Killinger, Mini Kamboj, Deborah Diotallevi, Giselle Melendez, Farid Boulad, Julia Glade Bender, Rachel Bright, Nicole Zakak, and Stephen S. Roberts
Subjects: Telemedicine, Adolescent, Context (language use), Telehealth, Cancer Care Facilities, Pediatrics, Young Adult, 03 medical and health sciences, Process Paper, 0302 clinical medicine, Neoplasms, Pandemic, medicine, Humans, Child, Strategic planning, 030504 nursing, Oncology (nursing), business.industry, COVID-19, medicine.disease, Strategic Planning, Pediatric cancer, United States, 030220 oncology & carcinogenesis, Preparedness, Medical emergency, 0305 other medical science, business
Abstract: Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reached the United States in January 2020. Located in New York City (NYC), MSK Kids, at Memorial Sloan Kettering Cancer Center services, is one of the largest pediatric cancer centers in the U.S., caring for children, teenagers, and young adults with cancer, immune deficiencies, and blood disorders. Methods: Implementation for infection mitigation and ongoing care of patients included: (1) the creation of a strategic planning team of physicians, advanced practice providers, nurses, and administrators to develop guidance and workflows, (2) continuous reassessment of patients’ needs for hospital services and visit frequency, (3) the use of telemedicine to replace in-person visits, (4) the use of satellite regional centers to manage patients living outside NYC, (5) pre-screening of patients prior to visits for risks and symptoms of coronavirus disease 2019 (COVID-19) infection, (6) day-of-service screening for risks or symptoms of COVID-19 infection, (7) surveillance testing of children and their caregivers, and (8) creation of cohort plans for the management of COVID-19 positive and uninfected patients within the same institution, in both the outpatient and inpatient settings. Results: We describe the timeline for planning mitigation during the first weeks of the pandemic, and detail in a stepwise fashion the rationale and implementation of COVID-19 containment efforts in the context of a large pediatric oncology program. Discussion: Our experience offers a model on which to base strategic planning efforts at other pediatric oncology centers, for continued preparedness to combat the threat posed by SARS-CoV-2 worldwide.
Published: 2021
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45. Internet and social media use in cancer patients: association with distress and perceived benefits and limitations

Author: Pryangka Rao, Shayan Kassirian, Jacqueline L. Bender, Arielle Geist, M. Catherine Brown, Karmugi Balaratnam, Katrina Hueniken, Geoffrey Liu, Lawson Eng, Ilana Geist, Chelsea Paulo, Abha A. Gupta, Elliot Charles Smith, Wei Xu, Alexander Magony, and Mindy Liang
Subjects: Coping (psychology), Cross-sectional study, business.industry, Nursing research, Cancer, medicine.disease, 03 medical and health sciences, Distress, Social support, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Social media, The Internet, 030212 general & internal medicine, business, Demography
Abstract: Cancer patients may turn to social media (SM) to cope with distress. We investigated associations between distress and internet/SM use for cancer information/support. Adult patients at a Canadian cancer centre completed a cross-sectional survey on sociodemographics, health status, use of cancer online resources and distress (EQ5D-5L). Statistical models adjusted for relevant variables. Of 376 participants, median age was 52 years, time since diagnosis was 1.63 years, 272 (74%) had post-secondary education and 192 (51%) were female. For cancer information/support, 276 (73%) used internet and 147 (39%) SM. Dose response relationships were observed between distress and cancer-related internet (p = 0.02), and SM use (p 30 min daily (OR = 3.4; 95% CI: 2.1–5.7), and were distressed (OR = 1.67, 95% CI: 1.0–2.7). SM benefits were to learn about cancer (93; 25%), distract from cancer (85; 23%) and connect with survivors (81; 22%). SM limitations were privacy (161; 43%), quality (90; 24%) and personal applicability (85; 23%). Females used SM more to connect with survivors than males (p = 0.001). Greater internet confidence, higher education and being female were associated with cancer-related internet/SM use. Distressed cancer patients were also more likely to turn to SM. Privacy concerns may limit SM use for coping. Future research should determine how to optimize SM in caring for and connecting with patients and reduce cancer-related distress.
Published: 2021
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46. Hearing loss prevalence and years lived with disability, 1990-2019: findings from the Global Burden of Disease Study 2019

Author: Rezaul Karim Ripon, Lydia M. Haile, Richard C. Franklin, Virginia Núñez-Samudio, Sonali G. Choudhari, Chythra R Rao, Maria Inês Schmidt, Jeff T. Zhao, Hanadi Al Hamad, Bing-Fang Hwang, Christopher R. Cederroth, Howard J. Hoffman, Naohiro Yonemoto, Rajaa Al-Raddadi, Avina Vongpradith, David Laith Rawaf, Valentin Yurievich Skryabin, Maja Pasovic, Ismail Tareque, Alessandra Lugo, Theo Vos, Rabia Hussain, Golnaz Heidari, Tarik A. Rashid, Ghozali Ghozali, Stephen S Lim, Bay Vo, Emma Elizabeth Spurlock, Himal Kandel, Jitendra Singh, Adrian Davis, Pankaj Bhardwaj, Houman Sotoudeh, Arif Mohammed, Rekha Thapar, Mohammad Rabiee, Florian Fischer, Deepika Singhal, Haroon Ahmed, Irina Filip, Michael Ekholuenetale, Amirhossein Sahebkar, Abdallah M. Samy, Fatemeh Pashazadeh Kan, Sathish Kumar Jayapal, Ionela-Roxana Glavan, Mikhail Sergeevich Zastrozhin, Bruce Bartholow Duncan, Aziz Rezapour, Jalal Arabloo, Sahel Valadan Tahbaz, Chuanhua Yu, Huong Lan Thi Nguyen, Vahid Rashedi, Shrikant Pawar, Shelly Chadha, Mahaveer Golechha, Bach Xuan Tran, Jaimie D Steinmetz, Deepak Dhamnetiya, Olayinka Stephen Ilesanmi, Masood Ali Shaikh, Charlie Ashbaugh, Stany W. Lobo, Akshaya Srikanth Bhagavathula, Biruk Wogayehu Taddele, Baye Dagnew, Walter Mendoza, Morteza Arab-Zozani, Turki Alanzi, Sandhya Neupane Kandel, Kebadnew Mulatu Mihretie, Zaheer-Ud-Din Babar, Jasvinder A. Singh, Veer Bala Gupta, Maheswar Satpathy, Ali H. Mokdad, Simon I. Hay, Sadia Bibi, Louis Jacob, Christopher J L Murray, Liaqat Ali, Keyvan Pakshir, Allen Seylani, Andre M. N. Renzaho, Eman Abu-Gharbieh, Till Bärnighausen, Segun Emmanuel Ibitoye, Voilet Rodrigues, Vahit Yigit, Mohammed Shannawaz, Mohammad Ali Moni, Ali Yadollahpour, Rose G Bender, Victor M. Oguoma, Rohollah Kalhor, Saif Ullah, Mohammad Zamani, Anna Aleksandrovna Skryabina, Mowafa Househ, Milena Santric-Milicevic, Juwel Rana, Fakher Rahim, Soraya Siabani, Mokhtar Mohammadi, Bolajoko O. Olusanya, Khezar Hayat, Teroj Abdulrahman Mohamed, Palash Chandra Banik, Nikha Bhardwaj, Brijesh Sathian, Fahad Alanezi, Jean Jacques Noubiap, Jagadish Rao Padubidri, Hans Orru, Nawzad K. Al-Salihi, Navid Rabiee, Xuefeng Liu, Iván Landires, Paul S Briant, Jost B. Jonas, Mayowa O. Owolabi, Zhi Jiang Zhang, Farhad Ghamari, Vahid Alipour, Sowmya J. Rao, Mehdi Hosseinzadeh, Desta Debalkie Atnafu, Lalit Dandona, Molly R Nixon, Rovshan Khalilov, Ai Koyanagi, Silvano Gallus, Saad M.A. Dahlawi, Salman Rawaf, Mohammad Abdollahi, Ted R. Miller, Masao Iwagami, Amanual Getnet Mersha, Savita Lasrado, Marcos Roberto Tovani-Palone, Umar Saeed, Fares Alahdab, Vafa Rahimi-Movaghar, Ivo Iavicoli, Yonas Akalu, Amir Masoud Rahmani, Kathleen Pillsbury Hopf, Assefa Desalew, Sheikh Mohammed Shariful Islam, Amare Belachew Dagnew, Ravi Prakash Jha, Jacob Olusegun Olusanya, Jingkai Wei, Mandira Lamichhane Dhimal, Kaloyan Kamenov, Anasthasia Zastrozhina, Samer Hamidi, Gbenga A. Kayode, Katrin Burkart, Anjali Singal, Shahina Pardhan, Rakhi Dandona, Jaykaran Charan, Akram Pourshams, Xiaochen Dai, Meghnath Dhimal, Kerrie E. Doyle, Seyed Sina Naghibi Irvani, Shilpa Gaidhane, Francesco Saverio Violante, Monika Sawhney, Animut Tagele Tamiru, Hai Quang Pham, Atif Amin Baig, Hubert Amu, Judie Arulappan, Ayele Semachew Kasa, Alaa Makki, Syed Amir Gilani, Abdollah Mohammadian-Hafshejani, Soewarta Kosen, Abhay Gaidhane, Birhanu Wubale Yirdaw, Ismaeel Yunusa, Ali Bijani, Billy Randall Hammond, Neeti Rustagi, Bogdan Oancea, Ahmad Ghashghaee, Amadou Barrow, Mosiur Rahman, Ashkan Afshin, Yigizie Yeshaw, Mahalaqua Nazli Khatib, Amir Radfar, Winfried Schlee, Andrew T Olagunju, Dinh-Toi Chu, Vasily Vlassov, Ejaz Ahmad Khan, Sanjeev Misra, Rosa A. S. Couto, Marina Pinheiro, Mohammad Hifz Ur Rahman, Amir Abdoli, Bárbara Niegia Garcia de Goulart, Wondimeneh Shibabaw Shiferaw, Seyed Hossein Yahyazadeh Jabbari, Aislyn U. Orji, Vivek Gupta, Giang Thu Vu, G Anil Kumar, Haile L.M., Kamenov K., Briant P.S., Orji A.U., Steinmetz J.D., Abdoli A., Abdollahi M., Abu-Gharbieh E., Afshin A., Ahmed H., Rashid T.A., Akalu Y., Alahdab F., Alanezi F.M., Alanzi T.M., Al Hamad H., Ali L., Alipour V., Al-Raddadi R.M., Amu H., Arabloo J., Arab-Zozani M., Arulappan J., Ashbaugh C., Atnafu D.D., Babar Z.-U.-D., Baig A.A., Banik P.C., Barnighausen T.W., Barrow A., Bender R.G., Bhagavathula A.S., Bhardwaj N., Bhardwaj P., Bibi S., Bijani A., Burkart K., Cederroth C.R., Charan J., Choudhari S.G., Chu D.-T., Couto R.A.S., Dagnew A.B., Dagnew B., Dahlawi S.M.A., Dai X., Dandona L., Dandona R., Desalew A., Dhamnetiya D., Dhimal M.L., Dhimal M., Doyle K.E., Duncan B.B., Ekholuenetale M., Filip I., Fischer F., Franklin R.C., Gaidhane A.M., Gaidhane S., Gallus S., Ghamari F., Ghashghaee A., Ghozali G., Gilani S.A., Glavan I.-R., Golechha M., Goulart B.N.G., Gupta V.B., Gupta V.K., Hamidi S., Hammond B.R., Hay S.I., Hayat K., Heidari G., Hoffman H.J., Hopf K.P., Hosseinzadeh M., Househ M., Hussain R., Hwang B.-F., Iavicoli I., Ibitoye S.E., Ilesanmi O.S., Irvani S.S.N., Islam S.M.S., Iwagami M., Jacob L., Jayapal S.K., Jha R.P., Jonas J.B., Kalhor R., Al-Salihi N.K., Kandel H., Kasa A.S., Kayode G.A., Khalilov R., Khan E.A., Khatib M.N., Kosen S., Koyanagi A., Kumar G.A., Landires I., Lasrado S., Lim S.S., Liu X., Lobo S.W., Lugo A., Makki A., Mendoza W., Mersha A.G., Mihretie K.M., Miller T.R., Misra S., Mohamed T.A., Mohammadi M., Mohammadian-Hafshejani A., Mohammed A., Mokdad A.H., Moni M.A., Kandel S.N., Nguyen H.L.T., Nixon M.R., Noubiap J.J., Nunez-Samudio V., Oancea B., Oguoma V.M., Olagunju A.T., Olusanya B.O., Olusanya J.O., Orru H., Owolabi M.O., Padubidri J.R., Pakshir K., Pardhan S., Kan F.P., Pasovic M., Pawar S., Pham H.Q., Pinheiro M., Pourshams A., Rabiee N., Rabiee M., Radfar A., Rahim F., Rahimi-Movaghar V., Ur Rahman M.H., Rahman M., Rahmani A.M., Rana J., Rao C.R., Rao S.J., Rashedi V., Rawaf D.L., Rawaf S., Renzaho A.M.N., Rezapour A., Ripon R.K., Rodrigues V., Rustagi N., Saeed U., Sahebkar A., Samy A.M., Santric-Milicevic M.M., Sathian B., Satpathy M., Sawhney M., Schlee W., Schmidt M.I., Seylani A., Shaikh M.A., Shannawaz M., Shiferaw W.S., Siabani S., Singal A., Singh J.A., Singh J.K., Singhal D., Skryabin V.Y., Skryabina A.A., Sotoudeh H., Spurlock E.E., Taddele B.W., Tamiru A.T., Tareque M.I., Thapar R., Tovani-Palone M.R., Tran B.X., Ullah S., Tahbaz S.V., Violante F.S., Vlassov V., Vo B., Vongpradith A., Vu G.T., Wei J., Yadollahpour A., Jabbari S.H.Y., Yeshaw Y., Yigit V., Yirdaw B.W., Yonemoto N., Yu C., Yunusa I., Zamani M., Zastrozhin M.S., Zastrozhina A., Zhang Z.-J., Zhao J.T., Murray C.J.L., Davis A.C., Vos T., Chadha S., Haile, Lydia M, Kamenov, Kaloyan, Briant, Paul Svitil, Orji, Aislyn U, Steinmetz, Jaimie D, Abdoli, Amir, Abdollahi, Mohammad, Abu-Gharbieh, Eman, Afshin, Ashkan, Ahmed, Haroon, Ahmed Rashid, Tarik, Akalu, Yona, Alahdab, Fare, Alanezi, Fahad Mashhour, Alanzi, Turki M, Al Hamad, Hanadi, Ali, Liaqat, Alipour, Vahid, Al-Raddadi, Rajaa M, Amu, Hubert, Arabloo, Jalal, Arab-Zozani, Morteza, Arulappan, Judie, Ashbaugh, Charlie, Atnafu, Desta Debalkie, Babar, Zaheer-Ud-Din, Baig, Atif Amin, Banik, Palash Chandra, Bärnighausen, Till Winfried, Barrow, Amadou, Bender, Rose G, Bhagavathula, Akshaya Srikanth, Bhardwaj, Nikha, Bhardwaj, Pankaj, Bibi, Sadia, Bijani, Ali, Burkart, Katrin, Cederroth, Christopher R, Charan, Jaykaran, Choudhari, Sonali Gajanan, Chu, Dinh-Toi, Couto, Rosa A S, Dagnew, Amare Belachew, Dagnew, Baye, Dahlawi, Saad M A, Dai, Xiaochen, Dandona, Lalit, Dandona, Rakhi, Desalew, Assefa, Dhamnetiya, Deepak, Dhimal, Mandira Lamichhane, Dhimal, Meghnath, Doyle, Kerrie E, Duncan, Bruce B, Ekholuenetale, Michael, Filip, Irina, Fischer, Florian, Franklin, Richard Charle, Gaidhane, Abhay Motiramji, Gaidhane, Shilpa, Gallus, Silvano, Ghamari, Farhad, Ghashghaee, Ahmad, Ghozali, Ghozali, Gilani, Syed Amir, Glavan, Ionela-Roxana, Golechha, Mahaveer, Goulart, Bárbara Niegia Garcia, Gupta, Veer Bala, Gupta, Vivek Kumar, Hamidi, Samer, Hammond, Billy Randall, Hay, Simon I, Hayat, Khezar, Heidari, Golnaz, Hoffman, Howard J, Hopf, Kathleen Pillsbury, Hosseinzadeh, Mehdi, Househ, Mowafa, Hussain, Rabia, Hwang, Bing-Fang, Iavicoli, Ivo, Ibitoye, Segun Emmanuel, Ilesanmi, Olayinka Stephen, Irvani, Seyed Sina Naghibi, Islam, Sheikh Mohammed Shariful, Iwagami, Masao, Jacob, Loui, Jayapal, Sathish Kumar, Jha, Ravi Prakash, Jonas, Jost B, Kalhor, Rohollah, Kameran Al-Salihi, Nawzad, Kandel, Himal, Kasa, Ayele Semachew, Kayode, Gbenga A, Khalilov, Rovshan, Khan, Ejaz Ahmad, Khatib, Mahalaqua Nazli, Kosen, Soewarta, Koyanagi, Ai, Kumar, G Anil, Landires, Iván, Lasrado, Savita, Lim, Stephen S, Liu, Xuefeng, Lobo, Stany W, Lugo, Alessandra, Makki, Alaa, Mendoza, Walter, Mersha, Amanual Getnet, Mihretie, Kebadnew Mulatu, Miller, Ted R, Misra, Sanjeev, Mohamed, Teroj Abdulrahman, Mohammadi, Mokhtar, Mohammadian-Hafshejani, Abdollah, Mohammed, Arif, Mokdad, Ali H, Moni, Mohammad Ali, Neupane Kandel, Sandhya, Nguyen, Huong Lan Thi, Nixon, Molly R, Noubiap, Jean Jacque, Nuñez-Samudio, Virginia, Oancea, Bogdan, Oguoma, Victor Maduabuchi, Olagunju, Andrew T, Olusanya, Bolajoko Olubukunola, Olusanya, Jacob Olusegun, Orru, Han, Owolabi, Mayowa O, Padubidri, Jagadish Rao, Pakshir, Keyvan, Pardhan, Shahina, Pashazadeh Kan, Fatemeh, Pasovic, Maja, Pawar, Shrikant, Pham, Hai Quang, Pinheiro, Marina, Pourshams, Akram, Rabiee, Navid, Rabiee, Mohammad, Radfar, Amir, Rahim, Fakher, Rahimi-Movaghar, Vafa, Rahman, Mohammad Hifz Ur, Rahman, Mosiur, Rahmani, Amir Masoud, Rana, Juwel, Rao, Chythra R, Rao, Sowmya J, Rashedi, Vahid, Rawaf, David Laith, Rawaf, Salman, Renzaho, Andre M N, Rezapour, Aziz, Ripon, Rezaul Karim, Rodrigues, Voilet, Rustagi, Neeti, Saeed, Umar, Sahebkar, Amirhossein, Samy, Abdallah M, Santric-Milicevic, Milena M, Sathian, Brijesh, Satpathy, Maheswar, Sawhney, Monika, Schlee, Winfried, Schmidt, Maria Inê, Seylani, Allen, Shaikh, Masood Ali, Shannawaz, Mohammed, Shiferaw, Wondimeneh Shibabaw, Siabani, Soraya, Singal, Anjali, Singh, Jasvinder A, Singh, Jitendra Kumar, Singhal, Deepika, Skryabin, Valentin Yurievich, Skryabina, Anna Aleksandrovna, Sotoudeh, Houman, Spurlock, Emma Elizabeth, Taddele, Biruk Wogayehu, Tamiru, Animut Tagele, Tareque, Md Ismail, Thapar, Rekha, Tovani-Palone, Marcos Roberto, Tran, Bach Xuan, Ullah, Saif, Valadan Tahbaz, Sahel, Violante, Francesco S, Vlassov, Vasily, Vo, Bay, Vongpradith, Avina, Vu, Giang Thu, Wei, Jingkai, Yadollahpour, Ali, Yahyazadeh Jabbari, Seyed Hossein, Yeshaw, Yigizie, Yigit, Vahit, Yirdaw, Birhanu Wubale, Yonemoto, Naohiro, Yu, Chuanhua, Yunusa, Ismaeel, Zamani, Mohammad, Zastrozhin, Mikhail Sergeevich, Zastrozhina, Anasthasia, Zhang, Zhi-Jiang, Zhao, Jeff T, Murray, Christopher J L, Davis, Adrian C, Vos, Theo, and Chadha, Shelly
Subjects: Hearing aid, Male, Hearing loss, medicine.medical_treatment, Psychological intervention, 030204 cardiovascular system & hematology, Affect (psychology), Health Services Accessibility, Global Burden of Disease, 03 medical and health sciences, Tinnitus, Medicine, General & Internal, 0302 clinical medicine, Neonatal Screening, Hearing Aids, Acquired immunodeficiency syndrome (AIDS), Hearing, General & Internal Medicine, Health care, otorhinolaryngologic diseases, Prevalence, Medicine, Humans, Age Factor, Disabled Persons, 030212 general & internal medicine, Hearing Loss, Hearing Lo, 11 Medical and Health Sciences, Science & Technology, business.industry, Infant, Newborn, Age Factors, Infant, GBD 2019 Hearing Loss Collaborators, General Medicine, Articles, medicine.disease, Otitis, Hearing Aid, Cytomegalovirus Infections, Disabled Person, Female, medicine.symptom, business, Life Sciences & Biomedicine, Human, Demography
Abstract: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods: We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings: An estimated 1·57 billion (95% uncertainty interval 1·51–1·64) people globally had hearing loss in 2019, accounting for one in five people (20·3% [19·5–21·1]). Of these, 403·3 million (357·3–449·5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430·4 million (381·7–479·6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127·1 million people [112·3–142·6]). Of all people with a hearing impairment, 62·1% (60·2–63·9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65·8% of the variation in national age-standardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2·45 billion (2·35–2·56) people will have hearing loss, a 56·1% (47·3–65·2) increase from 2019, despite stable age-standardised prevalence. Interpretation: As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings. Funding: Bill & Melinda Gates Foundation and WHO.
Published: 2020

47. Prediction and identification of synergistic compound combinations against pancreatic cancer cells

Author: Tai-Ping Fan, Yasaman KalantarMotamedi, Jo L. Bramhall, Andreas Bender, Siang-Boon Koh, Ran Joo Choi, Bender, Andreas [0000-0002-6683-7546], and Apollo - University of Cambridge Repository
Subjects: Multidisciplinary, Scoring system, Standard of care, Cancer systems biology, Entinostat, Molecular biology, Science, Treatment options, Computational bioinformatics, Thioridazine, Pharmacology, medicine.disease, Gemcitabine, Article, chemistry.chemical_compound, chemistry, Pancreatic cancer, medicine, medicine.drug
Abstract: Summary Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82–5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells., Graphical abstract, Highlights • We developed a computational approach to predict synergistic compound pairs • The approach uses transcriptional data and pathway information for scoring • The predicted combinations with gemcitabine were validated in vitro • Predicted combinations versus single agents had 2.82–5.18 times higher synergies, Molecular biology; Computational bioinformatics; Cancer systems biology
Published: 2021
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48. Platelet Shape Changes during Thrombus Formation: Role of Actin-Based Protrusions

Author: Markus Bender and Raghavendra Palankar
Subjects: Blood Platelets, 0301 basic medicine, Chemistry, Thrombosis, macromolecular substances, Hematology, Clot retraction, 030204 cardiovascular system & hematology, Platelet Activation, medicine.disease, Actin cytoskeleton, Actins, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, Humans, Platelet activation, Thrombus, Lamellipodium, Cytoskeleton, Hemostatic function, Filopodia
Abstract: Platelet activation and aggregation are essential to limit blood loss at sites of vascular injury but may also lead to occlusion of diseased vessels. The platelet cytoskeleton is a critical component for proper hemostatic function. Platelets change their shape after activation and their contractile machinery mediates thrombus stabilization and clot retraction. In vitro studies have shown that platelets, which come into contact with proteins such as fibrinogen, spread and first form filopodia and then lamellipodia, the latter being plate-like protrusions with branched actin filaments. However, the role of platelet lamellipodia in hemostasis and thrombus formation has been unclear until recently. This short review will briefly summarize the recent findings on the contribution of the actin cytoskeleton and lamellipodial structures to platelet function.
Published: 2021
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49. Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

Author: Panman, J. L., Venkatraghavan, V., Van Der Ende, E. L., Steketee, R. M. E., Jiskoot, L. C., Poos, J. M., Dopper, E. G. P., Meeter, L. H. H., Kaat, L. D., Rombouts, S. A. R. B., Vernooij, M. W., Kievit, A. J. A., Premi, E., Cosseddu, M., Bonomi, E., Olives, J., Rohrer, J. D., Sanchez-Valle, R., Borroni, B., Bron, E. E., Van Swieten, J. C., Papma, J. M., Klein, S., Afonso, S., Almeida, M. R., Anderl-Straub, S., Andersson, C., Antonell, A., Archetti, S., Arighi, A., Balasa, M., Barandiaran, M., Bargallo, N., Bartha, R., Bender, B., Black, S., Butler, C., Bocchetta, M., Borrego-Ecija, S., Bras, J., Bruffaerts, R., Caroppo, P., Cash, D., Castelo-Branco, M., Convery, R., Cope, T., Danek, A., De Arriba, M., De Mendonca, A., Di Fede, G., Diaz, Z., Ducharme, S., Duro, D., Fenoglio, C., Ferreira, C. B., Finger, E., Flanagan, T., Fox, N., Freedman, M., Fumagalli, G., Gabilondo, A., Galimberti, D., Gasparotti, R., Gauthier, S., Gazzina, S., Gerhard, A., Giaccone, G., Gorostidi, A., Graff, C., Greaves, C., Guerreiro, R., Heller, C., Hoegen, T., Indakoetxea, B., Jelic, V., Karnath, H. -O., Keren, R., Laforce, R., Leitao, M. J., Levin, J., Llado, A., Loosli, S., Maruta, C., Masellis, M., Mead, S., Miltenberger, G., Van Minkelenm Sara Mitchell, R., Moore, K., Moreno, F., Nicholas, J., Oijerstedt, L., Otto, M., Ourselin, S., Padovani, A., Peakman, G., Pijnenburg, Y., Polito, C., Prioni, S., Prix, C., Rademakers, R., Redaelli, V., Rittman, T., Rogaeva, E., Rosa-Neto, P., Rossi, G., Rosser, M., Rowe, J., Santana, I., Santiago, B., Scarpini, E., Schonecker, S., Shafei, E. S. R., Shoesmith, C., Synofzik, M., Tabuas-Pereira, M., Tagliavini, F., Tartaglia, C., Tainta, M., Taipa, R., Tang-Wai, D., Thomas, D. L., Thonberg, H., Timberlake, C., Tiraboschi, P., Todd, E., Vandamme, P., Vandenberghe, R., Vandenbulcke, M., Veldsman, M., Verdelho, A., Villanua, J., Warren, J., Wilkeione, C., Elisabeth, W., Henrik, W., Zulaica, Z. M., Neurology, Physics and medical technology, Radiology & Nuclear Medicine, Clinical Genetics, and Medical Research Council
Subjects: Male, Oncology, Disease, Neuropsychological Tests, GENFI consortium investigators, Primary progressive aphasia, Cognition, Progranulins, 0302 clinical medicine, Neurofilament Proteins, BEHAVIORAL VARIANT, HETEROGENEITY, Gray Matter, 11 Medical and Health Sciences, Language, Psychiatry, 0303 health sciences, Brain, Middle Aged, Magnetic Resonance Imaging, White Matter, 17 Psychology and Cognitive Sciences, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Phenotype, medicine.anatomical_structure, Frontotemporal Dementia, Disease Progression, Biomarker (medicine), Female, Life Sciences & Biomedicine, Frontotemporal dementia, medicine.medical_specialty, Clinical Neurology, EVENT-BASED MODEL, Grey matter, Lateralization of brain function, White matter, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, medicine, Humans, LOBAR DEGENERATION, PROGRANULIN, Aged, 030304 developmental biology, Science & Technology, Neurology & Neurosurgery, business.industry, DISEASE PROGRESSION, medicine.disease, Mutation, WHITE-MATTER INTEGRITY, Surgery, Neurosciences & Neurology, Neurology (clinical), business, GENFI, Biomarkers, 030217 neurology & neurosurgery, Progressive disease
Abstract: ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.
Published: 2021
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50. Unveiling the meaning attributed to nursing care at the perspective of person with cancer

Author: Vanessa de Nazaré Mendes Favacho, Leliane do Nascimento do Espírito Santo, Fabio Feitosa Camacho, Glauber Marcelo Dantas Seixas, Karina Raissa Rodrigues, Gisela Pereira Xavier Albuquerque, Samara Barbosa da Silva, Everson Vando Melo Matos, Samuel Oliveira da Vera, Marcilene Souza da Silveira, Bianca Blois Pinheiro Camboim, Emerson Glauber Abreu dos Santos, Luciana Moreira Batista, Enderson Vasconcelos de Lima, Bruno Mesquita Maia, Tatyellen Natasha da Costa Oliveira, Jofre Jacob da Silva Freitas, Suane Priscila dos Santos Antunes, Cláudia Rafaela Brandão de Lima, Joelia dos Santos Oliveira, Rúbia Caroline Silva Souza, Tania de Sousa Pinheiro Medeiros, Hermana Rayanne Lucas de Andrade Bender, Regina de Oliveira Benedito, Denise Karla de Abreu Silva, Maicon de Araujo Nogueira, Wenderson Melo Martins, Izabel Silva Carvalho, Marcio Almeida Lins, Edma Nogueira da Silva, Maria Caroline Barros de Matos, Juliane Ribeiro, Simone Aguiar da Silva Figueira, Maria Liduina Melo da Silva, Antonia Margareth Moita Sá, Darllene Lucas de Andrade, Yasmim Leão Fayal, Gabriela Nunes Pinheiro, Marlene Simões e Silva, Eliane de Brito Pereira, Viviane Pinto, Eimar Neri de Oliveira Junior, Fabricia de Sousa Franco, Jamyle Guedes da Costa, Alex Miranda Franco, Flávia Cristina Duarte Silva, Emmily Oliveira Amador, Lucilena Estumano Almeida, Danielle Oliveira Maciel, Elyade Nelly Pires Rocha Camacho, Sheila do Socorro dos Santos Miranda, Camila Melo da Silva, Raimunda de Fátima Carvalho Prestes, Renata Campos de Sousa Borges, Clarissa Porfírio Mendes, and Anderson Lineu Siqueta dos Santos
Subjects: Nursing care, Psychoanalysis, Perspective (graphical), medicine, Cancer, Meaning (existential), medicine.disease, Psychology
Published: 2021
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