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1. Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

Author: Wheeler, Allison, Snyder, Edward, Refaai, Majed, Cohn, Claudia, Poisson, Jessica, Fontaine, Magali, Sehl, Mary, Nooka, Ajay, Uhl, Lynne, Spinella, Philip, Fenelus, Maly, Liles, Darla, Coyle, Thomas, Becker, Joanne, Jeng, Michael, Gehrie, Eric, Spencer, Bryan, Young, Pampee, Johnson, Andrew, OBrien, Jennifer, Schiller, Gary, Roback, John, Malynn, Elizabeth, Jackups, Ronald, Avecilla, Scott, Liu, Kathy, Bentow, Stanley, Varrone, Jeanne, Benjamin, Richard, and Corash, Laurence
Subjects: Humans, Platelet Transfusion, Female, Middle Aged, Male, Aged, Acute Lung Injury, Blood Platelets, Prospective Studies, Adult, Thrombocytopenia, Hematologic Diseases
Abstract: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.
Published: 2024

2. Postsynaptic Serine Racemase Regulates NMDA Receptor Function

Author: Wong, Jonathan M, Folorunso, Oluwarotimi O, Barragan, Eden V, Berciu, Cristina, Harvey, Theresa L, Coyle, Joseph T, Balu, Darrick T, and Gray, John A
Subjects: Biomedical and Clinical Sciences, Neurosciences, Neurological, Age Factors, Animals, CA1 Region, Hippocampal, Dendrites, Female, Male, Mice, Mice, Knockout, Neuronal Plasticity, Pyramidal Cells, Racemases and Epimerases, Receptors, N-Methyl-D-Aspartate, Synapses, Synaptic Transmission, GluN2A, glycine, NR2A, NR2B, plasticity, Srr, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract: d-serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-serine availability remains limited. d-serine is synthesized in the brain by the neuronal enzyme serine racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-serine action at synapses.
Published: 2020

3. Dynamic impact of transfusion ratios on outcomes in severely injured patients: Targeted machine learning analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios randomized clinical trial.

Author: Nguyen, Minh, Pirracchio, Romain, Kornblith, Lucy Z, Callcut, Rachael, Fox, Erin E, Wade, Charles E, Schreiber, Martin, Holcomb, John B, Coyle, Jeremy, Cohen, Mitchell, and Hubbard, Alan
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Hematology, Clinical Trials and Supportive Activities, Physical Injury - Accidents and Adverse Effects, Blood, Good Health and Well Being, Blood Component Transfusion, Blood Platelets, Erythrocytes, Female, Hemorrhage, Hemostasis, Humans, Intention to Treat Analysis, Machine Learning, Male, North America, Plasma, Trauma Centers, Wounds and Injuries, Blood transfusion, trauma, hemorrhage, postinjury hemostasis, Clinical sciences, Nursing
Abstract: BackgroundMassive transfusion protocols to treat postinjury hemorrhage are based on predefined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury.MethodsThe Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 Level I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semiparametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different timepoints during the first 24 hours after admission.ResultsIn the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4 hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma/PRBC and high platelet/PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% confidence interval, 1.19-5.22) during the third hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis.ConclusionOur results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission.Level of evidenceTherapeutic IV.
Published: 2020

4. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

Author: Nelson, Peter T, Dickson, Dennis W, Trojanowski, John Q, Jack, Clifford R, Boyle, Patricia A, Arfanakis, Konstantinos, Rademakers, Rosa, Alafuzoff, Irina, Attems, Johannes, Brayne, Carol, Coyle-Gilchrist, Ian TS, Chui, Helena C, Fardo, David W, Flanagan, Margaret E, Halliday, Glenda, Hokkanen, Suvi RK, Hunter, Sally, Jicha, Gregory A, Katsumata, Yuriko, Kawas, Claudia H, Keene, C Dirk, Kovacs, Gabor G, Kukull, Walter A, Levey, Allan I, Makkinejad, Nazanin, Montine, Thomas J, Murayama, Shigeo, Murray, Melissa E, Nag, Sukriti, Rissman, Robert A, Seeley, William W, Sperling, Reisa A, White Iii, Charles L, Yu, Lei, and Schneider, Julie A
Subjects: Brain, Humans, Brain Diseases, Alzheimer Disease, Retrospective Studies, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, TDP-43 Proteinopathies, Frontotemporal Dementia, Neuroimaging, FTLD, MRI, PET, SNAP, epidemiology, and over, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract: We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
Published: 2019

5. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia

Author: Shao, Zhicheng, Noh, Haneul, Bin Kim, Woong, Ni, Peiyan, Nguyen, Christine, Cote, Sarah E, Noyes, Elizabeth, Zhao, Joyce, Parsons, Teagan, Park, James M, Zheng, Kelvin, Park, Joshua J, Coyle, Joseph T, Weinberger, Daniel R, Straub, Richard E, Berman, Karen F, Apud, Jose, Ongur, Dost, Cohen, Bruce M, McPhie, Donna L, Rapoport, Judith L, Perlis, Roy H, Lanz, Thomas A, Xi, Hualin Simon, Yin, Changhong, Huang, Weihua, Hirayama, Teruyoshi, Fukuda, Emi, Yagi, Takeshi, Ghosh, Sulagna, Eggan, Kevin C, Kim, Hae-Young, Eisenberg, Leonard M, Moghadam, Alexander A, Stanton, Patric K, Cho, Jun-Hyeong, and Chung, Sangmi
Subjects: Biomedical and Clinical Sciences, Biological Psychology, Neurosciences, Psychology, Pharmacology and Pharmaceutical Sciences, Stem Cell Research, Brain Disorders, Regenerative Medicine, Mental Health, Schizophrenia, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Animals, Cadherins, Female, Humans, Induced Pluripotent Stem Cells, Interneurons, Male, Mice, Mice, Knockout, Prefrontal Cortex, Protocadherins, Signal Transduction, Synapses, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract: We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.
Published: 2019

6. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

Author: Fox, Robert J, Coffey, Christopher S, Conwit, Robin, Cudkowicz, Merit E, Gleason, Trevis, Goodman, Andrew, Klawiter, Eric C, Matsuda, Kazuko, McGovern, Michelle, Naismith, Robert T, Ashokkumar, Akshata, Barnes, Janel, Ecklund, Dixie, Klingner, Elizabeth, Koepp, Maxine, Long, Jeffrey D, Natarajan, Sneha, Thornell, Brenda, Yankey, Jon, Bermel, Robert A, Debbins, Josef P, Huang, Xuemei, Jagodnik, Patricia, Lowe, Mark J, Nakamura, Kunio, Narayanan, Sridar, Sakaie, Ken E, Thoomukuntla, Bhaskar, Zhou, Xiaopeng, Krieger, Stephen, Alvarez, Enrique, Apperson, Michelle, Bashir, Khurram, Cohen, Bruce A, Coyle, Patricia K, Delgado, Silvia, Dewitt, L Dana, Flores, Angela, Giesser, Barbara S, Goldman, Myla D, Jubelt, Burk, Lava, Neil, Lynch, Sharon G, Moses, Harold, Ontaneda, Daniel, Perumal, Jai S, Racke, Michael, Repovic, Pavle, Riley, Claire S, Severson, Christopher, Shinnar, Shlomo, Suski, Valerie, Weinstock-Guttman, Bianca, Yadav, Vijayshree, and Zabeti, Aram
Subjects: Neurosciences, Neurodegenerative, Brain Disorders, Clinical Trials and Supportive Activities, Autoimmune Disease, Multiple Sclerosis, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Neurological, Adult, Atrophy, Brain, Depression, Diffusion Tensor Imaging, Disease Progression, Double-Blind Method, Female, Gastrointestinal Diseases, Headache, Humans, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive, Phosphodiesterase Inhibitors, Pyridines, NN102/SPRINT-MS Trial Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract: BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).
Published: 2018

7. Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Author: Rodriguez-Sosa, Jose R, Bondareva, Alla, Tang, Lin, Avelar, Gleide F, Coyle, Krysta M, Modelski, Mark, Alpaugh, Whitney, Conley, Alan, Wynne-Edwards, Katherine, França, Luiz R, Meyers, Stuart, and Dobrinski, Ina
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Contraception/Reproduction, Urologic Diseases, Animals, Apoptosis, Cell Differentiation, Dibutyl Phthalate, Diethylhexyl Phthalate, Environmental Exposure, Female, Germ Cells, Inhibins, Leydig Cells, Macaca mulatta, Male, Mice, Mice, SCID, Pregnancy, Prenatal Exposure Delayed Effects, Seminiferous Tubules, Sertoli Cells, Spermatogonia, Testis, Transplantation, Heterologous, Phthalates, Testis development, Steroidogenesis, Spermatogenesis, Non-human primates, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Endocrinology & Metabolism, Biochemistry and cell biology, Genetics, Clinical sciences
Abstract: Di-n-Butyl (DBP) and Di-(2-EthylHexyl) (DEHP) phthalates can leach from daily-use products resulting in environmental exposure. In male rodents, phthalate exposure results in reproductive effects. To evaluate effects on the immature primate testis, testis fragments from 6-month-old rhesus macaques were grafted subcutaneously to immune-deficient mice, which were exposed to 0, 10, or 500 mg/kg of DBP or DEHP for 14 weeks or 28 weeks (DBP only). DBP exposure reduced the expression of key steroidogenic genes, indicating that Leydig cell function was compromised. Exposure to 500 mg/kg impaired tubule formation and germ cell differentiation and reduced numbers of spermatogonia. Exposure to 10 mg/kg did not affect development, but reduced Sertoli cell number and resulted in increased expression of inhibin B. Exposure to DEHP for 14 week also affected steroidogenic genes expression. Therefore, long-term exposure to phthalate esters affected development and function of the primate testis in a time and dosage dependent manner.
Published: 2014

8. The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and Genome Organisation in the Centipede Strigamia maritima

Author: Chipman, Ariel D, Ferrier, David EK, Brena, Carlo, Qu, Jiaxin, Hughes, Daniel ST, Schröder, Reinhard, Torres-Oliva, Montserrat, Znassi, Nadia, Jiang, Huaiyang, Almeida, Francisca C, Alonso, Claudio R, Apostolou, Zivkos, Aqrawi, Peshtewani, Arthur, Wallace, Barna, Jennifer CJ, Blankenburg, Kerstin P, Brites, Daniela, Capella-Gutiérrez, Salvador, Coyle, Marcus, Dearden, Peter K, Du Pasquier, Louis, Duncan, Elizabeth J, Ebert, Dieter, Eibner, Cornelius, Erikson, Galina, Evans, Peter D, Extavour, Cassandra G, Francisco, Liezl, Gabaldón, Toni, Gillis, William J, Goodwin-Horn, Elizabeth A, Green, Jack E, Griffiths-Jones, Sam, Grimmelikhuijzen, Cornelis JP, Gubbala, Sai, Guigó, Roderic, Han, Yi, Hauser, Frank, Havlak, Paul, Hayden, Luke, Helbing, Sophie, Holder, Michael, Hui, Jerome HL, Hunn, Julia P, Hunnekuhl, Vera S, Jackson, LaRonda, Javaid, Mehwish, Jhangiani, Shalini N, Jiggins, Francis M, Jones, Tamsin E, Kaiser, Tobias S, Kalra, Divya, Kenny, Nathan J, Korchina, Viktoriya, Kovar, Christie L, Kraus, F Bernhard, Lapraz, François, Lee, Sandra L, Lv, Jie, Mandapat, Christigale, Manning, Gerard, Mariotti, Marco, Mata, Robert, Mathew, Tittu, Neumann, Tobias, Newsham, Irene, Ngo, Dinh N, Ninova, Maria, Okwuonu, Geoffrey, Ongeri, Fiona, Palmer, William J, Patil, Shobha, Patraquim, Pedro, Pham, Christopher, Pu, Ling-Ling, Putman, Nicholas H, Rabouille, Catherine, Ramos, Olivia Mendivil, Rhodes, Adelaide C, Robertson, Helen E, Robertson, Hugh M, Ronshaugen, Matthew, Rozas, Julio, Saada, Nehad, Sánchez-Gracia, Alejandro, Scherer, Steven E, Schurko, Andrew M, Siggens, Kenneth W, Simmons, DeNard, Stief, Anna, Stolle, Eckart, Telford, Maximilian J, Tessmar-Raible, Kristin, Thornton, Rebecca, van der Zee, Maurijn, von Haeseler, Arndt, Williams, James M, Willis, Judith H, Wu, Yuanqing, and Zou, Xiaoyan
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Prevention, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Arthropods, Circadian Rhythm Signaling Peptides and Proteins, DNA Methylation, Evolution, Molecular, Female, Genome, Genome, Mitochondrial, Hormones, Male, Multigene Family, Phylogeny, Polymorphism, Genetic, Protein Kinases, RNA, Untranslated, Receptors, Odorant, Selenoproteins, Sex Chromosomes, Synteny, Transcription Factors, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract: Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Published: 2014

9. Audit of epilepsy healthcare provision in a large UK category B prison

Author: Rachel, Thomasson, Helen, Coyle, Lorraine, Reynolds, Alison, Lees, Lindsey, Partington, and Paul, Cooper
Subjects: Male, Epilepsy, Neurology, Prisoners, Prisons, Prevalence, Humans, Neurology (clinical), General Medicine, Delivery of Health Care, United Kingdom
Abstract: We reviewed all prisoners diagnosed with epilepsy within a large UK category B prison: collecting demographic information and the prevalence and nature of their seizure disorder; and reviewed standards of their epilepsy healthcare provision. Previous work has highlighted poorer seizure control and limited access to specialist services in this patient group.Fifty-five male prisoners with a previously established diagnosis of epilepsy were identified by the prison healthcare manager during the six-month audit period. Anonymised audit data was collected during clinical interviews undertaken by members of a regional specialist epilepsy service and recorded on a standardised proforma. Data collection occurred during six prison visits within the audit period.Point prevalence of epilepsy was 2%. Data suggest that demographics are complex and challenging in this patient group. We found increased rates of alcohol (40%) and drug (82%) misuse and mental health problems (85.5%). Just over one third of cases were prescribed medications with potential for misuse (diversion). Further optimization of anti-seizure medication (ASM) regimens was required in 67.3% of the study sample, with only 12.7% of cases being free of seizures for the last 12 months. Access to specialist epilepsy services was limited; only 38.2% had a specialist review in the last 12 months. Most cases (76.4%) did not recall receiving guidance on precautions that should be taken regarding duties or cell arrangements in relation to having a diagnosis of epilepsy.Tighter collaboration between prison healthcare and local NHS specialist services is recommended to optimise epilepsy healthcare in UK prison settings.
Published: 2022

10. An Investigation of Sexual and Relationship Adjustment During COVID-19

Author: Stéphanie E. M. Gauvin, Maeve E. Mulroy, Meghan K. McInnis, Robyn A. Jackowich, Samantha L. Levang, Shannon M. Coyle, and Caroline F. Pukall
Subjects: Male, Relationship satisfaction, Sexual health, SARS-CoV-2, Sexual Behavior, COVID-19, Personal Satisfaction, Physical distancing, Special Section: Impact of Covid-19 on Sexual Health and Behavior, Sexual Partners, Arts and Humanities (miscellaneous), Surveys and Questionnaires, Humans, Female, Orgasm, Pandemics, Sexual functioning, General Psychology, Retrospective Studies
Abstract: The COVID-19 pandemic and the mitigation measures put in place have resulted in universal disruption in the usual ways of life for individuals. The current study sought to investigate how aspects of sexual health (well-being and functioning) and relationship satisfaction changed or remained stable during the pandemic. During two separate time points (Time 1 including Time 1 and a retrospective baseline, Time 2), participants completed online measures of sexual well-being (sexual pleasure, partnered and solitary orgasm frequency, sexual distress), sexual functioning, and relationship satisfaction. Participants reported slight declines in sexual pleasure, frequency of orgasms with a partner, and frequency of solitary orgasms from pre-COVID-19 (retrospective baseline) to Time 1, with no significant differences in sexual distress and relationship satisfaction. For individuals with vulvas, sexual functioning improved from Time 1 to Time 2, whereas no significant differences in sexual functioning were observed for individuals with penises. Aspects of sexual health and relational satisfaction did not sufficiently change across time points to be considered meaningful health outcome changes. Given that minimal disruptions were noted in pre-COVID-19 to COVID-19 sexuality, these results highlight the potential resiliency of individuals’ sexuality when facing sudden changes in their daily lives. Implications of COVID-19’s effects on sexual well-being and relationship satisfaction research are broadly discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-02212-4.
Published: 2022

11. A cost-utility analysis of the impact of electronic nicotine delivery systems on health care costs and outcomes in Canada

Author: Catherine M. Pound and Doug Coyle
Subjects: Male, Canada, Medicine (General), Epidemiology, Health Policy, Cost-Benefit Analysis, Vaping, Public Health, Environmental and Occupational Health, Health Care Costs, Electronic Nicotine Delivery Systems, Article, R5-920, Humans, Female
Abstract: We determined the impact of electronic nicotine delivery systems (ENDS) on health outcomes and costs in Canada, based on their effect on smoking cessation and smoking initiation rates.We used gender-specific Markov models to estimate lifetime discounted life years, quality-adjusted life years (QALYs) and smoking-related health care costs for cohorts of males and females aged 15 to 19 years, in scenarios in which (1) ENDS are available (status quo); (2) ENDS are completely unavailable; and (3) ENDS are available for smoking cessation through health care provider prescription, in addition to currently recognized smoking cessation tools. Analysis was from the perspective of a publicly funded health care system.Outcomes are expressed per 1000 individuals and based on expected values obtained through a Monte Carlo simulation of 10 000 replications. For males aged 15 to 19 years, life years, QALYs and smoking-related health care costs were 41 553, 35 871 and CAD 79 645 964, respectively, when ENDS were available; 41 568, 35 894 and CAD 79 645 960 when ENDS were unavailable; and 41 570, 35 897 and CAD 79 605 869 when ENDS were available through prescription only. For females, life years, QALYs and smoking-related health care costs were 43 596, 37 416 and CAD 69 242 856, respectively, when ENDS were available; 43 610, 37 438 and CAD 69 085 926 when ENDS were unavailable; and 43 611, 37 438 and CAD 69 076 034 when ENDS were available through prescription only. Thus, situations in which ENDS are unavailable, or available through prescription only are dominant over the status quo.These results show that a policy change whereby ENDS were unavailable to the Canadian population or available through prescription only would likely increase population health and reduce health care costs.Nous avons déterminé l’incidence des inhalateurs électroniques de nicotine sur les coûts et les résultats liés à la santé au Canada en fonction de leur effet sur les taux d’arrêt du tabagisme et d’initiation au tabagisme.Nous avons utilisé des modèles de Markov selon le genre pour estimer les années de vie actualisées sur un horizon à vie, les années de vie ajustées en fonction de la qualité (AVAQ) et les coûts des soins de santé liés au tabagisme pour des cohortes de garçons et de filles de 15 à 19 ans, selon des scénarios où 1) les inhalateurs électroniques de nicotine sont accessibles (statu quo), 2) les inhalateurs électroniques de nicotine ne sont aucunement accessibles et 3) les inhalateurs électroniques de nicotine sont accessibles sur ordonnance d’un fournisseur de soins de santé pour l’arrêt du tabagisme, en complément aux outils de cessation tabagique actuellement reconnus. L’analyse a été effectuée du point de vue d’un système de soins de santé financé par des fonds publics.Les résultats sont exprimés pour 1 000 personnes et reposent sur les valeurs attendues obtenues par une simulation de Monte-Carlo avec 10 000 itérations. Pour les garçons de 15 à 19 ans, les années de vie, les AVAQ et les coûts des soins de santé liés au tabagisme étaient de respectivement 41 553, 35 871 et 79 645 964 $ CA lorsque les inhalateurs électroniques de nicotine étaient accessibles, de respectivement 41 568, 35 894 et 79 645 960 $ CA lorsque les inhalateurs électroniques de nicotine n’étaient pas accessibles et de respectivement 41 570, 35 897 et 79 605 869 $ CA lorsque les inhalateurs électroniques de nicotine étaient accessibles sur ordonnance seulement. Pour les filles, les années de vie, les AVAQ et les coûts des soins de santé liés au tabagisme étaient de respectivement 43 596, 37 416 et 69 242 856 $ CA lorsque les inhalateurs électroniques de nicotine étaient accessibles, de respectivement 43 610, 37 438 et 69 085 926 $ CA lorsque les inhalateurs électroniques de nicotine n’étaient pas accessibles et de respectivement 43 611, 37 438 et 69 076 034 $ CA lorsque les inhalateurs électroniques de nicotine étaient accessibles sur ordonnance seulement. Ainsi, les scénarios dans lesquels les inhalateurs électroniques de nicotine ne sont pas accessibles ou ne sont accessibles que sur ordonnance l’emportent sur le statu quo.Ces résultats montrent qu’un changement de politique qui rendrait les inhalateurs électroniques de nicotine inaccessibles à la population canadienne ou accessibles sur ordonnance seulement permettrait probablement d’améliorer la santé de la population et de réduire les coûts des soins de santé.Vaping is commonly used by smokers to try to quit smoking. Vaping may increase smoking initiation in youth, resulting in negative long-term impacts on health. The results of this study show that, under our study assumptions, restricting access to vaping is likely to result in increased population health and reduced health care costs. Policy changes restricting access to vaping need to be examined with caution to avoid unintended consequences such as negative health impacts for current and former smokers who rely on vaping as a harm reduction strategy.Les fumeurs qui souhaitent arrêter de fumer ont souvent recours au vapotage. Le vapotage peut favoriser l’initiation au tabagisme chez les jeunes, ce qui a des effets négatifs à long terme sur la santé. D’après les résultats de cette étude, et avec nos hypothèses, la restriction de l’accès au vapotage est susceptible d’améliorer la santé de la population et de réduire les coûts des soins de santé. Les changements de politique qui restreignent l’accès au vapotage doivent être évalués avec prudence afin d’éviter les dommages collatéraux comme des effets négatifs sur la santé des fumeurs et des exfumeurs qui utilisent le vapotage comme stratégie de réduction des méfaits.
Published: 2022

12. The Positive Choices trial: study protocol for a Phase-III RCT trial of a whole-school social marketing intervention to promote sexual health and reduce health inequalities

Author: Karin Coyle, G. J. Melendez-Torres, Elizabeth Allen, Rebecca Meiksin, Honor Young, Maria Lohan, Rona Campbell, Steve Morris, Chris Bonell, Ruth Ponsford, Catherine H Mercer, Morris, Stephen [0000-0002-5828-3563], Bonell, Chris [0000-0002-6253-6498], and Apollo - University of Cambridge Repository
Subjects: Male, medicine.medical_specialty, Medicine (General), Referral, Adolescent, Sexual health, education, Medicine (miscellaneous), Adolescents, law.invention, Study Protocol, R5-920, SDG 3 - Good Health and Well-being, Randomized controlled trial, law, Pregnancy, Sexually transmitted infections, Medicine, Humans, Pharmacology (medical), Child, Reproductive health, Randomized Controlled Trials as Topic, School Health Services, Research ethics, Public health, Schools, Cluster trials, business.industry, SDG 16 - Peace, Justice and Strong Institutions, Health Status Disparities, Sexual competence, Social marketing, Whole-school, Family medicine, Social Marketing, Female, business, Inclusion (education), Unintended pregnancy
Abstract: Background Positive Choices is a whole-school social marketing intervention to promote sexual health among secondary school students. Intervention comprises school health promotion council involving staff and students coordinating delivery; student survey to inform local tailoring; teacher-delivered classroom curriculum; student-run campaigns; parent information; and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by ‘whole-school’ (e.g. student campaigns, sexual health services) and ‘social marketing’ (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK. Methods We will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections, and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022; implement the intervention over the 2022–2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025; and engage in knowledge exchange from December 2024. Discussion This trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices. Trial registration ISRCTN No: ISRCTN16723909. Trial registration summary: Date:. Funded by: National Institute for Health Research Public Health Research Programme (NIHR131487). Sponsor: LSHTM. Public/scientific contact: Chris Bonell. Public title: Positive Choices trial. Scientific title: Phase-III RCT of Positive Choices: a whole-school social marketing intervention to promote sexual health and reduce health inequalities. Countries of recruitment: UK. Intervention: Positive Choices. Inclusion criteria: Students in year 8 (age 12–13 years) at baseline deemed competent by schools to participate in secondary schools excluding pupil referral units, schools for those with special educational needs and disabilities, and schools with ‘inadequate’ Ofsted inspections. Study type: interventional study with superiority phase III cluster RCT design. Enrollment: 1/9/21-31/3/22. Sample size: 50 schools and 6440–8500 students. Recruitment status: pending. Primary outcome: binary measure of non-competent first sex. Secondary outcomes: non-competent last sex; age at sexual debut; non-use of contraception at first and last sex; number of sexual partners; dating and relationship violence (DRV) victimisation; sexually transmitted infections; pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys using adapted versions of the RIPPLE measures. Ethics review: LSHTM research ethics committee (reference 26411). Completion data: 1/3/25. Sharing statement: Data will be made available after the main trial analyses have been completed on reasonable request from researchers with ethics approval and a clear protocol. Amendments to the protocol will be communicated to the investigators, sponsor, funder, research ethics committee, trial registration and the journal publishing the protocol. Amendments affecting participants’ experience of the intervention or important amendments affecting the overall design and conduct of the trial will be communicated to participants.
Published: 2021

13. Comparative analysis of robotic-assisted versus laparoscopic cholecystectomy in pediatric patients

Author: Afif N. Kulaylat, Keigo Yada, David Coyle, Karen A. Diefenbach, Jennifer H. Aldrink, Rita D. Shelby, Holden Richards, Marc P. Michalsky, and Amanda Onwuka
Subjects: Male, Laparoscopic surgery, medicine.medical_specialty, Adolescent, Robotic assisted, medicine.medical_treatment, Operative Time, Robotic Surgical Procedures, Humans, Medicine, Cholecystectomy, Robotic surgery, Child, Laparoscopic cholecystectomy, Retrospective Studies, Univariate analysis, business.industry, General Medicine, Length of Stay, Surgery, Cholecystectomy, Laparoscopic, Pediatrics, Perinatology and Child Health, Cohort, Female, business, Pediatric population
Abstract: Despite increased utilization of robotic-assisted surgery in the pediatric population during the past decade, reports of comparative analysis between robotic surgery and laparoscopic surgery are lacking. Our aim was to evaluate outcomes between pediatric robotic-assisted cholecystectomy (RC) and laparoscopic cholecystectomy (LC).A single institution retrospective analysis of 299 patients undergoing either RC or LC, between January 2015 and December 2018 was performed. Demographic data as well as clinical characteristics and related outcomes were abstracted and compared using univariate analysis. Related hospital costs were estimated using a charge to cost methodology.The median age of the cohort was 15.5 years (IQR 14.0-17.0); 76% females and 70% white, with 74% (n = 220) undergoing LC and 26% (n = 79) undergoing RC. The majority of RC were performed using single-site technique and RC proportion increased with time (10% in 2015 vs. 41% in 2018, p0.001). The majority of RC were more commonly attributed to patients with nonacute indications for cholecystectomy compared to acute clinical indications (87% vs. 13%). Median operative time was 98 min vs. 79 min for RC and LC respectively (p0.001). Median postoperative LOS was similar between groups (22 h). There were no significant differences in postoperative complication, in-hospital opioid utilization and 30-day readmissions. Average total hospital costs for RC were $15,519 compared to $11,197 for LC.Pediatric robotic-assisted cholecystectomy is feasible with similar outcomes compared to laparoscopic cholecystectomy. However, it is associated with longer operative times and higher costs. The single-site RC technique may provide a potential cosmetic benefit.
Published: 2021

14. Outcomes Among Patients with Breakthrough SARS-CoV-2 Infection After Vaccination

Author: Yousuf Al Masalmani, Ali Nizar Latif, Peter Coyle, Abdul-Badi Abou-Samra, Laith J. Abu Raddad, Adeel A. Butt, Hiam Chemaitelly, Anvar Hassan Kaleeckal, Abdullatif Al Khal, Zeina Al Kanaani, Hanaa Nafady-Hego, and Roberto Bertollini
Subjects: Adult, Male, Risk, Microbiology (medical), medicine.medical_specialty, COVID-19 Vaccines, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, breakthrough infection, Severe disease, Infectious and parasitic diseases, RC109-216, Lower risk, Article, Primary outcome, Internal medicine, Humans, Medicine, Qatar, Mechanical ventilation, SARS-CoV-2, business.industry, COVID-19, Breakthrough infection, General Medicine, Middle Aged, vaccination, Vaccination, Infectious Diseases, business
Abstract: Background: Breakthrough infections after SARS-CoV-2 vaccination have been reported. Clinical outcomes in these persons are not widely known. Methods: We evaluated all vaccinated persons with breakthrough infection ≥14 days after the second vaccine dose and unvaccinated controls matched on age, sex, nationality, and reason for testing between December 23, 2020 and March 28, 2021 in Qatar. Our primary outcome was severe disease defined as hospitalization, mechanical ventilation, or death. Results: Among 456 persons cases of breakthrough infection and 456 unvaccinated matched controls with confirmed infection, median age was 45 years, 60.7% were males, and ≥1 comorbid condition was present in 61.2% of the vaccinated and 47.8% of the unvaccinated persons (P=0.009). Severe disease was recorded in 48 (10.5%) of the vaccinated and 121 (26.5%) of the unvaccinated group (P40–60 years, HR 2.32; >60–70 years, HR 4.34; >70 years, HR 5.43); presence of symptoms at baseline (HR 2.42, 95%CI 1.44-4.07); and being unvaccinated (HR 2.84, 95%CI 1.80-4.47). Conclusions: In persons with breakthrough SARS-CoV-2 infection, increasing age is associated with a higher risk of severe disease or death, while vaccination is associated with a lower risk. Presence of comorbidities was not associated with severe disease or death among persons with breakthrough infection.
Published: 2021

15. Mapping the human genetic architecture of COVID-19

Author: Niemi, MEK, Karjalainen, J, Liao, RG, Neale, BM, Daly, M, Ganna, A, Pathak, GA, Andrews, SJ, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, EC, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, MA, Wendt, FR, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H-N, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, MJ, Smith, GD, Willer, CJ, Buxbaum, JD, Mehtonen, J, Finucane, H, Cordioli, M, Martin, AR, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, MK, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, VG, van Heel, D, Deelen, P, Richards, JB, Nakanishi, T, Biesecker, L, Kerchberger, VE, Kenneth, J, Mari, F, Bernasconi, A, Ceri, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, AK, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Uddin, MM, Albertos, R, Perez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, RA, Zarate, R, Medina-Gomez, C, Gomez-Cabrero, D, Carnero-Montoro, E, Cadilla, CL, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, PR, Fave, M-J, Francioli, L, Lemacon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, JL, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, HF, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, SA, Prijatelj, V, Prokic, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, NM, Auton, A, Shelton, JF, Shastri, AJ, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O'Connell, J, Ye, C, Weldon, CH, Perera, M, O'Leary, K, Tuck, M, O'Brien, T, Meltzer, D, O'Donnell, P, Nutescu, E, Yang, G, Alarcon, C, Herrmann, S, Mazurek, S, Banagan, J, Hamidi, Z, Barbour, A, Raffat, N, Moreno, D, Friedman, P, Ferwerda, B, van de Beek, D, Brouwer, MC, Vlaar, APJ, Wiersinga, WJ, Posthuma, D, Tissink, E, Zwinderman, AHK, Uffelmann, E, van Agtmael, M, Algera, AG, van Baarle, F, Bax, D, Beudel, M, Bogaard, HJ, Bomers, M, Bonta, PI, Bos, L, Botta, M, de Brabander, J, de Bree, G, de Bruin, S, Bugiani, M, Bulle, E, Chouchane, O, Cloherty, A, Dongelmans, D, Elbers, P, Fleuren, L, Geerlings, S, Geerts, B, Geijtenbeek, T, Girbes, A, Goorhuis, B, Grobusch, MP, Hafkamp, F, Hagens, L, Hamann, J, Harris, V, Hemke, R, Hermans, SM, Heunks, L, Hollmann, M, Horn, J, Hovius, JW, de Jong, MD, Koning, R, van Mourik, N, Nellen, J, Nossent, EJ, Paulus, F, Peters, E, van der Poll, T, Preckel, B, Prins, JM, Raasveld, J, Reijnders, T, Schinkel, M, Schultz, MJ, Schuurman, A, Sigaloff, K, Smit, M, Stijnis, CS, Stilma, W, Teunissen, C, Thoral, P, Tsonas, A, van der Valk, M, Veelo, D, de Vries, H, van Vugt, M, Wouters, D, Minnaar, RP, Kromhout, A, van Uffelen, KWJ, Wolterman, RA, Roberts, G, Park, D, Ball, CA, Coignet, M, McCurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Hong, EL, Rand, K, Girshick, A, Guturu, H, Baltzell, AH, Guntz, J, Beguin, Y, Pigazzini, S, Nkambule, L, Bouysran, Y, Busson, A, Peyrassol, X, Wilkin, F, Pichon, B, Smits, G, Vandernoot, I, Goffard, J-C, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Jadot, L, Azarzar, S, Dellot, P, Gofflot, S, Claassen, S, Bertrand, A, Parzibut, G, Clarinval, M, Moermans, C, Malaise, O, El Kandoussi, K, Thonon, R, Huynen, P, Mesdagh, A, Melo, S, Jacques, N, Di Valentin, E, Giroule, F, Collignon, A, Radermecker, C, Lebrun, M, Peree, H, Latour, S, Barada, O, Sanchez, J, Josse, C, Boujemla, B, Meunier, M, Mariavelle, E, Anania, S, Gazon, H, Juszczak, D, Fadeur, M, Camby, S, Meuris, C, Thys, M, Jacques, J, Henket, M, Leonard, P, Frippiat, F, Giot, J-B, Sauvage, A-S, Von Frenckell, C, Mni, M, Wery, M, Staderoli, A, Belhaj, Y, Lambermont, B, Morrison, DR, Mooser, V, Forgetta, V, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chasse, M, Kaufmann, DE, Lathrop, GM, Adra, D, Davis, LK, Cox, NJ, Below, JE, Sealock, JM, Faucon, AB, Shuey, MM, Polikowsky, HG, Petty, LE, Shaw, DM, Chen, H-H, Zhu, W, Ludwig, KU, Schroeder, J, Maj, C, Rolker, S, Noethen, MM, Fazaal, J, Keitel, V, Jensen, B-EO, Feldt, T, Kurth, I, Marx, N, Dreher, M, Pink, I, Cornberg, M, Illig, T, Lehmann, C, Schommers, P, Augustin, M, Rybniker, J, Knopp, L, Eggermann, T, Volland, S, Altmueller, J, Berger, MM, Brenner, T, Hinney, A, Witzke, O, Bals, R, Herr, C, Ludwig, N, Walter, J, Fuchsberger, C, Pattaro, C, De Grandi, A, Pramstaller, P, Emmert, D, Melotti, R, Foco, L, Mascalzoni, D, Gogele, M, Domingues, F, Hicks, A, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Goldstein, DB, Kiryluk, K, Sengupta, S, Chung, W, Reilly, MP, Khan, A, Wang, C, Povysil, G, Bhardwaj, N, Gharavi, AG, Ionita-Laza, I, Shang, N, O'Byrne, SM, Nandakumar, R, Menon, A, So, YS, Hod, E, Pendrick, D, Park, S-K, Kim, H-L, Kang, CK, Lee, H-J, Song, K-H, Yoon, KJ, Paik, N-J, Seok, W, Yoon, H, Joo, E-J, Chang, Y, Ryu, S, Park, WB, Park, JS, Park, KU, Ham, SY, Jung, J, Kim, ES, Kim, HB, Ellinghaus, D, Degenhardt, F, Caceres, M, Juzenas, S, Lenz, TL, Albillos, A, Julia, A, Heidecker, B, Garcia, F, Kurth, F, Tran, F, Hanses, F, Zoller, H, Holter, JC, Fernandez, J, Sander, LE, Rosenstiel, P, Koehler, P, de Cid, R, Asselta, R, Schreiber, S, Hehr, U, Prati, D, Baselli, G, Valenti, L, Bujanda, L, Banales, JM, Duga, S, D'Amato, M, Romero-Gomez, M, Buti, M, Invernizzi, P, Franke, A, Hov, JR, Karlsen, TH, Folseraas, T, Maya-Miles, D, Teles, A, Azuure, C, Wacker, EM, Uellendahl-Werth, F, Elabd, H, Arora, J, Lerga-Jaso, J, Wienbrandt, L, Ruehlemann, MC, Wendorff, M, Vadla, MS, Lenning, OB, Oezer, O, Myhre, R, Raychaudhuri, S, Tanck, A, Gassner, C, Hemmrich-Stanisak, G, Kaessens, J, Basso, MEF, Schulzky, M, Wittig, M, Braun, N, Wesse, T, Albrecht, W, Yi, X, Ortiz, AB, Garrido Chercoles, A, Ruiz, A, Mantovani, A, Holten, AR, Mayer, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Barreira, A, Lleo, A, Kildal, AB, Glueck, A, Carreras Nolla, A, Latiano, A, Dyrhol-Riise, AM, Muscatello, A, Voza, A, Rando-Segura, A, Solier, A, Karina, B, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Bellinghausen, C, Ferrando, C, Quereda, C, Skurk, C, Thibeault, C, Spinner, CD, Lange, C, Hu, C, Cappadona, C, Bianco, C, Sancho, C, Hoff, DAL, Galimberti, D, Jimenez, D, Pestana, D, Toapanta, D, Azzolini, E, Scarpini, E, Helbig, ET, Urrechaga, E, Paraboschi, EM, Pontali, E, Reverter, E, Navas, E, Arana, E, Garcia Sanchez, F, Ceriotti, F, Malvestiti, F, Mesonero, F, Pezzoli, G, Lamorte, G, Neb, H, My, I, Hernandez, I, de Rojas, I, Galvan-Femenia, I, Heyckendorf, J, Badia, JR, Schneider, J, Goikoetxea, J, Kraft, J, Mueller, KE, Gaede, KI, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Sumoy, L, Lippert, LJ, Terranova, L, Garbarino, L, Tellez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Gutierrez-Stampa, MA, Vehreschild, MJGT, Marquie, M, Castoldi, M, Cecconi, M, Boada, M, Seilmaier, MJ, Mazzocco, M, Rodriguez-Gandia, M, Imaz Ayo, N, Blay, N, Martinez, N, Cornely, OA, Palmieri, O, Tentorio, P, Rodrigues, PM, Espana, PP, Hoffmann, P, Bacher, P, Suwalski, P, de Pablo, R, Nieto, R, Badalamenti, S, Ciesek, S, Bombace, S, Wilfling, S, Brunak, S, Heilmann-Heimbach, S, Ripke, S, Bahmer, T, Landmesser, U, Protzer, U, Rimoldi, V, Skogen, V, Andrade, V, Moreno, V, Poller, W, Farre, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, de Salazar, A, Palom, A, Garcia-Fernandez, A-E, Blanco-Grau, A, Zanella, A, Bandera, A, Nebel, A, Biondi, A, Caba Llero-Garralda, A, Gori, A, Lind, A, Fracanzani, AL, Peschuck, A, Pesenti, A, De la Horra, C, Milani, C, Paccapelo, C, Angelini, C, Cea, C, Muniz-Diaz, E, Sandoval, E, Calderon, EJ, Solligard, E, Aziz, F, Martinelli-Boneschi, F, Peyvandi, F, Blasi, F, Medrano, FJ, Rodriguez-Frias, F, Mueller, F, Grasselli, G, Costantino, G, Cardamone, G, Foti, G, Matullo, G, Kurihara, H, Afset, JE, Damas, JK, Ampuero, J, Martin, J, Erdmann, J, Bergan, J, Goerg, S, Ferrusquia-Acosta, J, Hernandez Quero, J, Delgado, J, Guerrero, JM, Risnes, K, Bettini, LR, Moreira, L, Gustad, LT, Santoro, L, Scudeller, L, Riveiro-Barciela, M, Schaefer, M, Carrabba, M, Valsecchi, MG, Hernandez-Tejero, M, Acosta-Herrera, M, D'Angio, M, Baldini, M, Cazzaniga, M, Ciccarelli, M, Bocciolone, M, Miozzo, M, Chueca, N, Montano, N, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Castro, P, Ferrer, R, Gualtierotti, R, Gallego-Duran, R, Morilla, R, Haider, S, Marsal, S, Aneli, S, Pelusi, S, Bosari, S, Aliberti, S, Dudman, S, Zheng, T, Pumarola, T, Gonzalez Cejudo, T, Monzani, V, Friaza, V, Peter, W, Dopazo, X, May, S, Grimsrud, MM, Gudbjartsson, DF, Stefansson, K, Sulem, P, Sveinbjornsson, G, Melsted, P, Norddahl, G, Moore, KHS, Thorsteinsdottir, U, Holm, H, Alarcon-Riquelme, ME, Bernardo, D, Martinez-Bueno, M, Rojo Rello, S, Magi, R, Milani, L, Metspalu, A, Laisk, T, Lall, K, Lepamets, M, Esko, T, Reimann, E, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Alavere, H, Metsalu, K, Puusepp, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Rivolta, C, Bochud, P-Y, Bibert, S, Boillat, N, Nussle, SG, Albrich, W, Quinodoz, M, Kamdar, D, Suh, N, Neofytos, D, Erard, V, Voide, C, Bochud, PY, Friolet, R, Vollenweider, P, Pagani, JL, Oddo, M, zu Bentrup, FM, Conen, A, Clerc, O, Marchetti, O, Guillet, A, Guyat-Jacques, C, Foucras, S, Rime, M, Chassot, J, Jaquet, 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Brent, Nakanishi, Tomoko, Biesecker, Le, Kerchberger, V. Eric, Baillie, J. 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J., Wiersinga, W. Joost, Posthuma, Danielle, Tissink, Elleke, Koos Zwinderman, A. H., Uffelmann, Emil, van Agtmael, Michiel, Algera, Anne Geke, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Jan Bogaard, Harm, Bomers, Marije, Bonta, Peter I., Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Dongelmans, Dave, Elbers, Paul, Fleuren, Luca, Geerlings, Suzanne, Geerts, Bart, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin P., Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine M., Heunks, Leo, Hollmann, Marku, Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, van Mourik, Niel, Nellen, Jeannine, Nossent, Esther J., Paulus, Frederique, Peters, Edgar, van der Poll, Tom, Preckel, Bennedikt, Prins, Jan M., Raasveld, Jorinde, Reijnders, Tom, Schinkel, Michiel, Schultz, Marcus J., Schuurman, Alex, Sigaloff, Kim, Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa, van der Valk, Marc, Veelo, Denise, de Vries, Heder, van Vugt, Michèle, Wouters, Dorien, Minnaar, René P., Kromhout, Adrie, van Uffelen, Kees W. 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Mark, Adra, Darin, Davis, Lea K., Cox, Nancy J., Below, Jennifer E., Sealock, Julia M., Faucon, Annika B., Shuey, Megan M., Polikowsky, Hannah G., Petty, Lauren E., Shaw, Douglas M., Chen, Hung-Hsin, Zhu, Wanying, Ludwig, Kerstin U., Schröder, Julia, Maj, Carlo, Rolker, Selina, Nöthen, Markus M., Fazaal, Julia, Keitel, Verena, Jensen, Björn-Erik Ole, Feldt, Torsten, Kurth, Ingo, Marx, Nikolau, Dreher, Michael, Pink, Isabell, Cornberg, Marku, Illig, Thoma, Lehmann, Clara, Schommers, Philipp, Augustin, Max, Rybniker, Jan, Knopp, Lisa, Eggermann, Thoma, Volland, Sonja, Altmüller, Janine, Berger, Marc M., Brenner, Thorsten, Hinney, Anke, Witzke, Oliver, Bals, Robert, Herr, Christian, Ludwig, Nicole, Walter, Jörn, Fuchsberger, Christian, Pattaro, Cristian, De Grandi, Alessandro, Pramstaller, Peter, Emmert, David, Melotti, Roberto, Foco, Luisa, Mascalzoni, Deborah, Gögele, Martin, Domingues, Francisco, Hicks, Andrew, Gignoux, Christopher R., Wicks, Stephen J., Crooks, Kristy, Barnes, Kathleen C., Daya, Michelle, Shortt, Jonathan, Rafaels, Nichola, Chavan, Sameer, Goldstein, David B., Kiryluk, Krzysztof, Sengupta, Soumitra, Chung, Wendy, Reilly, Muredach P., Khan, Atla, Wang, Chen, Povysil, Gundula, Bhardwaj, Nitin, Gharavi, Ali G., Ionita-Laza, Iuliana, Shang, Ning, O’Byrne, Sheila M., Nandakumar, Renu, Menon, Amritha, So, Yat S., Hod, Eldad, Pendrick, Danielle, Park, Soo-Kyung, Kim, Hyung-Lae, Kang, Chang Kyung, Lee, Hyo-Jung, Song, Kyoung-Ho, Jae Yoon, Kyung, Paik, Nam-Jong, Seok, Woojin, Yoon, Heejun, Joo, Eun-Jeong, Chang, Yoosoo, Ryu, Seungho, Park, Wan Beom, Su Park, Jeong, Un Park, Kyoung, Ham, Sin Young, Jung, Jongtak, Kim, Eu Suk, Kim, Hong Bin, Ellinghaus, David, Degenhardt, Frauke, Cáceres, Mario, Juzenas, Simona, Lenz, Tobias L., Albillos, Agustín, Julià, Antonio, Heidecker, Bettina, Garcia, Federico, Kurth, Florian, Tran, Florian, Hanses, Frank, Zoller, Heinz, Holter, Jan C., Fernández, Javier, Sander, Leif Erik, Rosenstiel, Philip, Koehler, Philipp, de Cid, Rafael, Asselta, Rosanna, Schreiber, Stefan, Hehr, Ute, Prati, Daniele, Baselli, Guido, Valenti, Luca, Bujanda, Lui, Banales, Jesus M., Duga, Stefano, D’Amato, Mauro, Romero-Gómez, Manuel, Buti, Maria, Invernizzi, Pietro, Franke, Andre, Hov, Johannes R., Karlsen, Tom H., Folseraas, Trine, Maya-Miles, Dougla, Teles, Ana, Azuure, Clinton, Wacker, Eike Matthia, Uellendahl-Werth, Florian, Elabd, Hesham, Arora, Jatin, Lerga-Jaso, Jon, Wienbrandt, Lar, Rühlemann, Malte Christoph, Wendorff, Mareike, Vadla, May Sissel, Lenning, Ole Bernt, Özer, Onur, Myhre, Ronny, Raychaudhuri, Soumya, Tanck, Anja, Gassner, Christoph, Hemmrich-Stanisak, Georg, Kässens, Jan, Figuera Basso, Maria E., Schulzky, Martin, Wittig, Michael, Braun, Nicole, Wesse, Tanja, Albrecht, Wolfgang, Yi, Xiaoli, Ortiz, Aaron Blandino, Chercoles, Adolfo Garrido, Ruiz, Agustín, Mantovani, Alberto, Holten, Aleksander Rygh, Mayer, Alena, Cherubini, Alessandro, Protti, Alessandro, Aghemo, Alessio, Gerussi, Alessio, Ramirez, Alfredo, Braun, Alice, Barreira, Ana, Lleo, Ana, Kildal, Anders Benjamin, Glück, Andrea, Nolla, Anna Carrera, Latiano, Anna, Dyrhol-Riise, Anne Ma, Muscatello, Antonio, Voza, Antonio, Rando-Segura, Ariadna, Solier, Aurora, Karina, Banasik, Cortes, Beatriz, Mateos, Beatriz, Nafria-Jimenez, Beatriz, Schaefer, Benedikt, Bellinghausen, Carla, Ferrando, Carlo, Quereda, Carmen, Skurk, Carsten, Thibeault, Charlotte, Spinner, Christoph D., Lange, Christoph, Hu, Cinzia, Cappadona, Claudio, Bianco, Cristiana, Sancho, Cristina, Lihaug Hoff, Dag Arne, Galimberti, Daniela, Jiménez, David, Pestaña, David, Toapanta, David, Azzolini, Elena, Scarpini, Elio, Helbig, Elisa T., Urrechaga, Eloisa, Paraboschi, Elvezia Maria, Pontali, Emanuele, Reverter, Enric, Navas, Enrique, Arana, Eunate, Sánchez, Félix García, Ceriotti, Ferruccio, Malvestiti, Francesco, Mesonero, Francisco, Pezzoli, Gianni, Lamorte, Giuseppe, Neb, Holger, My, Ilaria, Hernández, Isabel, de Rojas, Itziar, Galván-Femenia, Iván, Heyckendorf, Jan, Badia, Joan Ramon, Schneider, Jochen, Goikoetxea, Josune, Kraft, Julia, Müller, Karl Erik, Gaede, Karoline I., Garcia-Etxebarria, Koldo, Tonby, Kristian, Heggelund, Lar, Izquierdo-Sanchez, Laura, Sumoy, Lauro, Lippert, Lena J., Terranova, Leonardo, Garbarino, Lucia, Téllez, Lui, Roade, Luisa, Ostadreza, Mahnoosh, Intxausti, Maider, Kogevinas, Manoli, Gutiérrez-Stampa, María A., Vehreschild, Maria J. G. T., Marquié, Marta, Castoldi, Massimo, Cecconi, Maurizio, Boada, Mercè, Seilmaier, Michael J., Mazzocco, Michela, Rodríguez-Gandía, Miguel, Ayo, Natale Imaz, Blay, Natalia, Martínez, Nilda, Cornely, Oliver A., Palmieri, Orazio, Tentorio, Paolo, Rodrigues, Pedro M., España, Pedro P., Hoffmann, Per, Bacher, Petra, Suwalski, Phillip, de Pablo, Raúl, Nieto, Rosa, Badalamenti, Salvatore, Ciesek, Sandra, Bombace, Sara, Wilfling, Sibylle, Brunak, Søren, Heilmann-Heimbach, Stefanie, Ripke, Stephan, Bahmer, Thoma, Landmesser, Ulf, Protzer, Ulrike, Rimoldi, Valeria, Skogen, Vegard, Andrade, Victor, Moreno, Victor, Poller, Wolfgang, Farre, Xavier, Wang, Xiaomin, Khodamoradi, Yascha, Karadeniz, Zehra, de Salazar, Adolfo, Palom, Adriana, Garcia-Fernandez, Alba-Estela, Blanco-Grau, Albert, Zanella, Alberto, Bandera, Alessandra, Nebel, Almut, Biondi, Andrea, Caballero-Garralda, Andrea, Gori, Andrea, Lind, Andrea, Fracanzani, Anna Ludovica, Peschuck, Anna, Pesenti, Antonio, de la Horra, Carmen, Milani, Chiara, Paccapelo, Cinzia, Angelini, Claudio, Cea, Cristina, Muñiz-Diaz, Eduardo, Sandoval, Elena, Calderón, Enrique J., Solligård, Erik, Aziz, Fátima, Martinelli-Boneschi, Filippo, Peyvandi, Flora, Blasi, Francesco, Medrano, Francisco J., Rodriguez-Frias, Francisco, Müller, Fredrik, Grasselli, Giacomo, Costantino, Giorgio, Cardamone, Giulia, Foti, Giuseppe, Matullo, Giuseppe, Kurihara, Hayato, Afset, Jan Egil, Damås, Jan Kristian, Ampuero, Javier, Martín, Javier, Erdmann, Jeanette, Bergan, Jona, Goerg, Siegfried, Ferrusquía-Acosta, Jose, Quero, Jose Hernández, Delgado, Juan, Guerrero, Juan M., Risnes, Kari, Bettini, Laura Rachele, Moreira, Leticia, Gustad, Lise Tuset, Santoro, Luigi, Scudeller, Luigia, Riveiro-Barciela, Mar, Schaefer, Marco, Carrabba, Maria, Valsecchi, Maria G., Hernandez-Tejero, María, Acosta-Herrera, Marialbert, D’Angiò, Mariella, Baldini, Marina, Cazzaniga, Marina, Ciccarelli, Michele, Bocciolone, Monica, Miozzo, Monica, Chueca, Natalia, Montano, Nicola, Faverio, Paola, Preatoni, Paoletta, Bonfanti, Paolo, Omodei, Paolo, Castro, Pedro, Ferrer, Ricard, Gualtierotti, Roberta, Gallego-Durán, Rocío, Morilla, Rubén, Haider, Sammra, Marsal, Sara, Aneli, Serena, Pelusi, Serena, Bosari, Silvano, Aliberti, Stefano, Dudman, Susanne, Zheng, Tenghao, Pumarola, Toma, Cejudo, Trinidad Gonzalez, Monzani, Valter, Friaza, Vicente, Peter, Wolfgang, Dopazo, Ximo, May, Sandra, Grimsrud, Marit M., Gudbjartsson, Daniel F., Stefansson, Kari, Sulem, Patrick, Sveinbjornsson, Gardar, Melsted, Pall, Norddahl, Gudmundur, Swerford Moore, Kristjan Helgi, Thorsteinsdottir, Unnur, Holm, Hilma, Alarcón-Riquelme, Marta E., Bernardo, David, Martínez-Bueno, Manuel, Rello, Silvia Rojo, Magi, Reedik, Milani, Lili, Metspalu, Andre, Laisk, Triin, Läll, Kristi, Lepamets, Maarja, Esko, Tõnu, Reimann, Ene, Naaber, Paul, Laane, Edward, Pesukova, Jaana, Peterson, Pärt, Kisand, Kai, Tabri, Jekaterina, Allos, Raili, Hensen, Kati, Starkopf, Joel, Ringmets, Inge, Tamm, Anu, Kallaste, Anne, Alavere, Helene, Metsalu, Kristjan, Puusepp, Mairo, Kristiansson, Kati, Koskelainen, Sami, Perola, Marku, Donner, Kati, Kivinen, Katja, Palotie, Aarno, Rivolta, Carlo, Bochud, Pierre-Yve, Bibert, Stéphanie, Boillat, Noémie, Nussle, Semira Gonseth, Albrich, Werner, Quinodoz, Mathieu, Kamdar, Dhryata, Suh, Noémie, Neofytos, Dionysio, Erard, Véronique, Voide, Cathy, Bochud, P. 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Mandalà, Marco, Zucchi, Patrizia, Giannattasio, Ferdinando, Coviello, Domenico A., Mussini, Cristina, Bosio, Giancarlo, Tavecchia, Luisa, Crotti, Lia, Rizzi, Marco, La Rovere, Maria Teresa, Sarzi-Braga, Simona, Bussotti, Maurizio, Ravaglia, Sabrina, Artuso, Rosangela, Perrella, Antonio, Romani, Davide, Bergomi, Paola, Catena, Emanuele, Vincenti, Antonella, Ferri, Claudio, Grassi, Davide, Pessina, Gloria, Tumbarello, Mario, Di Pietro, Massimo, Sabrina, Ravaglia, Luchi, Sauro, Barbieri, Chiara, Acquilini, Donatella, Andreucci, Elena, Paciosi, Francesco, Segala, Francesco Vladimiro, Tiseo, Giusy, Falcone, Marco, Lista, Mirjam, Poscente, Monica, De Vivo, Oreste, Petrocelli, Paola, Guarnaccia, Alessandra, Baroni, Silvia, Perticaroli, Valentina, Furini, Simone, Dei, Simona, Benetti, Elisa, Picchiotti, Nicola, Sanarico, Maurizio, Ceri, Stefano, Pinoli, Pietro, Raimondi, Francesco, Biscarini, Filippo, Stella, Alessandra, Bergomi, Mattia, Zguro, Kristina, Capitani, Katia, Tanfoni, Marco, 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Piacentini, Paolo, Desanctis, Elena, Cappelli, Silvia, Verzuri, Agnese, Anemoli, Valentina, Pancrazi, Alessandro, Lorubbio, Maria, Merlini, Esther, Miraglia, Federica Gaia, Venturelli, Sophie, Cossarizza, Andrea, Vergori, Alessandra, Gabrieli, Arianna, Riva, Agostino, Andretta, Francesca, Gatti, Francesca, Parisi, Saverio Giuseppe, Baratti, Stefano, Piscopo, Carmelo, Russo, Roberta, Andolfo, Immacolata, Iolascon, Achille, Carella, Massimo, Merla, Giuseppe, Squeo, Gabriella Maria, Raggi, Pamela, Marciano, Carmen, Perna, Rita, Bassetti, Matteo, Sanguinetti, Maurizio, Giorli, Alessia, Salerni, Lorenzo, Parravicini, Pierpaolo, Menatti, Elisabetta, Trotta, Tullio, Coiro, Gabriella, Lena, Fabio, Martinelli, Enrico, Mancarella, Sandro, Gabbi, Chiara, Maggiolo, Franco, Ripamonti, Diego, Bachetti, Tiziana, Suardi, Claudia, Parati, Gianfranco, Bottà, Giordano, Di Domenico, Paolo, Rancan, Ilaria, Bianchi, Francesco, Colombo, Riccardo, van Heel, David A., Hunt, Karen A., Trembath, Richard C., Huang, Qin Qin, Martin, Hilary C., Mason, Dan, Trivedi, Bhavi, Wright, John, Finer, Sarah, Griffiths, Christopher J., Akhtar, Shaheen, Anwar, Mohammad, Arciero, Elena, Ashraf, Samina, Breen, Gerome, Chung, Raymond, Curtis, Charles J., Chowdhury, Maharun, Colligan, Grainne, Deloukas, Pano, Durham, Ceri, Griffiths, Chri, Hurles, Matt, Hussain, Shapna, Islam, Kamrul, Khan, Ahsan, Khan, Amara, Lavery, Cath, Lee, Sang Hyuck, Lerner, Robin, Macarthur, Daniel, Maclaughlin, Bev, Martin, Hilary, Miah, Shefa, Newman, Bill, Safa, Nishat, Tahmasebi, Farah, Smith, Albert V., Boughton, Andrew P., Li, Kevin W., Lefaive, Jonathon, Annis, Aubrey, Jannes, Cinthia E., Krieger, Jose E., Pereira, Alexandre C., Velho, Mariliza, Marques, Emanuelle, Lima, Isabella Ramo, Tada, Mauricio Teruo, Valino, Karina, Mccarthy, Mark, Rosenberger, Carrie, Lee, Jong Eun, Chang, Diana, Hammer, Christian, Hunkapiller, Julie, Mahajan, Anubha, Pendergrass, Sarah, Sucheston-Campbell, Lara, Yaspan, Brian, Lee, Hyun Soo, Shin, Eunsoon, Jang, Hye Yoon, Kim, Sunmie, Kym, Sungmin, Kim, Yeon-Sook, Jeong, Hyeongseok, Kwon, Ki Tae, Kim, Shin-Woo, Kim, Jin Yong, Jang, Young Rock, Kim, Hyun ah, Lee, Ji Yeon, Lee, Jeong Eun, Lee, Shinwon, Choe, Kang-Won, Kang, Yu Min, Jee, Sun Ha, Jung, Keum Ji, Parikh, Victoria, Ashley, Euan, Wheeler, Matthew, Rivas, Manuel, Bustamante, Carlo, Pinksy, Benjamin, Febbo, Phillip, Farh, Kyle, Schroth, Gary P., Desouza, Franci, Dalton, Karen, Christle, Jeff, Deboever, Christopher, Szalma, Sándor, Rubinacci, Simone, Delaneau, Olivier, Gorzynski, John, de Jong, Hannah, Sutton, Shirley, Youlton, Nathan, Joshi, Ruchi, Jimenez-Morales, David, Hughes, Christopher, Amar, David, Ioannidis, Alex, Hershman, Steve, Kirillova, Anna, Seo, Kinya, Huang, Yong, Shoura, Massa, Hammond, Nathan, Watson, Nathaniel, Raja, Archana, Huang, Chunhong, Sahoo, Malaya, Wang, Hannah, Zhen, Jimmy, Rakitko, Alexander, Ilinsky, Valery, Yermakovich, Danat, Popov, Iaroslav, Chernitsov, Alexander, Kovalenko, Elena, Krasnenko, Anna, Plotnikov, Nikolay, Stetsenko, Ivan, Kim, Anna, Cirulli, Elizabeth T., Schiabor Barrett, Kelly M., Bolze, Alexandre, White, Simon, Washington, Nicole L., Lu, James T., Riffle, Stephen, Tanudjaja, Francisco, Wang, Xueqing, Ramirez, Jimmy M., Leonetti, Nicole, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Grzymski, Joseph J., Esteban Miñano, Juan Ignacio, Aguirre, Luis A., López-Collazo, Eduardo, de la Mata Pazos, Manuel, Cerrato, Luciano, Lozano-Rodríguez, Roberto, Avendaño-Ortiz, José, Arcos, Verónica Terrón, Montalbán-Hernández, Karla Marina, Quiroga, Jaime Valentín, Pascual-Iglesias, Alejandro, Maroun-Eid, Charbel, Martín-Quirós, Alejandro, Namkoong, Ho, Imoto, Seiya, Katayama, Kazuhiko, Fukunaga, Koichi, Kitagawa, Yuko, Sato, Toshiro, Hasegawa, Naoki, Kumanogoh, Atsushi, Kimura, Akinori, Ai, Masumi, Tokunaga, Katsushi, Kanai, Takanori, Miyano, Satoru, Ogawa, Seishi, Edahiro, Ryuya, Sonehara, Kyuto, Shirai, Yuya, Ishii, Makoto, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Tanaka, Hiromu, Morita, Atsuho, Lee, Ho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Mikami, Yohei, Tomono, Kazunori, Kato, Kazuto, Matsuda, Fumihiko, Takahashi, Meiko, Hizawa, Nobuyuki, Takeda, Yoshito, Hirata, Haruhiko, Shiroyama, Takayuki, Miyawaki, Satoru, Suzuki, Ken, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Takahashi, Kunihiko, Anzai, Tatsuhiko, Hasegawa, Takanori, Ito, Satoshi, Koike, Ryuji, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro, Nakajima, Jun, Nannya, Yasuhito, Omae, Yosuke, Takahashi, Kazuhisa, Harada, Norihiro, Hiki, Makoto, Takagi, Haruhi, Nakamura, Ai, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Ishiguro, Takashi, Takayanagi, Noboru, Isono, Taisuke, Takaku, Yotaro, Takano, Kenji, Anan, Ryusuke, Nakajima, Yukiko, Nakano, Yasushi, Nishio, Kazumi, Ueda, Soichiro, Hayashi, Reina, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Mitamura, Keiko, Saito, Fumitake, Ueda, Tetsuya, Azuma, Masanori, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Yoshiyama, Takashi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Watanabe, Kazuyoshi, Manabe, Tadashi, Ito, Fumimaro, Fukui, Takahiro, Funatsu, Yohei, Koh, Hidefumi, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Saito, Fukuki, Yoshiya, Kazuhisa, Yoshihara, Tomoyuki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Nishi, Koichi, Nishitsuji, Masaru, Tani, Maiko, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Ogura, Takashi, Kitamura, Hideya, Murohashi, Kota, Nakachi, Ichiro, Baba, Rie, Arai, Daisuke, Fuke, Satoshi, Saito, Hiroshi, Kuwahara, Naota, Fujiwara, Akiko, Okada, Takenori, Baba, Tomoya, Noda, Junya, Mashimo, Shuko, Yagi, Kazuma, Shiomi, Tetsuya, Hashiguchi, Mizuha, Odani, Toshio, Mochimaru, Takao, Oyamada, Yoshitaka, Mori, Nobuaki, Izumi, Namiki, Nagata, Kaoru, Taki, Reiko, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Gon, Yasuhiro, Fujitani, Shigeki, Tsuchida, Tomoya, Yoshida, Toru, Kagaya, Takashi, Kita, Toshiyuki, Sakagami, Satoru, Kimizuka, Yoshifumi, Kawana, Akihiko, Nakamura, Yoshihiko, Ishikura, Hiroyasu, Takata, Tohru, Kikuchi, Takahide, Taniyama, Daisuke, Nakamura, Morio, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Ito, Akihiro, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Hashimoto, Naozumi, Wakahara, Keiko, Ando, Akira, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Sageshima, Hisako, Nakada, Taka-Aki, Abe, Ryuzo, Shimada, Tadanaga, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Yamasaki, Masaki, Hashimoto, Satoru, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Takada, Minoru, Kanda, Hidenori, Komase, Yuko, Sano, Fumiaki, Asano, Koichiro, Oguma, Tsuyoshi, Harada, Masahiro, Takahashi, Takeshi, Shibusawa, Takayuki, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Izumo, Takehiro, Inomata, Minoru, Awano, Nobuyasu, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Kitagawa, Yuichiro, Yoshida, Shozo, Ogura, Shinji, Nishiyama, Kei, Yoshida, Kousuke, Beppu, Satoru, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Inoue, Yoshiaki, Yamagata, Kunihiro, Chiba, Shigeru, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Shibata, Yoko, Tanino, Yoshinori, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Imamura, Tomonori, Umeda, Akira, Shimada, Hisato, Endo, Mayu, Hayashi, Shinichi, Takahashi, Mai, Nakano, Shigefumi, Yatomi, Masakiyo, Maeno, Toshitaka, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Boezen, Marike, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Obeidat, Ma’En, Hernández Cordero, Ana I., Sin, Don D., Bossé, Yohan, Joubert, Philippe, Hao, Ke, Nickle, David, Timens, Wim, van den Berge, Maarten, Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Jan Hottenga, Jouke, Bartels, Meike, de Geus, Eco J. C., Nivard, Michel G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Iacomino, Michele, Scudieri, Paolo, Bocciardi, Renata, Minetti, Carlo, Riva, Antonella, Vari, Maria Stella, Rahier, Jean-Françoi, Giorgio, Elisa, Carli, Diana, Louis, Edouad, Bulik, Cynthia M., Landén, Mikael, Brusco, Alfredo, Ferrero, Giovanni Battista, Madia, Francesca, Fundín, Bengt, Ismail, Said I., Saad, Chadi, Al-Sarraj, Yaser, Badji, Radja Messai, Al-Muftah, Wadha, Al Thani, Asma, Afifi, Nahla, Klovins, Jani, Rovite, Vita, Rescenko, Raimond, Peculis, Raiti, Ustinova, Monta, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Johnson, Ruth, Geschwind, Daniel H., Freimer, Nelson, Butte, Manish J., Ding, Yi, Chiu, Alec, Chang, Timothy S., Boutros, Paul, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Wilson, Daniel J., Spencer, Chris A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Mian, Michael, Scaggiante, Federica, Chang, Xiao, Glessner, Joseph R., Hakonarson, Hakon, Mcguigan, Peter J., Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Hall, Kathryn, Campbell, Andy, Nichol, Ailstair, Ward, Geraldine, Page, Valerie Joan, Semple, Malcolm G., Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L., Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nichola, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chri, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, Drummond, Andrew, Durand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B., Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tama, Lillie, Patrick, Limb, Jame, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, Macmahon, Michael, Macnaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, Mccullough, Katherine, Mcewen, Ruth, Meda, Manjula, Mills, Gary H., Minton, Jane, Ward, Karl, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, Jame, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapa, Nelson, Mark, O’Shea, Matthew K., Otahal, Igor, Ostermann, Marlie, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikola, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tama, Tatham, Kate, Thomas, Jo, Thompson, Chri, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wooton, Daniel G., Workman, Andrew, Yates, Bryan, Young, Peter, Beale, Rupert, Bretherick, Andrew D., Clohisey, Sara, Fourman, Max Head, Furniss, Jame, Gountouna, Elvina, Grimes, Graeme, Haley, Chri, Harrison, David, Hayward, Caroline, Keating, Sean, Klaric, Lucija, Klenerman, Paul, Law, Andy, Meynert, Alison M., Millar, Jonathan, Pairo-Castineira, Erola, Parkinson, Nichola, Ponting, Chris P., Porteous, David J., Rawlik, Konrad, Richmond, Anne, Rowan, Kathy, Russell, Clark D., Shen, Xia, Shih, Barbara, Tenesa, Albert, Vitart, Veronique, Wang, Bo, Wilson, James F., Wu, Yang, Yang, Jian, Yang, Zhijian, Zechner, Marie, Zhai, Ranran, Zheng, Chenqing, Norman, Lisa, Pius, Riinu, Drake, Thomas M., Fairfield, Cameron J., Knight, Stephen R., Mclean, Kenneth A., Murphy, Derek, Shaw, Catherine A., Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Hendry, Ro, Scott-Brown, Jame, Begg, Colin, Hinds, Charle, Wai Ho, Antonia Ying, Horby, Peter W., Knight, Julian, Ling, Lowell, Maslove, David, Mcauley, Danny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J. M., Summers, Charlotte, Walsh, Timothy, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, Mcparland, C., Packham, Sophie, Alldis, Zoe, Astin-Chamberlain, Raine, Bibi, Fatima, Biddle, Jack, Blow, Sarah, Bolton, Matthew, Borra, Catherine, Bowles, Ruth, Burton, Maudrian, Choudhury, Yasmin, Collier, David, Cox, Amber, Easthope, Amy, Ebano, Patrizia, Fotiadis, Stavro, Gurasashvili, Jana, Halls, Rosslyn, Hartridge, Pippa, Kallon, Delordson, Kassam, Jamila, Lancoma-Malcolm, Ivone, Matharu, Maninderpal, May, Peter, Mitchelmore, Oliver, Newman, Tabitha, Patel, Mital, Pheby, Jane, Pinzuti, Irene, Prime, Zoe, Prysyazhna, Oleksandra, Shiel, Julian, Taylor, Melanie, Tierney, Carey, Wood, Suzanne, Zak, Anne, Zongo, Olivier, Forsey, Miranda, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Grauslyte, Lina, Hussain, Musarat, Pogreban, Tatiana, Rosaroso, Lace, Salciute, Erika, Franke, George, Wong, Joanna, George, Aparna, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, Jame, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, Mcgowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Loosley, Ronda, Mcguinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Gibson, Sian, Lyle, Amanda, Mcneela, Fiona, Radhakrishnan, Jayachandran, Hughes, Alistair, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ro, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Antcliffe, David, Banach, Dorota, Brett, Stephen, Coghlan, Phoebe, Fernandez, Ziortza, Gordon, Anthony, Rojo, Roceld, Arias, Sonia Sousa, Templeton, Maie, Jha, Rajeev, Krishnamurthy, Vinodh, Lim, Lai, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Allan, Angela, Anderson, Felicity, Kaye, Callum, Liew, Jade, Medhora, Jasmine, Scott, Teresa, Trumper, Erin, Botello, Adriana, Polgarova, Petra, Stroud, Katerina, Meaney, Eoghan, Jones, Megan, Ng, Anthony, Agrawal, Shruti, Pathan, Nazima, White, Deborah, Daubney, Esther, Elston, Kay, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Jacob, Reni, Jones, Cathy, Denmade, Craig, Croft, Maria, White, Ian, Lim, Li, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Bastion, Victoria, Clarke, Daphene, David, Beena, Kent, Harriet, Lorusso, Rachel, Lubimbi, Gamu, Murdoch, Sophie, Penacerrada, Melchizedek, Thomas, Alastair, Valentine, Jennifer, Vochin, Ana, Wulandari, Retno, Djeugam, Brice, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, de Almeida Martins, Laura Gome, Carungcong, Jaime, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Cowley, Anne, Highgate, Judith, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Benham, Leonie, Bradshaw, Zena, Brown, Joanna, Caswell, Melanie, Melling, Sarah, Preston, Stephen, Slawson, Nicola, Stoddard, Emma, Warden, Scott, Combes, Edward, Joefield, Teishel, Monnery, Sonja, Beech, Valerie, Trotman, Sallyanne, Hopkins, Bridget, Scriven, Jame, Thrasyvoulou, Laura, Willis, Heather, Anderson, Susan, Birch, Janine, Collins, Emma, Hammerton, Kate, O’Leary, Ryan, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Kapoor, Ritoo, Loader, David, Castle, Karen, Brandwood, Craig, Smith, Lara, Clark, Richard, Birchall, Katie, Kolakaluri, Laurel, Baines, Deborah, Sukumaran, Anila, Mapfunde, Isheunesu, Meredith, Megan, Morris, Lucy, Ryan, Lucy, Clark, Amy, Sampson, Julia, Peters, Cecilia, Dent, Martin, Langley, Margaret, Ashraf, Saima, Wei, Shuying, Andrew, Angela, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Bates, Michelle, Dasgin, Jo, Gill, Jaspret, Nilsson, Annette, Apetri, Elena, Basikolo, Cathrine, Blackledge, Bethan, Catlow, Laura, Charles, Bethan, Doonan, Reece, Harris, Jade, Harvey, Alice, Horner, Daniel, Knowles, Karen, Lee, Stephanie, Lomas, Diane, Lyons, Chloe, Marsden, Tracy, Mclaughlan, Danielle, Mcmorrow, Liam, Pendlebury, Jessica, Perez, Jane, Poulaka, Maria, Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Clark, Martyn, Coulding, Martina, Jude, Edward, Mccormick, Jacqueline, Mercer, Oliver, Potla, Darsh, Rehman, Hafiz, Savill, Heather, Turner, Victoria, Davey, Miriam, Golden, David, Seaman, Rebecca, Hunt, Jodie, Dearden, Joy, Dobson, Emma, Mulcahy, Michelle, Munt, Sheila, O’Connor, Grainne, Philbin, Jennifer, Rishton, Chloe, Tully, Redmond, Winnard, Sarah, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, K., Vuylsteke, Alain, Zamikula, Julie, Bercades, Georgia, Brealey, David, Hass, Ingrid, Maccallum, Niall, Martir, Glady, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Alexander, Peter, Allen, Schvearn, Bradley-Potts, Joanne, Brantwood, Craig, Egan, Jasmine, Felton, Timothy, Padden, Grace, Ward, Luke, Moss, Stuart, Glasgow, Susannah, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Je, Pippard, Lucy, Wood, Di, Buckley, Clare, Brown, Alison, Gregory, Jane, O’Connell, Susan, Smith, Tim, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Jardine, Catherine, Williams, Dewi, Parris, Victoria, Quaid, Sheena, Watson, Ekaterina, Melville, Julie, Naisbitt, Jay, Joseph, Rosane, Lazo, Maria, Walton, Olivia, Neal, Alan, Hill, Michaela, Kannan, Thogulava, Wild, Laura, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llino, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Coetzee, Samantha, Gales, Alistair, Raj, Meena, Sell, Craig, Langton, Helen, Watters, Malcolm, Novis, Catherine, Arbane, Gill, Bociek, Aneta, Campos, Sara, Grau, Neu, Jones, Tim Owen, Lim, Rosario, Marotti, Martina, Whitton, Christopher, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Thwaites, Vicky, Mahay, Kanta, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Bancroft, Hollie, Bellamy, Mary, Carmody, Margaret, Daglish, Jacqueline, Moore, Faye, Rhodes, Joanne, Sangombe, Mirriam, Kadiri, Salma, Ayers, Amanda, Harrison, Wendy, North, Julie, Cavazza, Anna, Cockrell, Maeve, Corcoran, Eleanor, Depante, Maria, Finney, Clare, Jerome, Ellen, Mcphail, Mark, Nayak, Monalisa, Noble, Harriet, O’Reilly, Kevin, Pappa, Evita, Saha, Rohit, Saha, Sian, Smith, John, Knighton, Abigail, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Baptista, David, Crowe, Rebecca, Fernandes, Rita, Herdman-Grant, Rosaleen, Joseph, Anna, Loveridge, Adam, Mckenley, India, Morino, Eriko, Naranjo, Andre, Simms, Richard, Sollesta, Kathryn, Swain, Andrew, Venkatesh, Harish, Khera, Jacyntha, Fox, Jonathan, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, George, Linsha, Twiss, Sophie, Wright, David, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chri, Mahenthran, Mervin, Carter, Emma, Kong, Thoma, Adanini, Oluronke, Bhatia, Nikhil, Msiska, Maine, Mew, Louise, Mwaura, Esther, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Battle, Ceri, Brinkworth, Elaine, Harford, Rachel, Murphy, Carl, Newey, Luke, Rees, Tabitha, Williams, Marie, Arnold, Sophie, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Abdelrazik, Marwa, Bakthavatsalam, Dhanalakshmi, Elhassan, Munzir, Ganesan, Arunkumar, Haldeos, Anne, Moreno-Cuesta, Jeronimo, Purohit, Dharam, Vincent, Rachel, Xavier, Kugan, Rohit, Kumar, Alasdair, Frater, Saleem, Malik, David, Carter, Jenkins, Samuel, Lamond, Zoe, Wall, Alanna, Reynolds, Jessica, Campbell, Helen, Thompsom, Maria, Dodds, Steve, Duffy, Stacey, Butcher, Deborah, O’Sullivan, Susie, Butterworth-Cowin, Nicola, Deacon, Bethan, Hibbert, Meg, Pothecary, Carla, Tetla, Dariusz, Woodford, Christopher, Durga, Latha, Kennard-Holden, Gareth, de Gordoa, Laura Ortiz-Ruiz, Peasgood, Emily, Phillips, Claire, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Davies, Ellie, Roche, Lisa, Sathe, Sonia, Brimfield, Lutece, Daly, Zoe, Pogson, David, Rose, Steve, Collins, Amy, Khaliq, Waqa, Gude, Estefania Treu, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Giles, Julian, Booth, Simon, Bell, Gillian, English, Katy, Katary, Amro, Wilcox, Louise, Campbell, Rachael, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O’Hara, Marianne, O’Keefe, Laura, Bradley, Clare, Collier, Dawn, Walker, Rachel, Maynard, Victoria, Patel, Tahera, Smith, Matthew, Kazi, Aayesha, Hartley, Janice, Dykes, Joseph, Hijazi, Muhammad, Keith, Sarah, Khan, Meherunnisa, Ryan-Smith, Janet, Springle, Philippa, Thomas, Jacqueline, Truman, Nick, Saad, Samuel, Coleman, Dabheoc, Fine, Christopher, Matt, Roseanna, Gay, Bethan, Dalziel, Jack, Ali, Syamlan, Goodchild, Drew, Harling, Rhiannan, Bhatterjee, Ravi, Goddard, Wendy, Davison, Chloe, Duberly, Stephen, Hargreaves, Jeanette, Bolton, Rachel, Verlander, Mark, Williams, Alexandra, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charle, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Abel, Lynn, Brett, Michael, Digby, Brian, Gemmell, Lisa, Hornsby, Jame, Macgoey, Patrick, O’Neil, Pauline, Price, Richard, Rodden, Natalie, Rooney, Kevin, Sundaram, Radha, Thomson, Nicola, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, Mckenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh V., Salmi, Sara, Sloane, Geraldine, Varghese, Mathew, Zborowski, Anelise C., Bean, Sarah, Burt, Karen, Spivey, Michael, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, De Neef, Mark, Lynch, Ceri, Howe, Gwenllian Sera, Singh, Jayaprakash, Turner, Keri, Ellis, Hannah, Stroud, Natalie, Cherian, Shiney, Cutler, Sean, Heron, Anne Emma, Roynon-Reed, Anna, Williams, Gemma, Richards, Owen, Cheema, Yusuf, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kri, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, Jame, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, Bandla, Nageswar, Gellamucho, Minnie, Davies, Michelle, Thompson, Christopher, Trim, Fiona, Eapen, Beena, Ahmed, Cecilia, Baines, Balvinder, Clamp, Sarah, Colley, Julie, Haq, Risna, Hayes, Anne, Hulme, Jonathan, Hussain, Samia, Joseph, Sibet, Kumar, Rita, Maqsood, Zahira, Purewal, Manjit, Chandler, Ben, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Delgado, Carlos Castro, Dawson, Deborah, Ding, Lijun, Durrant, Georgia, Ezeobu, Obiageri, Farnell-Ward, Sarah, Harrison, Abiola, Kanu, Rebecca, Leaver, Susannah, Maccacari, Elena, Manna, Soumendu, Saluzzio, Romina Peperman, Queiroz, Joana, Samakomva, Tinashe, Sicat, Christine, Texeira, Joana, Da Gloria, Edna Fernande, Lisboa, Ana, Rawlins, John, Mathew, Jisha, Kinch, Ashley, Hurt, William Jame, Shah, Nirav, Clark, Victoria, Thanasi, Maria, Yun, Nikki, Patel, Kamal, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Anderson, Peter, Archer, Katie, Austin, Karen, Davis, Caroline, Durie, Alison, Kelsall, Olivia, Thrush, Jessica, Vigurs, Charlie, Wood, Hannah-Louise, Tranter, Helen, Harrison, Alison, Cowley, Nichola, Mcalindon, Michael, Digby, Stephen, Low, Emma, Morgan, Aled, Cother, Naiara, Rankin, Tobia, Clayton, Sarah, Mccurdy, Alex, Allibone, Suzanne, Mary-Genetu, Roman, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Fernandez-Roman, Jaime, Hamilton, David O., Johnson, Emily, Johnston, Brian, Martinez, Maria Lopez, Mulla, Suleman, Shaw, David, Waite, Alicia A. C., Waugh, Victoria, Welters, Ingeborg D., Williams, Karen, Bemand, Thoma, Black, Ethel, Rosa, Arnold Dela, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, West, Joe, Baird, Tracy, Ruddy, Jim, Reece-Anthony, Rosie, Birt, Mark, Cowton, Amanda, Kay, Andrea, Kent, Melanie, Potts, Kathryn, Wilkinson, Ami, Naylor, Suzanne, Brown, Ellen, Clark, Michele, Purvis, Sarah, Cole, Jade, Davies, Rhy, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D’Sylva, Stuart, Norman, Kathryn, Coventry, Tina, Fowler, Susan, Mcgregor, Amanda, Brady, Ailbhe, Chan, Rebekah, Mcivor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Baird, Yolanda, Butler, Aaron, Chadbourn, Indra, Folkes, Linda, Fox, Heather, Gardner, Amy, Gomez, Raquel, Hobden, Gillian, King, Kirsten, Margarson, Michael, Martindale, Tim, Meadows, Emma, Raynard, Dana, Thirlwall, Yvette, Helm, David, Margalef, Jordi, Greer, Sandra, Shuker, Karen, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewi, Claire, Watkin, Birkinshaw, Isobel, Carter, Joseph, Howard, Kate, Ingham, Joanne, Joy, Rosie, Pearson, Harriet, Roche, Samantha, Scott, Zoe, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chri, Abraheem, Azmerelda, Bamford, Peter, Cawley, Kathryn, Dunmore, Charlie, Faulkner, Maria, Girach, Rumanah, Jeffrey, Helen, Jones, Rhianna, London, Emily, Nagra, Imrun, Nasir, Farah, Sainsbury, Hannah, Smedley, Clare, Khade, Reena, Sundar, Ashok, Tsinaslanidis, George, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Burns, Karen, Higham, Andrew, Anderson, Taya, Hawcutt, Dan, O’Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Lankester, Liana, Nikitas, Nikita, Wells, Colin, Stowe, Bethan, Spencer, Kayleigh, Cathcart, Susanne, Duffy, Katharine, Puxty, Alex, Puxty, Kathryn, Turner, Lynne, Ireland, Jane, Semple, Gary, Barry, Peter, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Irvine, Val, Shelley, Benjamin, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A. L., Mchugh, Tara, Meghari, Hamza, O’Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Bonner, Stephen, Hugill, Keith, Jones, Jessica, Liggett, Steven, Bashyal, Archana, Davidson, Neil, Hutton, Paula, Mckechnie, Stuart, Wilson, Jean, Flint, Neil, Rekha, Patel, Hales, Dawn, Cruz, Carina, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Clement, Ian, Patel, Bijal, Gulati, A., Hays, Carole, Webster, K., Hudson, Anne, Webster, Andrea, Stephenson, Elaine, Mccormack, Louise, Slater, Victoria, Nixon, Rachel, Hanson, Helen, Fearby, Maggie, Kelly, Sinead, Bridgett, Victoria, Robinson, Philip, Almaden-Boyle, Christine, Austin, Pauline, Cabrelli, Louise, Cole, Stephen, Casey, Matt, Chapman, Susan, Whyte, Clare, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nichola, Parkin, Juliet, Tuckey, Victoria, van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Bruce, Michelle, Connolly, Karen, Duncan, Tracy, T. -Michael, Helen, Lindergard, Gabriella, Hey, Samuel, Fox, Claire, Alfonso, Jordan, Durrans, Laura Jayne, Guerin, Jacinta, Hruska, Martin, Eltayeb, Ayaa, Lamb, Thoma, Hodgkiss, Tracey, Cooper, Lisa, Rothwell, Joanne, Dennis, Catherine, Mcgregor, Alastair, Srikaran, Sinduya, Sukha, Anisha, Davies, Kim, O’Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Brooke, Hollie, Buckley, Sarah, Suarez, Jose Cebrian, Charlesworth, Ruth, Hansson, Karen, Norris, John, Poole, Alice, Rose, Alastair, Sandhu, Rajdeep, Sloan, Brendan, Smithson, Elizabeth, Thirumaran, Muthu, Wagstaff, Veronica, Metcalfe, Alexandra, Camsooksai, Julie, Humphrey, Charlotte, Jenkins, Sarah, Wadams, Beverley, Death, Yasmin, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, Jame, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Bokhari, Maria, Lucas, Rachael, Mccormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, Mcparland, Christopher, Rooney, Laura, Sim, Malcolm, Mccreath, Gordan, Brunton, Mark, Caterson, Je, Coles, Holly, Frise, Matthew, Rai, Sabi Gurung, Keating, Liza, Tilney, Emma, Bartley, Shauna, Bhuie, Parminder, Downes, Charlotte, Holding, Kathleen, Riches, Katie, Hilton, Mary, Hayman, Mel, Subramanian, Deepak, Daniel, Priya, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Andrew, Gillian, Barclay, Lucy, Callaghan, Marie, Clark, Sarah, Hope, Dave, Marshall, Lucy, Mcculloch, Corrienne, Briton, Kate, Singleton, Jo, Birch, Sophie, Simpson, Kerry, Craig, Jayne, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nichola, Sowter, Jason, Howlett, Alex, Criste, Kristine, Cusack, Rebecca, Golder, Kim, Golding, Hannah, Jones, Oliver, Leggett, Samantha, Male, Michelle, Marani, Martyna, Prager, Kirsty, Williams, Toran, Roberts, Belinda, Salmon, Karen, Gondo, Prisca, Hadebe, B., Kayani, Abdul, Masunda, Bridgett, Ahmed, Ashar, Morris, Anna, Jakkula, Sriniva, Long, Kate, Whiteley, Simon, Wilby, Elizabeth, Ogg, Bethan, Moultrie, Sam, Odam, M., Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Bennett, Sara, Goodwin, Emma, Jackson, Matthew, Kent, Alissa, Tibke, Clare, Woodyatt, Wiesia, Zaki, Ahmed, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, Bremmer, Pamela, Allan, J., Geary, T., Houston, Gordon, Meikle, A., O’Brien, P., Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Charnock, Rob, Mcfarland, Denise, Cosgrove, Denise, Attwood, Ben, Parsons, Penny, Carmody, Siobhain, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Cosier, Tracey, Millen, Gemma, Schumacher, Natasha, Weston, Heather, Rand, Jame, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S., Bogaert, Debby, Chand, Meera, Cooke, Graham S., Docherty, Annemarie B., Dunning, Jake, da Silva Filipe, Ana, Fletcher, Tom, Green, Christoper A., Harrison, Ewen M., Hiscox, Julian A., Ijaz, Samreen, Khoo, Saye, Lim, Wei Shen, Mentzer, Alexander J., Merson, Laura, Noursadeghi, Mahdad, Moore, Shona C., Palmarini, Massimo, Paxton, William A., Pollakis, Georgio, Price, Nichola, Rambaut, Andrew, Robertson, David L., Sancho-Shimizu, Vanessa, Scott, Janet T., de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Tedder, Richard S., Thomson, Emma C., Roger Thompson, A. A., Thwaites, Ryan S., Turtle, Lance C. W., Gupta, Rishi K., Palmieri, Carlo, Swann, Olivia V., Zambon, Maria, Dumas, Marc-Emmanuel, Griffin, Julian L., Takats, Zoltan, Chechi, Kanta, Andrikopoulos, Petro, Osagie, Anthonia, Olanipekun, Michael, Liggi, Sonia, Lewis, Matthew R., Correia, Gonçalo dos Santo, Sands, Caroline J., Takis, Panteleimon, Maslen, Lynn, Greenhalf, William, Shaw, Victoria, Mcdonald, Sarah E., Keating, Seán, Ahmed, Katie A., Armstrong, Jane A., Ashworth, Milton, Asiimwe, Innocent G., Bakshi, Siddharth, Barlow, Samantha L., Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A., Clark, Jordan J., Clarke, Emily A., Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chri, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. S., Foster, Terry, Garcia-Dorival, Isabel, Gunning, Philip, Hartley, Catherine, Jensen, Rebecca L., Jones, Christopher B., Jones, Trevor R., Khandaker, Shadia, King, Katharine, Kiy, Robyn T., Koukorava, Chrysa, Lake, Annette, Lant, Suzannah, Latawiec, Diane, Lavelle-Langham, Lara, Lefteri, Daniella, Lett, Lauren, Livoti, Lucia A., Mancini, Maria, Mcdonald, Sarah, Mcevoy, Laurence, Mclauchlan, John, Metelmann, Soeren, Miah, Nahida S., Middleton, Joanna, Mitchell, Joyce, Murphy, Ellen G., Penrice-Randal, Rebekah, Pilgrim, Jack, Prince, Tessa, Reynolds, Will, Ridley, P. Matthew, Sales, Debby, Shaw, Victoria E., Shears, Rebecca K., Small, Benjamin, Subramaniam, Krishanthi S., Szemiel, Agnieska, Taggart, Aislynn, Tanianis-Hughes, Jolanta, Thomas, Jordan, Trochu, Erwan, van Tonder, Libby, Wilcock, Eve, Zhang, J. Eunice, Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Carracedo, Alejandra Doce, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, Mccafferty, Sarah, Morrice, Kirstie, Maclean, Alan, Armstrong, Ruth, Boz, Ceilia, Brown, Adam, Coutts, Audrey, Cullum, Louise, Day, Nicky, Donnelly, Lorna, Duncan, Esther, Fawkes, Angie, Finernan, Paul, Gilchrist, Tammy, Golightly, Ailsa, Hafezi, Katarzyna, Law, Dawn, Law, Rachel, Law, Sarah, Macgillivray, Louise, Mal, Hanning, Mcmaster, Ellie, Meikle, Jen, Oosthuyzen, Wilna, Paterson, Trevor, Stenhouse, Andrew, Swets, Maaike, Szoor-McElhinney, Helen, Taneski, Filip, Wackett, Tony, Ward, Mairi, Weaver, Jane, Coyle, Judy, Gallagher, Bernadette, Lidstone-Scott, Rebecca, Hamilton, Debbie, Schon, Katherine, Furlong, Anita, Biggs, Heather, Griffiths, Fiona, Andrews, Eleanor, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Carson, Gail, Hardwick, Hayley, Donohue, Chloe, Pérez-Tur, Jordi [0000-0002-9111-1712], Martín, Javier [0000-0002-2202-0622], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], A list of authors and their affiliations appears in the Supplementary Information, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Niemi, M, Karjalainen, J, Liao, R, Neale, B, Daly, M, Ganna, A, Pathak, G, Andrews, S, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, E, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, M, Wendt, F, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, M, Smith, G, Willer, C, Buxbaum, J, Mehtonen, J, Finucane, H, Cordioli, M, Martin, A, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, M, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, V, van Heel, D, Deelen, P, Richards, J, Nakanishi, T, Biesecker, L, Kerchberger, V, Baillie, J, Mari, F, Bernasconi, A, Baillie, S, Canakoglu, A, 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A., de Almeida Martins, L. G., Mclaughlan, D., Mcmorrow, L., Mccormick, J., Mitchell, A. M., Maccallum, N., Hughes, R. A., Jones, T. O., Mcphail, M., Mckenley, I., Sutherland, S. -B., de Gordoa, L. O. -R., Gude, E. T., Macgoey, P., Mckenna, E., Patel, B. V., Zborowski, A. C., Garcia, S. M., Howe, G. S., Heron, A. E., Mills, G. H., Brown, C. W., Akhtar, M. N., Delgado, C. C., Saluzzio, R. P., Da Gloria, E. F., Hurt, W. J., Wood, H. -L., Mcalindon, M., Mccurdy, A., Ali, I. A. M., Ally, S. M., Hamilton, D. O., Lopez Martinez, M., Waite, A. A. C., Welters, I. D., Rosa, A. D., Baikady, R. R., Tatham, K. C., Beith, C. M., Mcgregor, A., Mcivor, S., Allison, K. S., Jones, G. A. L., Mchugh, T., Peters, M. J., Tomas, A. L., Mckechnie, S., Mccormack, L., Michael, H. T., Durrans, L. J., Suarez, J. C., Death, Y., Mccormick, W., Mccreath, G., Rai, S. G., Mcculloch, C., Mcfarland, D., Barclay, W. S., Cooke, G. S., Docherty, A. B., Green, C. A., Harrison, E. M., Hiscox, J. A., Lim, W. S., Mentzer, A. J., Paxton, W. A., Robertson, D. L., Scott, J. T., Tedder, R. S., Thomson, E. C., Thwaites, R. S., Gupta, R. K., Swann, O. V., Dumas, M. -E., Griffin, J. L., Lewis, M. R., dos Santos Correia, G., Sands, C. J., Mcdonald, S. E., Ahmed, K. A., Armstrong, J. A., Asiimwe, I. G., Barlow, S. L., Catterall, B. W. A., Clark, J. J., Clarke, E. A., Fisher, L. W. S., Jensen, R. L., Jones, C. B., Jones, T. R., Kiy, R. T., Livoti, L. A., Mcdonald, S., Mcevoy, L., Mclauchlan, J., Miah, N. S., Moore, S. C., Murphy, E. G., Matthew Ridley, P., Shaw, V. E., Shears, R. K., Subramaniam, K. S., Eunice Zhang, J., Carracedo, A. D., Mccafferty, S., Turtle, L. C. W., Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, HUS Helsinki and Uusimaa Hospital District, University of Helsinki, Research Programs Unit, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, and University of Zurich
Subjects: Male, 45/43, Autoimmunity, Autoimmunity/genetics, Body Mass Index, COVID-19/genetics, COVID-19/virology, Critical Illness, Female, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Geographic Mapping, Hospitalization, Host-Pathogen Interactions/genetics, Humans, Inflammation/complications, Information Dissemination, Multifactorial Inheritance, Racial Groups/genetics, SARS-CoV-2/pathogenicity, Smoking, environmental risk factors, Q1, 631/208, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genetics, Genome-wide association studies, SARS-CoV-2, Viral infection, GWAS, Aetiology, Lung, QC, 0303 health sciences, HERITABILITY, 3. Good health, covid-19, Science & Technology - Other Topics, Identification (biology), Infection, Human, 631/208/205/2138, Settore BIO/11 - Biologia Molecolare, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical Research, Biodefense, Genetics, GENOME-WIDE ASSOCIATION, Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], METAANALYSIS, 1000 Multidisciplinary, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Prevention, Racial Groups, Pneumonia, genetic architecture, Human genetics, Genetic Loci, genetic factors, 570 Life sciences, biology, 030217 neurology & neurosurgery, Medizin, Infektionsmedicin, Genome-wide association studies, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Pandemic, 2.1 Biological and endogenous factors, pandemi, Multidisciplinary, article, Public Health, Global Health, Social Medicine and Epidemiology, Racial Group, 10124 Institute of Molecular Life Sciences, Host-Pathogen Interaction, Multidisciplinary Sciences, Infectious Diseases, Host-Pathogen Interactions, Critical Illne, COVID-19, GWAS, genetic factors, environmental risk factors, therapy, Infectious Medicine, Coronavirus disease 2019 (COVID-19), SUSCEPTIBILITY LOCI, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Computational biology, Biology, Vaccine Related, 692/699/255/2514, Environmental risk, Mendelian randomization, COVID-19 Host Genetics Initiative, QH426, 631/326/596/4130, 030304 developmental biology, Inflammation, therapy, SARS-CoV-2, Human Genome, COVID-19, Genetic architecture, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Emerging Infectious Diseases, Good Health and Well Being, Viral infection, 3111 Biomedicine
Abstract: Niemi, Mari E. K. et al. 39 páginas, figuras y tablas. Contiene material suplementario., The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Published: 2021

16. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author: Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P
Published: 2020

17. New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids

Author: Johanna Vappiani, Terezinha de Souza, Theo M. de Kok, Luke Coyle, Julio Saez-Rodriguez, Danyel Jennen, Daniel C. Sévin, D. F. Rodrigues, Seung-Wook Chung, Matteo Di Piazza, Bram Herpers, Attila Gábor, Mian Zhang, Anthony M. Lynch, Jos C. S. Kleinjans, Sofia Ferreira, Toxicogenomics, RS: GROW - R1 - Prevention, RS: FSE MaCSBio, RS: FPN MaCSBio, and RS: FHML MaCSBio
Subjects: 0301 basic medicine, Male, PHARMACOKINETICS, Health, Toxicology and Mutagenesis, Cell, Apoptosis, Toxicology, Toxicogenomics and Omics Technologies, COLORECTAL-CANCER, Transcriptome, 0302 clinical medicine, Intestine, Small, E2F1, TISSUE DISTRIBUTION, GENE-EXPRESSION, Cell Cycle, General Medicine, Cell cycle, STEM, 5-FU toxicity, 3. Good health, Cell biology, Organoids, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Antimetabolites, Antineoplastic, Cell Survival, Colon, Human organoid models, Biology, HIGH-THROUGHPUT, Models, Biological, 03 medical and health sciences, Metabolomics, Organoid, Metabolome, medicine, Humans, Transcriptomics, MUCOSAL INJURY, Transcription factor, Dose-Response Relationship, Drug, Molecular mechanisms, IN-VITRO, FLUOROURACIL, MODEL, Oxidative Stress, 030104 developmental biology
Abstract: 5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03092-2.
Published: 2021

18. Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Author: Graeme J. Hankey, Maree L. Hackett, Osvaldo P. Almeida, Leon Flicker, Gillian E. Mead, Martin S. Dennis, Christopher Etherton-Beer, Andrew H. Ford, Laurent Billot, Stephen Jan, Thomas Lung, Erik Lundström, Katharina S. Sunnerhagen, Craig S. Anderson, Huy Thang-Nguyen, John Gommans, Qilong Yi, Veronica Murray, Robert Herbert, Gregory Carter, Geoffrey A. Donnan, Huy-Thang Nguyen, Qiang Li, Severine Bompoint, Sarah Barrett, Anne Claxton, Julia O’Dea, Michelle Tang, Clare Williams, Shenae Peterson, Christie Drummond, Uyen-Ha Hong, Linh-Thi My Le, Tram-Thi Bich Ngo, Yen-Bao Mai, Huyen-Thanh Han, Nhu-Quynh Truong, Huong-Thi Nguyen, Hai-Thanh Ngo, Thi Binh Nguyen, Oanh-Thi Kieu Ha, Trang-Le Huyen Nguyen, Richard I. Lindley, Peter New, Andrew Lee, Thanh-Trung Tran, Loan-Tran Truc Mai Le, Thuy-Le Vu Kieu, Sang-Van Nguyen, Thuy-Anh Diem Nguyen, Tam-Nhat Dang, Hanh-Thi Truc Phan, Loan-Thi Ngoc Vo, Mai-Hue Nguyen, Hanh-Cao Dang, Hong-Thi Tran, Linh-Thi Cam Dam, Trinh-Thi Kim Ngo, Thai-Nguyen Thanh Pham, Binh-Nguyen Pham, Nha-Thi Thanh Dao, Huong-Thi Bich Nguyen, Linh-Thi Cam Le, Chi-Minh Do, Huy-Quoc Huynh, Giau-Thi Kim Tran, Oanh-Thi Le, Ly-Thi Khanh Tran, Chinh-Dinh Duong, Duong-Van Kieu, Na Le, Hoa-Ngoc Nguyen, Binh-Van Le, Long-Thanh Nguyen, Long-Van Nguyen, Tuan-Quoc Dinh, Tan-Van Vo, Tram-Ngoc Bui, Uyen-Thi To Hoang, Hien-Thi Bich Nguyen, Ha-Thi Thu Nguyen, Nga-Thuy Lam, Khanh-Kim Le, Phuong-Thanh Trinh, Hop-Quang Huynh, Thao-Thi Thu Nguyen, Huyen-Ngoc Lu, Tham-Hong Pham, Sam-Hoanh Nguyen, Ninh-Hong Le, Giang-Truong Nguyen, Bich-Thi Doan, Sung-Phuoc Pham, Duong-Huu Luong, Ha-Van Mai, Thuc-Van Tran, Phuong-Thi Do, Hoai-Thi Le, Chi-Van Nguyen, Phuong-Doan Nguyen, Ton-Duy Mai, Phuong-Viet Dao, Dung-Tien Nguyen, Dai-Quoc Khuong, Trung-Xuan Vuong, Lan-Tuong Vu, Ngoc-Duc Ngo, Hanh-Hong Dang, Phuong-Thai Truong, Ngan-Thi Le, Hoa-Van Hoang, Chung-Quang Do, Minh-Thao Nguyen, Anh-Hai Dam, Quynh-Nhu Le, Ngoc-Hoang Nguyen, Tuyen-Van Nguyen, Toan-Dinh Le, Ha-Thi Hai Dinh, Cuong–Van Pham, Khanh-Thi Ngoc Thach, Linh-Hai Nguyen, Loan-Thi Nguyen, Vien-Chi Le, Phuong-Hong Tran, Tai-Anh Nguyen, Tuan-Van Le, Luyen-Van Truong, Tue-Chau Bui, Ngoc-Xuan Huynh, Lap-Van Dinh, An-Gia Pham, Trang-Thi Huyen Le, Vy-Tuong Nguyen, Yen-Hai Nguyen, Thang-Ba Nguyen, Huy Thai, Quyen-Thi Ngoc Pham, Khoa-Duy Dao, Quoc-Nguyen Bao Pham, Thuong-Thi Huyen Dang, Huong-Huynh To Dinh, Trang-Mai Tong, Thuy-Thi Vu, Si-Tri Le, Tai-Ngoc Tran, Phuong-Hoai Tran, Ngoc-Thuy Nhu Dinh, Binh-Thanh Nguyen, Vinh-Phuong Do, Anh-Ngoc Nguyen, Binh-Thi Thanh Nguyen, David Blacker, Lindsey Bunce, Ai Ling Tan, Darshan Ghia, Gillian Edmonds, Nicole O’Loughlin, Megan Ewing, Kerri-Ann Whittaker, Lorralee Deane, Yash Gawarikar, Brett Jones, Maria Lopez, Koushik Nagesh, Emma Siracusa, Stephen Davis, Amy McDonald, Jess Tsoleridis, Rachael McCoy, David Jackson, Gab Silver, Timothy R. Bates, Amanda Boudville, Lynda Southwell, Dennis Cordato, Alan J. McDougall, Cecilia Cappelen-Smith, Zeljka Calic, Shabeel Askar, Qi Cheng, Raymond Kumar, Richard Geraghty, Maree Duroux, Megan Ratcliffe, Samantha Shone, Cassandra McLennan, Ramesh Sahathevan, Casey Hair, Stanley Levy, Beverley Macdonald, Benjamin Nham, Louise Rigney, Dev Nathani, Sumana Gopinath, Vishal Patel, Abul Mamun, Benjamin Trewin, Chun Phua, Ho Choong, Lauren Tarrant, Kerry Boyle, Luisa Hewitt, Monique Hourn, Amanda Masterson, Kim Oakley, Karen Ruddell, Colette Sanctuary, Kimberley Veitch, Camelia Burdusel, Lina Lee, Gary Cheuk, Jeremy Christley, Tabitha Hartwell, Craig Davenport, Kate Hickey, Rosanna Robertson, Michelle Carr, Sam Akbari, Hannah Coyle, Megan O’Neill, Cameron Redpath, Caroline Roberts, Marjan Tabesh, Toni Withiel, Kapila Abeysuriya, Andrew Granger, Angela Abraham, Chermaine Chua, Dung Do Nguyen, Vathani Surendran, Melissa Daines, David Shivlal, Mudassar Latif, Noreen Mughal, Patricia Morgan, Martin Krause, Miriam Priglinger, Ehsan E. Shandiz, Susan Day, Lay Kho, Michael Pollack, Judith Dunne, Helen Baines, Merridie Rees, Jenni White, Aicuratiya Withanage, Candice Delcourt, Cheryl Carcel, Alejandra Malavera, Amy Kunchok, Elizabeth Ray, Elizabeth Pepper, Emily Duckett, Sally Ormond, Andrew Moey, Timothy Kleinig, Vanessa Maxwell, Chantal Baldwin, Wilson Vallat, Deborah Field, Romesh Markus, Kirsty Page, Danielle Wheelwright, Sam Bolitho, Steven Faux, Fix Sangvatanakul, Alexis Brown, Susan Walker, Jennifer Massey, Hillary Hayes, Pesi Katrak, Annie Winker, Alessandro Zagami, Alanah Bailey, Sarah Mccormack, Andrew Murray, Mark Rollason, Christopher Taylor, Fintan O’Rourke, Ye Min Kuang, Heike Burnet, Yvonne Liu, Aileen Wu, Diana Ramirez, Tissa Wijeratne, Sherisse Celestino, Essie Low, Cynthia Chen, Jennifer Bergqvist, Andrew Evans, Queenie Leung, Martin Jude, Rachael McQueen, Katherine Mohr, Latitia Kernaghan, Paul Stockle, Boon L. Tan, Sara Laubscher, Diana Schmid, Melissa Spooner, Bhavesh Lallu, Bronwen Pepperell, John Chalissery, Karim Mahawish, Susan DeCaigney, Paula Broughton, Karen Knight, Veronica Duque, Harry McNaughton, Jeremy Lanford, Vivian Fu, and Lai-Kin Wong
Subjects: Male, medicine.medical_specialty, Steering committee, medicine.medical_treatment, Placebo, B700, Fractures, Bone, Cognition, Double-Blind Method, Recurrence, Seizures, Fluoxetine, Internal medicine, Humans, Medicine, Stroke, Fatigue, Aged, Ischemic Stroke, Acute stroke, Advanced and Specialized Nursing, business.industry, Recovery of Function, Middle Aged, Functional recovery, medicine.disease, Clinical trial, Affect, Hemorrhagic Stroke, Quality of Life, Accidental Falls, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Stroke recovery, Selective Serotonin Reuptake Inhibitors, medicine.drug
Abstract: Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.
Published: 2021

19. Four-Second Power Cycling Training Increases Maximal Anaerobic Power, Peak Oxygen Consumption, and Total Blood Volume

Author: Mercedes J Nagel, Sophie Lalande, Edward F. Coyle, Sungmo Hong, and Remzi Satiroglu
Subjects: Adult, Male, Blood Volume, Time Factors, Anaerobic Threshold, business.industry, chemistry.chemical_element, Physical Therapy, Sports Therapy and Rehabilitation, Blood volume, High-Intensity Interval Training, Oxygen, Interval training, Bicycling, Intensity (physics), Animal science, chemistry, Power cycling, Humans, Medicine, Female, Orthopedics and Sports Medicine, Cycling, business, Cardiovascular fitness, Anaerobic exercise
Abstract: INTRODUCTION High-intensity interval training is an effective tool to improve cardiovascular fitness and maximal anaerobic power. Different methods of high-intensity interval training have been studied but the effects of repeated maximal effort cycling with very short exercise time (i.e., 4 s) and short recovery time (15-30 s) might suit individuals with limited time to exercise. PURPOSE We examined the effects of training at near maximal anaerobic power during cycling (PC) on maximal anaerobic power, peak oxygen consumption (V˙O2peak), and total blood volume in 11 young healthy individuals (age: 21.3 ± 0.5 yr) (six men, five women). METHODS Participants trained three times a week for 8 wk performing a PC program consisting of 30 bouts of 4 s at an all-out intensity (i.e., 2 min of exercise per session). The cardiovascular stress progressively increased over the weeks by decreasing the recovery time between sprints (30-24 s to 15 s), and thus, total session time decreased from 17 to
Published: 2021

20. Cerebellar granule cell axons support high-dimensional representations

Author: Frederic Lanore, Diccon Coyle, Harsha Gurnani, R. Angus Silver, N. Alex Cayco-Gajic, Department of Neuroscience, Physiology & Pharmacology, University College of London [London] (UCL), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lanore, Frédéric, École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)
Subjects: Male, 0301 basic medicine, Cerebellum, Population, Purkinje cell, Mice, Transgenic, Biology, Article, Mice, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, medicine, Animals, Premovement neuronal activity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], education, education.field_of_study, Neocortex, Behavior, Animal, General Neuroscience, Granule cell, Axons, Associative learning, 030104 developmental biology, medicine.anatomical_structure, nervous system, Cerebellar cortex, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Locomotion, 030217 neurology & neurosurgery
Abstract: In classical theories of cerebellar cortex, high-dimensional sensorimotor representations are used to separate neuronal activity patterns, improving associative learning and motor performance. Recent experimental studies suggest that cerebellar granule cell (GrC) population activity is low-dimensional. To examine sensorimotor representations from the point of view of downstream Purkinje cell ‘decoders’, we used three-dimensional acousto-optic lens two-photon microscopy to record from hundreds of GrC axons. Here we show that GrC axon population activity is high dimensional and distributed with little fine-scale spatial structure during spontaneous behaviors. Moreover, distinct behavioral states are represented along orthogonal dimensions in neuronal activity space. These results suggest that the cerebellar cortex supports high-dimensional representations and segregates behavioral state-dependent computations into orthogonal subspaces, as reported in the neocortex. Our findings match the predictions of cerebellar pattern separation theories and suggest that the cerebellum and neocortex use population codes with common features, despite their vastly different circuit structures. By recording from hundreds of cerebellar granule cell axons with three-dimensional two-photon calcium imaging, Lanore et al. show that population activity is high-dimensional and that quiet wakeful and active states are orthogonally arranged in neuronal activity space.
Published: 2021

21. Case Report: Prolonged Viral Shedding in Six COVID-19 Patients

Author: Arun Prabhakaran Nair, Mouhand F H Mohamed, Mohamed Abu Khattab, Arwa Alsaud, Ahmad S. Matarneh, Sreethish Sasi, Rania El Hassan, Peter Coyle, and Fahmi Yousef Khan
Subjects: Adult, Male, Time Factors, viruses, 030231 tropical medicine, Disease, Asymptomatic, Virus, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Virology, Throat, medicine, Humans, Viral shedding, Aged, Immunosuppression Therapy, Infectivity, SARS-CoV-2, business.industry, Transmission (medicine), COVID-19, Articles, Middle Aged, medicine.disease, Virus Shedding, COVID-19 Drug Treatment, Pneumonia, Infectious Diseases, medicine.anatomical_structure, Immunology, Parasitology, medicine.symptom, business
Abstract: COVID-19 has surfaced as a multi-organ disease predominantly affecting the respiratory system. Detection of the viral RNA through reverse transcriptase–PCR (RT-PCR) from a nasopharyngeal or throat sample is the preferred method of diagnosis. Recent evidence has suggested that COVID-19 patients can shed the SARS-CoV-2 for several weeks. Herein, we report six cases of COVID-19 who had persistently positive SARS-CoV-2 on repeat RT-PCR testing reaching up to 9 weeks. The spectrum of cases described ranges from asymptomatic infection to severe COVID-19 pneumonia. A full understanding of the virus’s transmission dynamics needs further research. Prolonged viral shedding currently has unclear implications on the management and isolation decisions—the role of the cycle threshold (Ct) value in guiding therapeutic decisions is yet to be clarified. More data on the relationship between Ct values and viral cultivation are needed, especially in patients with prolonged viral shedding, to understand the virus’s viability and infectivity.
Published: 2021

22. SARS-CoV-2 infection in mortuary and cemetery workers

Author: Mohammed A.A. Alahmed, Andrew Jeremijenko, Adeel A. Butt, Adham Ammar, Meryem Bensaad, Hamed Elgendy, Mohamed Elgendy, Hanaa Nafady-Hego, Rayyan Abdulaziz Attya Fadel, Moza Alishaq, Anil George Thomas, Peter Coyle, Bayan Al-Barghouthi, Abdul-Badi Abou-Samra, and Jameela Ali A.A. Al Ajmi
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), Mortuary, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 030106 microbiology, Mortuary Practice, Infectious and parasitic diseases, RC109-216, Asymptomatic, Serology, 03 medical and health sciences, 0302 clinical medicine, Prevalence, medicine, Healthcare workers, Humans, Cemeteries, Serologic Tests, 030212 general & internal medicine, Qatar, Cemetery, SARS-CoV-2, business.industry, Clinical course, COVID-19, General Medicine, Middle Aged, Occupational Diseases, Infectious Diseases, Female, medicine.symptom, business, Demography
Abstract: Background: Mortuary and cemetery workers may be exposed to the bodies of people with SARS-CoV-2 infection; however, prevalence of infection among these groups is unknown. Methods: Nasopharyngeal swabs (NPS) for RT-PCR and serologic testing for SARS-CoV-2 were performed on mortuary and cemetery workers in Qatar. Data on specific job duties, living conditions, contact history, and clinical course were gathered. Environmental sampling was carried out to explore any association with infection. Logistic regression analysis was used to determine the factors associated with infection. Results: Forty-seven mortuary workers provided an NPS and seven (14.9%) were PCR positive; 32 provided a blood sample and eight (25%) were antibody positive, six (75%) who were seropositive were also PCR positive. Among the 81 cemetery workers, 76 provided an NPS and five (6.6%) were PCR positive; 64 provided a blood sample and 22 (34.4%) were antibody positive, three (13.6%) who were seropositive were also PCR positive. Three (22.2%) and 20 (83.3%) of the infected mortuary and cemetery workers were asymptomatic, respectively. Age 35. Conclusion: A substantial proportion of mortuary and cemetery workers had evidence of SARS-CoV-2 infection, which was incidentally detected upon serologic testing. These data are most consistent with community acquisition rather than occupational acquisition.
Published: 2021

23. Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Author: Henry Ma, Eleni Sakka, Hugues Chabriat, Duncan Wilson, Appu Suman, Peter J. Kelly, SL Ho, Charlotte Zerna, Eric Jouvent, Lawrence K.S. Wong, Anthea Parry, Frances Harrington, Jan Stam, Christopher Patterson, Rustam Al-Shahi Salman, Shigeru Inamura, Krishna A Dani, Henry Houlden, Sebastian Thilemann, Kotaro Iida, Chao Xu, Eunbin Ko, Daniel Guisado-Alonso, Urs Fischer, Caroline E. Lovelock, Man Yu Tse, Wing Chi Fong, Azlisham Mohd Nor, Clare Shakeshaft, Philippe Maeder, Henrik Gensicke, Stefan T. Engelter, James Okwera, Christopher Chen, Dulka Manawadu, John F. Corrigan, Efrat Kliper, Shelagh B. Coutts, Alexander P. Leff, Kam Tat Leung, Chathuri Yatawara, Leopold Hertzberger, M. Eline Kooi, Kazuhisa Yoshifuji, Hing Lung Ip, Keon-Joo Lee, Sanjeevikumar Meenakishundaram, Hiroyuki Irie, Marc Randall, Hatice Ozkan, Hideo Hara, Jill Abrigo, Raquel Delgado-Mederos, Shaloo Singhal, Enrico Flossmann, Beatriz Gómez-Ansón, Paul O'Mahony, Carmen Barbato, Ahamad Hassan, Francesca M Chappell, Harald Proschel, Vincent Mok, Masashi Nishihara, Lakshmanan Sekaran, Derya Selcuk Demirelli, Chu Peng Hoi, Hakan Ay, Joan Martí-Fàbregas, Rebeca Marín, Anne Cristine Guevarra, Martin Cooper, Einor Ben Assayag, Anne-Marie Mendyk, Christine Roffe, Myung Suk Jang, Maarten van Gemert, Hannah Cohen, Jae-Sung Lim, YK Wong, Bonnie Y.K. Lam, Janet Putterill, Wouter Schoonewille, Nick S. Ward, Nikola Sprigg, Kui Kai Lau, Bernard Esisi, Peter M. Rothwell, Henk Verbiest, Kirsty Harkness, Elisa Merino, Gareth Ambler, Arumug Nallasivam, Nigel Smyth, Paul A. Armitage, Heinrich Mattle, Pol Camps-Renom, Martin M. Brown, David Cohen, Min Lou, Pankaj Sharma, Sarah Gunkel, Elles Douven, Andreas Charidimou, Djamil Vahidassr, Cathy Soufan, Alexandros A Polymeris, Michael G. Hennerici, Chris Moran, Rachel Marsh, Mahmud Sajid, Kyohei Fujita, David J. Werring, Joanna M. Wardlaw, Derek Hayden, Joseph Kwan, Timothy J. England, Jaap van der Sande, Luis Prats-Sánchez, Paul Guyler, Ryan Hoi Kit Cheung, Koon-Ho Chan, Frank-Erik de Leeuw, Simone Browning, Jon Scott, Adrian Barry, Alejandro Martínez-Domeño, Luc Bracoub, Dinesh Chadha, Ijaz Anwar, Deborah Kelly, Moon-Ku Han, Anil M. Tuladhar, Thomas Gattringer, Fiona Carty, Abduelbaset Elmarim, Syed Mansoor, Enrico Flossman, Dilek Necioglu Orken, Jane Sword, Velandai Srikanth, Ping Wing Ng, Thomas W. Leung, Richard Shek-kwan Chang, Hans Rolf Jäger, Marwan El-Koussy, Jeroen Hendrikse, Khaled Darawil, Kazunori Toyoda, Mathuri Prabhakaran, Karim Mahawish, Ethem Murat Arsava, Jihoon Kang, Kwok Kui Wong, Michael Power, Felix Fluri, Enas Lawrence, Maam Mamun, Sissi Ispoglou, Mathew Burn, Siu Hung Li, Henry K.F. Mak, Kaori Miwa, Els De Schryver, Franz Fazekas, Jonathan G. Best, Louise Shaw, Hen Hallevi, Keith W. Muir, Ilse Burger, Adrian Wong, Nils Peters, Susana Muñoz-Maniega, Yusuke Yakushiji, David Calvet, Mark White, Michael McCormick, Vinodh Krishnamurthy, David Hargroves, Jan C. Purrucker, Tae Jin Song, Masayuki Shiozawa, Noortje A.M. Maaijwee, Prasanna Aghoram, Nicolas Christ, Lino Ramos, Yannie Soo, Thanh G. Phan, Parashkev Nachev, David J. Seiffge, Kim Wiegertjes, Leo H. Bonati, Chahin Pachai, Oi Ling Chan, Yvo B.W.E.M. Roos, Santiago Medrano-Martorell, Natan M. Bornstein, Elizabeth A. Warburton, Richard Li, Prabel Datta, Pascal P. Gratz, Edmund Ka Ming Wong, Hedley C. A. Emsley, Marie-Yvonne Douste-Blazy, Gunaratam Gunathilagan, Nagaendran Kandiah, Masatoshi Koga, Roland Veltkamp, Lee-Anne Slater, Suk Fung Tsang, Beom Joon Kim, Simon Jung, Zeynep Tanriverdi, Sarah Caine, Peter J. Koudstaal, Laurence Legrand, Kari Saastamoinen, Ale Algra, Jean-Louis Mas, Christine Delmaire, Fidel Nuñez, Robert J. van Oostenbrugge, Sebastian Eppinger, Lillian Choy, Robert Luder, Vincent I.H. Kwa, Aad van der Lugt, Marie Dominique Fratacci, Stephen Makin, Layan Akijian, Régis Bordet, Mi Hwa Yang, Ying Zhou, Elio Giallombardo, Adrian R Parry-Jones, John S. Thornton, Amos D. Korczyn, Narayanaswamy Venketasubramanian, David J. Williams, Aravindakshan Manoj, Julie Staals, Solveig Horstmann, Dianne H.K. van Dam-Nolen, Claire Cullen, Benjamin Wagner, Jun Tanaka, Martin Dennis, Stef Bakker, Gregory Y.H. Lip, L. Jaap Kappelle, Robin Lemmens, Achim Gass, David Mangion, Matthew Smith, Toshio Imaizumi, Wenyan Liu, Jeremy Molad, Christopher Price, Paul J. Nederkoorn, P. J. A. M. Brouwers, Vincent Thijs, Sze Ho Ma, Mark Schembri, Peter Wilkinson, Janice E. O’Connell, Karen Ma, John Ly, Leonidas Panos, Chung Yan Chan, Toshihiro Ide, Christopher Traenka, Joost Jöbsis, Gargi Banerjee, Paul Berntsen, Michael J. Thrippleton, Raymond T.F. Cheung, Christopher Karayiannis, Werner H. Mess, Robert Simister, Jayesh Modi Medanta, Syuhei Ikeda, John Mitchell, Linxin Li, Mauro S.B. Silva, Eric Vicaut, John Coyle, Shoichiro Sato, Michelle Davis, Jonathan Birns, Richard J. Perry, Sean M. Murphy, KC Teo, Maria del C. Valdés Hernández, Bibek Gyanwali, Tarek A. Yousry, Kath Pasco, Sebastian Köhler, Joachim Fladt, Edward S. Hui, Philippe Lyrer, Young Dae Kim, Anna K. Heye, Eric E. Smith, Saima Hilal, Ender Uysal, Ji Hoe Heo, Ysoline Beigneux, Cisca Linn, Hee-Joon Bae, Simon Leach, Winnie C.W. Chu, Ronil V. Chandra, Neurology, ACS - Atherosclerosis & ischemic syndromes, ANS - Neurovascular Disorders, MUMC+: HZC Med Staf Spec Klinische Neurofys (9), RS: Carim - B06 Imaging, MUMC+: HZC Klinische Neurofysiologie (5), Klinische Neurowetenschappen, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Neurologie (3), RS: Carim - B05 Cerebral small vessel disease, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Med Staf Spec Neurologie (9), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Beeldvorming, and MUMC+: DA BV Klinisch Fysicus (9)
Subjects: Adult, Male, Risk, EXTERNAL VALIDATION, medicine.medical_specialty, Neurology, MODELS, Clinical Neurology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Recurrence, Internal medicine, Antithrombotic, Humans, Medicine, Prospective cohort study, 610 Medicine & health, Stroke, METAANALYSIS, Aged, Ischemic Stroke, Science & Technology, medicine.diagnostic_test, business.industry, Proportional hazards model, Magnetic resonance imaging, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Magnetic Resonance Imaging, Ischemic Attack, Transient, ATRIAL-FIBRILLATION, Cardiology, Female, Neurology (clinical), Neurosciences & Neurology, business, Intracranial Hemorrhages, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Fibrinolytic agent, Cohort study
Abstract: Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.
Published: 2021

24. Clinical Features and Risk Factors for In-Hospital Mortality From COVID-19 Infection at a Tertiary Care Medical Center, at the Onset of the US COVID-19 Pandemic

Author: Meredith Coyle, Miriam Levine, Louis Saravolatz, Somero Michael, Johnson Leonard, Mamta Sharma, Susanna M. Szpunar, Wei Zhao, Nikhil Gandhi, Dima Youssef, Elisa Akagi Fukushima, Sami Hoshi, Farah Tanveer, and Ashish Bhargava
Subjects: Adult, Male, Michigan, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Tertiary care, Article, Tertiary Care Centers, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pandemic, Humans, Medicine, infections, 030212 general & internal medicine, Aged, Retrospective Studies, Aged, 80 and over, hospital mortality, In hospital mortality, Tertiary Healthcare, business.industry, COVID-19, Retrospective cohort study, Middle Aged, medicine.disease, Obesity, Hospitalization, Clinical research, clinical research, Emergency medicine, Female, business, Clinical risk factor
Abstract: Background:Mortality from COVID-19 has been associated with older age, black race, and comorbidities including obesity, Understanding the clinical risk factors and laboratory biomarkers associated with severe and fatal COVID-19 will allow early interventions to help mitigate adverse outcomes. Our study identified risk factors for in-hospital mortality among patients with COVID-19 infection at a tertiary care center, in Detroit, Michigan.Methods:We conducted a single-center, retrospective cohort study at a 776-bed tertiary care urban academic medical center. Adult inpatients with confirmed COVID-19 (nasopharyngeal swab testing positive by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay) from March 8, 2020, to June 14, 2020, were included. Clinical information including the presence of comorbid conditions (according to the Charlson Weighted Index of Comorbidity (CWIC)), initial vital signs, admission laboratory markers and management data were collected. The primary outcome was in-hospital mortality.Results:Among 565 hospitalized patients, 172 patients died for a case fatality rate of 30.4%. The mean (SD) age of the cohort was 64.4 (16.2) years, and 294 (52.0%) were male. The patients who died were significantly older (mean [SD] age, 70.4 [14.1] years vs 61.7 [16.1] years; P < 0.0001), more likely to have congestive heart failure (35 [20.3%] vs 47 [12.0%]; P = 0.009), dementia (47 [27.3%] vs 48 [12.2%]; P < 0.0001), hemiplegia (18 [10.5%] vs 18 [4.8%]; P = 0.01) and a diagnosis of malignancy (16 [9.3%] vs 18 [4.6%]; P = 0.03).From multivariable analysis, factors associated with an increased odds of death were age greater than 60 years (OR = 2.2, P = 0.003), CWIC score (OR = 1.1, P = 0.023), qSOFA (OR = 1.7, P < 0.0001), WBC counts (OR = 1.1 , P = 0.002), lymphocytopenia (OR = 2.0, P = 0.003), thrombocytopenia (OR = 1.9, P = 0.019), albumin (OR = 0.6 , P = 0.014), and AST levels (OR = 2.0, P = 0.004) on admission.Conclusions:This study identified risk factor for in-hospital mortality among patients admitted with COVID-19 in a tertiary care hospital at the onset of U.S. Covid-19 pandemic. After adjusting for age, CWIC score, and laboratory data, qSOFA remained an independent predictor of mortality. Knowing these risk factors may help identify patients who would benefit from close observations and early interventions.
Published: 2021

25. Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study*

Author: Robert Talarico, Alan J Forster, Lauralyn McIntyre, Kednapa Thavorn, Kelly Farrah, Dean Fergusson, Christopher J. Doig, Monica Taljaard, Doug Coyle, and Murray Krahn
Subjects: Adult, Male, medicine.medical_specialty, Population, Aftercare, Critical Care and Intensive Care Medicine, Patient Readmission, Insurance Coverage, Cohort Studies, Sepsis, Internal medicine, medicine, Humans, Hospital Mortality, Propensity Score, education, Aged, Proportional Hazards Models, Ontario, Cross Infection, education.field_of_study, business.industry, Proportional hazards model, Mortality rate, Organ dysfunction, Hazard ratio, Middle Aged, medicine.disease, Patient Discharge, Intensive Care Units, Cohort, medicine.symptom, business, Cohort study
Abstract: Objectives To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls. Design Propensity-matched population-based cohort study using administrative data. Setting Ontario, Canada. Patients We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date. Interventions None. Measurements and main results Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63-1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50-1.55 and hazard ratio, 1.41; 95% CI, 1.40-1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568-$29,913) for severe and $9,475 (95% CI, $9,150-$9,727) for nonsevere sepsis. Conclusions Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors.
Published: 2020

26. A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis

Author: Radhika C. Desai, Hyo Jin Kim, Julia D. Mackay, Weijun Feng, Randall J. Mrsny, Lisa Song, Linh P. Nyugen, Nicole C. Fay, Mahmood Tahir, Sally Postlethwaite, Apurva Chandalia, Baby Periyanayaki Muthusamy, Keyi Liu, Michael P. Coyle, Olson Charles, Elbert Seto, Tom Hunter, Khushdeep Mangat, Alistair Taverner, Minji Seung, Aatif Alam, and Maziyar Saberi
Subjects: Male, Colon, medicine.medical_treatment, Immunology, Mice, SCID, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Intestinal mucosa, medicine, Animals, Humans, Immunology and Allergy, Intestinal Mucosa, Rats, Wistar, Colitis, Cells, Cultured, Inflammation, Mice, Inbred BALB C, Lamina propria, Mucous Membrane, business.industry, Macrophages, Mucosal Immunology, medicine.disease, Intestinal epithelium, Interleukin-10, Rats, Mice, Inbred C57BL, Macaca fascicularis, Interleukin 10, medicine.anatomical_structure, Cytokine, Transcytosis, Cytokines, Female, business, 030215 immunology
Abstract: IL-10 is a potent anti-inflammatory cytokine capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease. Clinical use of human IL-10 (hIL-10) has been limited by anemia and thrombocytopenia following systemic injection, side effects that might be eliminated by a gut-restricted distribution. We have identified a transcytosis pathway used by cholix, an exotoxin secreted by nonpandemic forms of the intestinal pathogen Vibrio cholerae. A nontoxic fragment of the first 386 aa of cholix was genetically fused to hIL-10 to produce recombinant AMT-101. In vitro and in vivo characterization of AMT-101 showed it to efficiently cross healthy human intestinal epithelium (SMI-100) by a vesicular transcytosis process, activate hIL-10 receptors in an engineered U2OS osteosarcoma cell line, and increase cellular phospho-STAT3 levels in J774.2 mouse macrophage cells. AMT-101 was taken up by inflamed intestinal mucosa and activated pSTAT3 in the lamina propria with limited systemic distribution. AMT-101 administered to healthy mice by oral gavage or to cynomolgus monkeys (nonhuman primates) by colonic spray increased circulating levels of IL-1R antagonist (IL-1Ra). Oral gavage of AMT-101 in two mouse models of induced colitis prevented associated pathological events and plasma cytokine changes. Overall, these studies suggest that AMT-101 can efficiently overcome the epithelial barrier to focus biologically active IL-10 to the intestinal lamina propria.
Published: 2020

27. Lower Cumulative Antiretroviral Exposure in People Living With HIV and Diabetes Mellitus

Author: Sarah Mann, Lane R. Bushman, Jennifer J. Kiser, Samantha MaWhinney, Jose R Castillo-Mancilla, Lucas Ellison, Mary Morrow, Stacey S Coleman, Jia-Hua Zheng, Austin M. Saderup, Ryan P Coyle, and Peter L. Anderson
Subjects: Adult, Male, medicine.medical_specialty, Renal function, HIV Infections, Hematocrit, Article, Medication Adherence, Diabetes mellitus, Internal medicine, Hyperlipidemia, Diabetes Mellitus, medicine, Humans, Pharmacology (medical), Univariate analysis, medicine.diagnostic_test, business.industry, Middle Aged, Viral Load, medicine.disease, Confidence interval, Infectious Diseases, HIV-1, Female, business, Viral load, Body mass index
Abstract: OBJECTIVE People living with HIV (PLWH) are living longer and developing more non-AIDS comorbidities, which negatively impact antiretroviral therapy (ART) adherence. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a novel pharmacologic measure of cumulative ART adherence that is predictive of viral suppression and future viremia. However, the relationship between non-AIDS comorbidities and this adherence measure is unknown. We aimed to evaluate the association between 3 non-AIDS comorbidities (diabetes mellitus (DM), hypertension, and hyperlipidemia) and TFV-DP in DBS in PLWH. METHODS Blood for TFV-DP in DBS and HIV viral load was prospectively collected from PLWH on tenofovir disoproxil fumarate for up to 3 times over 48 weeks. Non-AIDS comorbidities were recorded. Mixed effect multivariable linear regression models were used to estimate the changes in TFV-DP concentrations in DBS according to the presence of comorbidities and to estimate the percent differences in TFV-DP concentrations between these groups. RESULTS A total of 1144 person-visits derived from 523 participants with available concentrations of TFV-DP in DBS were included in this analysis. In univariate analysis, no significant association between non-AIDS comorbidities (categorized as having 0, 1, 2, or 3 comorbidities) and the concentrations of TFV-DP in DBS was observed (P = 0.40). Participants who had DM had 25% lower (95% confidence interval: -36% to -12%; P < 0.001) TFV-DP in DBS than participants without DM after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4 T-cell count, hematocrit, ART class, patient-level medication regimen complexity index, and 3-month self-reported adherence. CONCLUSIONS Diabetic PLWH have lower concentrations of TFV-DP in DBS compared with those without DM. Further research is required to identify the clinical implications and biological mechanisms underlying these findings.
Published: 2020

28. A qualitative analysis of psychosocial needs and support impacts in families affected by young sudden cardiac death: The role of community and peer support

Author: Lada Timotijevic, Adrian Coyle, and Edith Maria Steffen
Subjects: Male, unascertained death, cardiac arrest, peer support, 030204 cardiovascular system & hematology, Peer support, Sudden cardiac death, 0302 clinical medicine, Surveys and Questionnaires, Medicine, 030212 general & internal medicine, Child, Qualitative Research, media_common, Aged, 80 and over, bereavement, sudden arrhythmic death syndrome, Focus Groups, Middle Aged, Europe, Medical–Surgical Nursing, Child, Preschool, Child Mortality, Female, Thematic analysis, Cardiology and Cardiovascular Medicine, Psychosocial, Needs Assessment, Adult, Adolescent, media_common.quotation_subject, Psychology of self, Young sudden cardiac death, Young Adult, 03 medical and health sciences, Nursing, Humans, Family, Aged, Advanced and Specialized Nursing, business.industry, Infant, Newborn, Infant, Social Support, Original Articles, medicine.disease, Focus group, Death, Sudden, Cardiac, Grief, business, Meaning (linguistics)
Abstract: Background Young sudden cardiac death (YSCD), often occurring in previously healthy individuals, is a tragic event with devastating impact on affected families, who are at heightened risk of posttraumatic stress and prolonged grief and may themselves be at risk of YSCD. Previous research suggests that surviving family members’ psychosocial support needs are often unmet. Purpose This study sought to identify how YSCD-affected families experience dedicated community and peer support in light of their psychosocial support needs. Methods The study used a qualitative design, employing a thematic analysis of focus group and interview data. Three focus groups and five individual interviews were conducted with affected family members (N = 19). The sample was drawn from a UK-based charity, Cardiac Risk in the Young. Audio-recordings of the focus groups and interviews were transcribed and subjected to thematic analysis. Results Three super-ordinate themes were identified: 1. YSCD community support as offering a place of safety, 2. YSCD community support as fostering sense-making, 3. YSCD community support as facilitating finding new meaning. Conclusions YSCD-affected families can benefit from access to dedicated community and peer support that offers a safe environment, provides affiliation, understanding and normalisation and enables sense-making and the rebuilding of a sense of self. Dedicated community support can facilitate meaningful re-engagement with life through helping prevent YSCD and through memorialisation and legacy-building to maintain a continuing bond with the deceased. Clinicians need to be aware of the need to incorporate available community and peer support into patient pathways.
Published: 2020

29. Examining the effects of applying ActiGraph low-frequency extension feature to analyze the sleeping behaviours of preschool-aged children

Author: Jess Haines, Hannah J. Coyle-Asbil, Lori Ann Vallis, Becky Breau, and David W.L. Ma
Subjects: Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, Audiology, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Humans, Medicine, Child, Trial registration, Ontario, Nutrition and Dietetics, Kinesiology, business.industry, Outcome measures, Signal Processing, Computer-Assisted, 030229 sport sciences, General Medicine, Actigraphy, Sleep time, Child, Preschool, Female, Sleep (system call), Sleep, business, Software, 030217 neurology & neurosurgery
Abstract: This study compares sleep outcome measures obtained using normal- and low-frequency extension (LFE) settings (Actilife). Forty-two children (aged 3–6 years) were instructed to wear an ActiGraph GT3X+ accelerometer on their hip for 7 days, 24 h/day. Total sleep time (min), sleep efficiency (%), and number and cumulative length (min) of awakening were used to compare the settings. Results suggest that the LFE setting results in significant but relatively small reductions in the sleep metrics of children. Trial registration no.: clincialtrials.gov (ID no. NCT02223234) Novelty LFE setting, available through ActiGraph, estimates a significantly reduced total sleep time and efficiency.
Published: 2020

30. The Positive Choices trial: update to study protocol for a phase-III RCT trial of a whole-school social-marketing intervention to promote sexual health and reduce health inequalities

Author: Ruth Ponsford, Rebecca Meiksin, Elizabeth Allen, G. J. Melendez-Torres, Steve Morris, Catherine Mercer, Rona Campbell, Honor Young, Maria Lohan, Karin Coyle, Chris Bonell, Bonell, Chris [0000-0002-6253-6498], and Apollo - University of Cambridge Repository
Subjects: Male, Adolescent, Sexual health, education, Medicine (miscellaneous), Adolescents, Update, SDG 3 - Good Health and Well-being, Pregnancy, Sexually transmitted infections, Humans, Pharmacology (medical), Randomized Controlled Trials as Topic, School Health Services, Public health, Schools, Cluster trials, SDG 16 - Peace, Justice and Strong Institutions, Health Status Disparities, Sexual competence, Whole-school, Clinical Trials, Phase III as Topic, Social Marketing, Female
Abstract: Background Positive Choices is a whole-school social-marketing intervention to promote sexual health among secondary school students. Intervention comprises the following: school health promotion council involving staff and students coordinating delivery, student survey to inform local tailoring, teacher-delivered classroom curriculum, student-run campaigns, parent information and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot-RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by ‘whole-school’ (e.g. student campaigns, sexual health services) and ‘social marketing’ (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK. Methods We will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022, implement the intervention over the 2022–2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025 and engage in knowledge exchange from December 2024. Discussion This trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices. Trial registration ISRCTN No: ISRCTN16723909. Registered on 3 September 2021.
Published: 2022

31. Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST)

Author: Johnathan K, Joffe, Fay H, Cafferty, Laura, Murphy, Gordon J S, Rustin, Syed A, Sohaib, Rhian, Gabe, Sally P, Stenning, Elizabeth, James, Dipa, Noor, Simona, Wade, Francesca, Schiavone, Sarah, Swift, Elaine, Dunwoodie, Marcia, Hall, Anand, Sharma, Jeremy, Braybrooke, Jonathan, Shamash, John, Logue, Henry H, Taylor, Ivo, Hennig, Jeff, White, Sarah, Rudman, Jane, Worlding, David, Bloomfield, Guy, Faust, Hilary, Glen, Rachel, Jones, Michael, Seckl, Graham, MacDonald, Thiagarajan, Sreenivasan, Satish, Kumar, Andrew, Protheroe, Ramachandran, Venkitaraman, Danish, Mazhar, Victoria, Coyle, Martin, Highley, Tom, Geldart, Robert, Laing, Richard S, Kaplan, and Robert A, Huddart
Subjects: Male, Cancer Research, Oncology, Testicular Neoplasms, Chemotherapy, Adjuvant, Humans, Neoplasm Recurrence, Local, Orchiectomy, Follow-Up Studies, Neoplasm Staging, Seminoma
Abstract: PURPOSE Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (–3.5 to –0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION Surveillance is a safe management approach—advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.
Published: 2022

32. Safety of hospital discharge before return of bowel function after elective colorectal surgery

Author: J Chapman, S, Blanco-Colino, R, Pérez-Ajates, S, O Anabitarte Bautista, Hodson, J, C Glasbey, J, Pata, F, Pellino, G, Sgrò, A, Soares, A, T van Elst, S Van Straten, Nepogodiev, D, Borakati, A, F Bath, M, H Yasin, I, Mclean, K, Arthur, T, Kovacevic, M, Delibegovic, S, Karamanliev, M, Swamad, M, Žebrák, R, Paramasivam, R, Martensen, A, M Larsen, H, Rädeker, L, E Frey, P, Kechagias, A, Venara, A, Duchalais, E, Ioannidis, A, Pasquali, S, Simioni, A, Farina, V, Podda, M, Lorenzon, L, Schaeff, V, Otto, A, Jakubauskas, M, R van Elst, T, Chu, M, Pvb, Fagan, I Wells, C, A Alagoa João, Juloski, J, Y El Kasmy El Kasmi, Espin-Basany, E, Clerc, D, Ciubotaru, C, Popescu, S, Yanishev, A, Lee, S, B Ozkan, B, A Yagız Sen, K Aktas, M, E Baki, B, Yüksek, B, Kamarajah, S, A Khaw, R, Mills, E, Goodson, R, Thakral, N, D Ablett, A, Adra, M, Kwek, I, M Khan, S, Quinn, P, R Manley, L, Badran, A, Ramjeeawon, A, Campbell, A, L Tan, H, S Rye, D, Rajaraman, N, G Norman, J, Vutipongsatorn, K, Solomou, G, Akhbari, M, Ali, A, Murray, V, M Baker, D, D Brandao, B, Stainer, B, Thavayogan, R, Jones, D, O Onafowokan, O, Gharooni, A, Dabab, N, Carlton-Carew, S, Kungwengwe, G, Gabriel, M, Sewart, E, C Shortland, T, Lawday, S, Pockney, P, Dawson, A, D Brumfitt, C, Stewart, P, B, Ng, K Luong, J, Ivanov, V, Borisova, A, Neykov, V, Kunčarová, K, Kološová, B, Antonova, T, Farkašová, M, L Harbjerg, J, Brandsborg, S, Brinck, S, D Kjaer, M, Mark-Christensen, A, P Unbehaun, K, Dalsgaard, P, D Lycke, K, Lenaoures, P, Brigand, C, Dumange, E, Gout, M, Moehwald, C, Prem, M, Alhalabi, O, Sliwinski, S, Krupp, J, Gablenz, E, Schmitzer, L, Kopp, A, Steinle, J, Gsenger, J, J Pohl, L, Riccardi, M, M Christodoulou, I, Konstantinidis, M, Machairas, N, Zoikas, A, Balalis, D, K Manatakis, D, L Aguilera, M, Marano, L, Fleres, F, Lovisetto, F, Sasia, D, Segalini, E, Pata, G, Lucchi, A, Sagnotta, A, Campagnaro, T, Petrelli, F, Gallo, G, Papandrea, M, Testa, V, Sinibaldi, G, F Di Candido, Colombo, F, Perrone, G, Aresu, S, Biancafarina, A, Canonico, G, Pagnanelli, M, Curletti, G, Bini, R, A de Manzoni Garberini, Impellizzeri, H, Cillara, N, Tutino, R, Picciariello, A, Coletta, D, Savino, G, Ferrara, F, Tamini, N, Talamo, G, Parini, D, Giamundo, P, A Lo Conte, Pagano, G, Ripetti, V, Pesce, A, Menduni, N, Giudicissi, R, Goldin, E, Rega, D, Belli, A, Andriola, V, Gordini, L, Foppa, C, Piccolo, G, Birindelli, A, Ferrari, C, Ballarini, Z, Tirelli, F, Milone, M, M De Rosa, S Pipitone Federico, N, Molteni, B, L Tilocca, P, Sancini, G, N Piozzi, G, Lauretta, A, Poillucci, G, Mulas, S, Simcikas, D, Portelli, L, Jwm van Wijnbergen, L Dinger, T, Sfh Ten Doesschate, Ashm van Dalen, D van den Bos, D, Hansmann, M, J Medina Feliz, Z Kuiper, S, Abdulrahman, Z, R Pruijssers, S, Farik, S, M Elliott, B, P Geneta, V, Wilton, S, Kandelaki, H, L Peng, S, Campbell, S, K Lim, Y, S Yassaie, S, Murray, M, Haran, C, Tan, J, Castro, J, Laranjeira, A, Catarino, S, Neves-Marques, C, G Correia, J, N Vieira, B, C Quintela, A, L 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Ven, Poelman, M, Lps, Stassen, Slooter, G, Yiz, Acherman, Hoff, C, F Gerhards, M, Mwj, Stommel, J Hazebroek, E, Aaw van Geloven, A Schasfoort, R, L van Leeuwen, B, B Tuynman, J, Mwa van Tilburg, G Boerma, E, Sharma, P, Jenkins, B, P Bissett, I, Herd, A, Gordon, A, Vernon, D, Omundsen, M, J, Ly, Reddy, A, Bonnet, G, Harmston, C, Morales, M, Francisco, V, Costa, S, Manso, A, Amorim, E, Pereira, J, Cardoso, J, Ourô, S, Caratão, M, Nascimento, C, B Ribeiro da Silva, Taranu, V, Dias, R, Mendes, J, Allen, M, Silva, A, Carlos, S, Barbosa, E, Carneiro, C, Ramos, L, Lencastre, L, Martins, R, Silva-Vaz, P, F Ridgway, P, A McNamara, D, Cahill, R, Hogan, A, Larkin, J, R O'Connell, P, Negoi, I, Abelevich, A, M Ćuk, V, Vician, M, Ede, C, Sardiwalla, I, Mulira, S, Montwedi, D, Oyomno, M, Sabia, D, V Portugal Porras, Vigorita, V, G Sanz Ortega, García, J, A Espí Macías, F Blanco Antona, A Luján Mompeán, J, S Salvans Ruiz, Villarejo-Campos, P, M Romero Simó, Sánchez-Guillén, L, M Jiménez-Gómez, L, A Sánchez López, Golda, T, D Julià Bergkvist, Nevado, C, F Noguera Aguilar, J, B Ricardo Felipe, Septiem, J, A Rodríguez Sánchez, Cañete-Gómez, J, I Ruiz Montesinos, Millán-Scheiding, M, Prieto-Nieto, I, Frasson, M, D García Olmo, Hübner, M, Petermann, D, O Sauvain, M, Ozben, V, E Geçim, I, Disçi, E, Rencuzogullari, A, Kurt, A, Bisgin, T, Pehlivan, M, Isik, A, Onur, E, Leventoglu, S, C Haksal, M, S Erturk, M, Keskin, M, Guner, A, S Tutcu Sahin, S Ozbalci, G, Pergel, A, Albayrak, D, Bruce, D, Fearnhead, N, Arthur, J, Harron, M, Beattie, G, Titu, L, Saunders, M, Phillips, J, Dindyal, S, Cresswell, B, Gercek, Y, Lee, J, Linn, T, Faulkner, G, Lockwood, S, Rees, J, Charalabopoulos, A, Campbell, B, Kontovounisios, C, Amarnath, T, Johnson, M, Epanomeritakis, E, Vigs, S, Nastro, P, Gilliam, A, Smolarek, S, Wilson, T, Orbell, J, Mcintyre, R, Agarwal, T, Hainsworth, P, Patel, P, Vijay, J, Liu, B, P Dhruva Rao, Roxburgh, C, Vipond, M, Youssef, H, Thorn, C, Schizas, A, Denley, S, Bowley, D, Das, K, 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H., Buari, M., Ahmed, K., Sheikh, Z., Monks, M., Lehmann, J., Rotimi, O., Bell, T., Limnatitou, D., Gormley, S., Taleongpong, P., Patel, V., Macgregor, L., Amini, S., Turner, C., Dwyer-Hemmings, L., Busuttil, A., Powell, J., Hensher, C., Vivian, F., Wcislo, K., Millar, Z., Hirosue, S., Ogunmwonyi, I., Nakakande, D., Gaze, H., Pillai, S., Khoury, G., Powell, T., Maleyko, I., Sangheli, A., Ransome, M., Isse, M., Aromolaran, O., Bholah, H., Anbarasan, J., Rehman, S., Hu, E., Timms, S., Reynolds, W., Hotchkies, A., Misra, V., Murray, V., Theocharidou, L., Malik, T., Janmohamed, I., Carhart, B., Khan, A., Hullait, R., Rylance, A., Butt, S., Leathes, J., Rajathasan, T. P., Jeddy, H., Kyaw, H. A., Wong, N., Karelia, S., Clements, J. M., Rainey, M., Joshi, N., Rahman, A., Gallagher, M., Rebuffa, N., Abdelgalil, R., Lai, R. S. Y., Laurence, N., Thomas, S., Green, C., Frostick, R., Khera, R., Povey, M., Wong, H. L., Mccusker, C., Hlukha, L., Pike, G., Kamel, F., Thakkar, R., Donaldson, C., Campos, M. S., Bradbury, M., Osunronbi, T., Tam, L. Y. C., Kaabneh, A. K., Lawther, J., Fisher, P., Tribedi, T., Moosa, A., Ramdin, A., Goble, M., Downs, E., Wheldon, L., Baggus, E., Mandal, A., Nayeem, A., Ahmed, S., Fradley, W., Wilson, C., Gallagher, S., Criswell, T., Ward, J., Mukkavilli, A., Stubbs, B., Fordyce, W., Suchdev, N., Lim, S. W., Sookramanien, S. R., Chan, A., Bointas, G., Paul, M., Ward, K. L., Bagnall, M., Pherwani, S. A., Wang, K., Mitchell, L., Heyworth, J., Ayyar, S., Polson, R., Mackenzie, E., Doyle, N., Habib, Z., Zardab, M., Sartaj, F., Farooq, H., Tabibi, M., Drury, D. J., James, S. J., Barnett, R., Cahya, E., Lou, G., Coyle, M., Homyer, K., Zhu, L. Y., Woods, M., Chang, J., O'Callaghan, H., Suchett-Kaye, I., Mihailidis, T. H., Alawattegama, H., Seite, E., Barrett, A., Riordan, E., Lam, W., Dowdeswell, M., Mulvenna, C., Awokoya, O., Gurowich, L., Dhera, K., Hayat, S., Tincknell, L., Spazzapan, M., Teeling, F., Sysum, K., Latter, J., Latter, M., Khan, S., Woodmass, M., Hayden, H., Ali, Y., Husain, S., Arnold, A., Pedersen, A. C., Cunha, P., Ahmed, M., Al Zawawi, S., Kudva, V., Theodoropoulou, K., Miscampbell, M., Robinson, A. V., Johnston, J., Dharni, A., Lamb, S., Westerman, T., Evans, E., Campbell, L., Gillespie, M., Cheong, C. M., Kulathevanayagam, K., Varghese, A., Ike, S. I., Chu, T. S. M., Baljer, B., Mogg, J. A. W., Rai, P., Claireaux, H. A., Williams, M., Smillie, R., Goetz, J., Appleby, E., Fadipe, T., Vaughan-Burleigh, S., Jovaisaite, A., Shah, S. M., Khalid, N., Gutmann, D., Davison, S., Alame, Y. J., Syed, L., Owen, W. J., Ahsan, S. D., Anthony-Uzoeto, U., Hall, C. M., Zheng, S., Wynter, K., James, C., Sapre, D., Ghosh, R., Baird, J., Cockburn, L., Blackwood, O., Simpson, W., Jeong, S., Bishop, S., Bate, R., Hobson, C., Adam, A. H., Redclift, C., Do, J., Adeleye, O., Poli, F., Batterham, A., Brown, S., Parekh, J. N., Clay, W., Pieri, K., Jackson, A., Saxena, A., Gurung, B., Oyebola, T., O'Brien, F., Djeugam, B., Gardezi, S., Ul-Hasan, S., Martin-Hernandez, M. P., Sisley, M., Modi, S., Antakia, R., Elbayouk, A., Soh, Y. J., Mather, J., Yusuf, Z., Al-Sarraf, Z., Naja, M., Rassool, S. B., Convill, J., Nikookam, Y., Warsame, A., Pace, C., Kiandee, M., Ridwan, R., Carey, C., Hirri, F., Mcmillan, M. J. A., Ling, J. J., Pendelbury, L., Kerimzade, K., Tang, A., Howard, E. O., Humayun, S., Wadsworth, O. J., Tan, K., Abdelhameed, F., Haglund, C., Radnaeva, I., Hu, N., Rambhatla, S., Waldron, D., Madahar, P., Malik, S., Meney, L. C., Ibrahim, I., Kang, C. K., Chiu, J. Z. J., Livie, V., Ibrahim, B., Khalil, M., Pooley, G., Shishkin, B., Docherty, J., Southgate, A., Coomes, A., Mcgee, F., Flanagan, S., Tan, Q. J., Anwar, H., Clough, R., Chrisp, B., Cassels, J., Cross, G. W. V., Mercer, L., Mercer, C., Refalo, A., Hadley, R., Mctighe, A., Farrow, F., Brodie, A., Davis, G., Shah, D. R., Bowers, C., Patel, S., Morice, O., Burzic, A., Cheung, J., Shashidhara, A., Theodoraki, G., Birk, J., Ong, A., Ng, M. P. E., Wong, R. T. W., Maese, S., Yeap, B., Iqbal, Z., Melaugh, T., Perchard, W., Scurr, T., Campbell, E., Kelk, L., Ghosh, A., Gibbins, A., Mala, D., Loizidou, A., Hall, O., Mecia, L., Hew, C., Varathan, K., Tong, L., Chandrasekar, B., Buchanan, E., O'Connell, M., Kwak, S. Y., Ong, E. H., Gardner, S., Lim, J., Maden, C., Illahi, M., Tan, Z. X., Edwards, S., Stahl, R., Stahl, J., Hickman, A., Collett, D., Goolam-Mahomed, Z., Allen, B., Atiyah, A., Ahmad, H., Jones, J., Mcgregor, O., Ogundiya, E., Boulbadaoui, A., Kirnon-Jackman, O., Lim, Q. X., Peckham, H., Yeoh, T., Yong, S. Q., Chen, J. Y., Siva, S., Sam, Z. H., Gilani, M., Goh, Y. N., Muthukumar, M. G., Phillips, S., Tjoakarfa, J., Giri, A., Suresan, S., Thomas, P., Johnson, T. A., Williams, R. I., Rashid, A., Kushairi, A., Rais, A., James, A., Bugelli, M., Chechelnitskaya, Y., Sandhu, N., Tandon, R., Gray, M., Kumar, A., Ciurleo, C., Nyamali, I., Hiremath, S., Sinha, S., Chowdhary, M., Bradley, E., Mctiernan, M., Macdonald, S., Sharkey, S., Mclaughlin, N., Amey, C., Kraria, L., Skan, O., Kind, C., Tupper, P., Van Rhee, C., Honeyman, S. I., Menon, G., Jegatheeswaran, L., Madhavan, A., Warne, M., Malcolm, F. L., Lessware, T., Wilkerson, H. T., Chatterjee-Woolman, S., Yoong, A., Ahmed, W. U. R., Longshaw, A., Flannery, O., Green, R., Leaning, M., Cragg, J., Sharriff, H., Doherty, C., Kwan, K. W. L., Sanders-Crook, L., Bhatia, S., Eames, S., Lewis, F., Kirupananthan, P., Boh, Z. Y., Dass, S., Soma, A., Newton, A., Hill, M., Shafiq, Y., Brkljac, M., Boyce, L., English, W. J., Lam, S., Chipeta, C., Jain, C., Garofalidou, T., Novotny, S. A., Locke, S., Bowman, C., Begaj, A., Murphy, C., Radcliffe, K., Chong, J. T., Jeffrey, E., Chaudhury, N., Rajendran, K., Akbar, Z., Walters, B., Kulendrarajah, B., Tran, N., Shrestha, S., Parmar, S., Gallagher, C., Hennessy, L., Pentti, E., Badhrinarayanan, S., Fung, A., Mansoor, M., Kenny, R., Kan, P., Lee, D. E., Khosla, S., Samake, M., Shaban, F., Aftab, R., Gough, M., Woodburn, B., Vayalapra, S., Mcmurrugh, K., Jimulia, D., Deol, S., Pike, S., Embury-Young, Y., Patel, M., Kilgallon, E., Keating, R., Walsh, A., Khan, H., Logue, G., Orekoya, M., Alasmar, M., Charalambides, M., Llavall, A. C., Williamson, E., Bharwada, Y., Zearmal, S., Evans, H., Panikkar, M., de la Cruz, G., Caplan, J., Ruparelia, A., Tanvir, T., Soare, C., Pang, Y. L., Trotter, J., Zaidi, A., Thakrar, V., Pulickal, P., Ahmed, H., Parnell, J., Lennock, S., Ford, V., Brignall, R., O'Neill, D., Hanna, R., Kane, R., Nicola, M., Rajput, K., Xiao, Y., Michael, S., Wright, E., Juniper, S., Thompson, E., Hoskyns, L., Kanitkar, A., Ross, C., Unsworth, A., Rshaidat, H., Demarre, K., Chiang, A., Bareh, A., van Dellen, J., Faqihinejad, C., Gadhvi, A., Grant, R., Lewsey, J., Morris, A., Martin, H., Mcclarty, C., Sanyal, S., Alsaif, A., Palkhi, A., Bhopal, S., Burford, C., Huq, T., Irwin, E., Matthews, L., Ngu, W. S., Hosfield, T., Muneeb, F., Page, O., Zeb, E., Al-Azzawi, A., Mcintosh, J., Vucicevic, A., Hughes, M., Brooks, L., Fanibi, B., Dixon, M., Njoku, P., Morris, D., Jobson, J., Chowdhury, H., Joseph, N., Zulkefley, N., Hunt, G., Christodoulou, T., Wright, O., Soman, S., Jamal, M., Beqiri, S., Borgas, P., Christie, S., Pereira, F., Browne, S., Yiu, J., Dworkin, A., Brayley, J., Palmer, A., Charalambos, M., Jones, C. S., Toner, S., Cowden, R., Lee, L., Nicol, P., Holman, O., Imtiaz, M., Albert, V., Leung, S. P., Erotocritou, M., Stroud, R., Wilkin, R., Thomson, W., Mackee, L., Kler, A., Reynolds, L., Mohamed, S. H., Majeed, Y., Fakim, B., Jones, A., Liversedge, G., Carrington, Z., Windebank, J., Izzarina, A., Akbani, U., Craven, J., Aldarragi, A., Harding, S., Millward, A., Bedford, M., Gopalan, V., Midgen, A., Khadka, P., Cheng, O., Taneja, S., Manobharath, N., Kok, J. Y., Lim, D. W. E., Buick, T., Boland, M., Piya, S., Devlin, R., Fairfield, C. J., George, R. J., Rahi, M., Zaman, S., Hajiev, S., Ross, T., Crisp, E., Thompson, C., Charalambous, A., Hollywood, J. L., Hammond, R. F. L., Matthews, J., Mendonca, V., Spinty, J., Khan, K., Cheng, J., Glynn, N., Muhammad, U., Khan, M., Anderson, L., Mccormack, K., Mak, J., Patrawala, S., Milinkovic, N., Schofield, R., Chauhan, M., Hartley, L., Hind, J., Nelson, L., Ratnasingham, D., Whitehead, T., Dimitriadis, S., Marshall, K., Flint, E. J., Horner, C., Heybourne, A., Morgan, H., Wickstone, C., Panagiotou, D., O'Connell, E., Dean, K., Iqbal, R., Walsh, L., Yu, N., Rana, N., Massie, E., Ng, J., Jung, M., Lee, Y. D., Harris, M., White, S., Boev, B., Tonchev, P., Prochazka, V., Risko, J., Skalicky, A., Ravn, S., Ojakaar, A., Dorr-Harim, C., Koutserimpas, C., Giraudo, G., Armellini, A., Ruzzenente, A., Mazzeo, C., De Padua, C., Luc, A. R., Maroli, A., Vitali, M., Gusai, G. P., Quattromani, R., Virgilio, E., Berti, S., Di Mola, F. F., Papagni, V., Tuminello, F., Vittori, L., Longheu, A., Loche, G. A., Braccio, B., De Luca, E., Resta, G., Ancans, G., Tamosiunas, A., Petrulionis, M., Abdulrahman, N., van de Pas, K. G. H., Thomas, G., Brandsma, A. M., Davids, J., Rottier, S. J., de Roy van Zuidewijn, D., Hawkins, R., Ong, H. I., Li, Y., Desmond, B., Winstanley, J., Martins, M., Americano, M., Frade, S., Senhorinho, R., Peixoto, R., Alves-Vale, C., Lamas, M., O'Connor, D. B., Hoo, M., Gopaul, A., Scanlon, K., O'Dwyer, N., Jovanovic, M., Panyko, A., Van Vuuren, S., Centeno, A., Bernado, I. R., Senorans, M. P. G., Amor, L. G., Ramirez, A. C., Abrisqueta, J., Gomez, M. E., Arroyo, A., Cerdan, C., Romeu, N. G., Enriquez-Navascues, J. M., Collado-Roura, F., Curchod, P., Gaspar, S., Imadalou, L., Mutlu, D., Akyol, C., Uygur, F. A., Eray, I. C., Biyiklioglu, O., Cetin, M. F., Isik, A. E., Karip, B., Dogan, H., Sarigul, L., Tunc, E., Aydin, T., Bodur, S., Karabulut, K., Francis, A. A., Al-hadithi, A., Lau, I. S. F., Smith, E., Mahapatra, S., Mcauliffe, O., Imam, L., Akram, B., Hossaini, S., Davies, R., Ko, M., Collins, J., Pandya, A., Reilly, S., Archer, J., Livie, J., Chaudhry, F. A., Ntakomyti, E., Diallo, R., Bylinski, T., Wright, J., Masiha, E., Tung, J., Shirazi, B., Neilson, A., Epton, S., Patel, N., Trussell, S., Couldrey, A., and Donnelly, C.
Subjects: operative, Male, postoperative discharge, Postoperative Complications, 0302 clinical medicine, Colostomy, CRITERIA, Prospective Studies, Bowel function, Colectomy, IMAGINE, stoma, intestines, Proctectomy, Ileostomy, digestive, oral, and skin physiology, patient discharge, colorectal surgery, hospital discharge, bowel function, RECOVERY, Middle Aged, adult, colostomy, elective surgical procedures, female, follow-up studies, humans, ileostomy, ileus, male, middle aged, multivariate analysis, patient readmission, patient safety, postoperative complications, prospective studies, recovery of function, colectomy, proctectomy, Patient Discharge, Colorectal surgery, ileus - - discharge - bowel function - elective - colorectal surgery, Elective Surgical Procedures, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Patient Safety, Cohort study, safety, Adult, medicine.medical_specialty, Ileus, Patient Readmission, defecation, 03 medical and health sciences, medicine, Hospital discharge, Humans, colorectal surgery, colorectal resection, Colorectal resection, defecation, postoperative complications, colorectal surgery, intestines, patient discharge, patient readmission, safety, surgical procedures, operative, colorectal resection, ileus, business.industry, Recovery of Function, Odds ratio, medicine.disease, digestive system diseases, surgical procedures, Surgery, Multivariate Analysis, Defecation, business, Follow-Up Studies
Abstract: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110).Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients.El íleo es frecuente tras la cirugía colorrectal y se asocia con un aumento del riesgo de las complicaciones postoperatorias. Identificar las características de una recuperación normal del tránsito y la idoneidad para el alta hospitalaria es una tarea difícil. Este estudio examinó la seguridad del alta hospitalaria antes del restablecimiento de la función intestinal. MÉTODOS: Se llevó a cabo un estudio de cohortes prospectivo y multicéntrico a través de una red de colaboración internacional. Se incluyeron pacientes adultos sometidos a resección electiva colorrectal entre enero y abril 2018. El objetivo principal fue el reingreso hospitalario durante los 30 primeros días tras la intervención. Se utilizó un análisis de regresión multivariable para evaluar el impacto del momento del alta en función del restablecimiento de la función intestinal. El objetivo secundario fue las complicaciones postoperatorias en los primeros 30 días después de la cirugía, valoradas mediante el sistema de clasificación de Clavien-Dindo.Se incluyeron en el análisis 3.288 pacientes, de los cuales 301 (9,2%) fueron dados de alta antes del restablecimiento de la función intestinal. La mediana de la estancia hospitalaria de los pacientes dados de alta antes y después del restablecimiento de la función intestinal fue 5 (rango intercuartílico: 4-7) y 7 (6-8) días, respectivamente (P 0,001). No hubo diferencias significativas en las tasas de reingreso entre estos grupos (6,6% versus 8,0%; P = 0,499), y este resultado se mantuvo en el análisis multivariable tras el ajuste por diferencias basales (razón de opotunidades, odds ratio, OR 0,90; i.c. del 95% 0,55-1,46, P = 0,659). Las tasas de complicaciones postoperarorias fueron similares en aquellos dados de alta antes o después del restablecimiento de la función intestinal (complicaciones menores: 34,7% versus 39,5%; complicaciones mayores 3,3% versus 3,4%; P = 0,110). CONCLUSIÓN: Dar de alta antes del restablecimiento de la función intestinal tras cirugía colorrectal electiva parece ser seguro en pacientes debidamente seleccionados.
Published: 2020

33. Daily Step Count and Postprandial Fat Metabolism

Author: Edward F. Coyle and Heath M Burton
Subjects: Adult, Male, medicine.medical_specialty, Evening, Physical Therapy, Sports Therapy and Rehabilitation, Fitness Trackers, law.invention, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Accelerometry, Dietary Carbohydrates, Humans, Medicine, Orthopedics and Sports Medicine, Exercise physiology, Exercise, Triglycerides, Morning, Meal, Cross-Over Studies, business.industry, Area under the curve, 030229 sport sciences, Postprandial Period, Dietary Fats, Crossover study, Endocrinology, Postprandial, Area Under Curve, Female, Energy Metabolism, business
Abstract: INTRODUCTION Two benefits of acute exercise are the next day's lowering of the postprandial plasma triglyceride response to a high-fat meal and increased fat oxidation. However, if activity levels (daily steps) are very low, these acute adaptations to exercise do not occur. This phenomenon has been termed "exercise resistance." This study sought to systematically reduce daily step number and identify the range of step counts that elicit "exercise resistance." METHODS Ten participants completed three, 5-d trials in a randomized, crossover design with differing levels of step reduction. After 2 d of controlled activity, participants completed 2 d of LOW, LIMITED, or NORMAL steps (2675 ± 314, 4759 ± 276, and 8481 ± 581 steps per day, respectively). Participants completed a 1-h bout of running on the evening of the second day. High-fat tolerance tests were performed on the next morning, and postprandial responses were compared. RESULTS After LOW and LIMITED, postprandial incremental area under the curve (AUC) of plasma triglyceride was elevated 22%-23% compared with NORMAL (P < 0.05). Whole body fat oxidation was also significantly lower (16%-19%, P < 0.05, respectively) in LOW and LIMITED compared with NORMAL. No significant differences were found between LOW and LIMITED. CONCLUSION Two days of step reduction to approximately 2500-5000 steps per day in young healthy individuals impairs the ability of an acute bout of exercise to increase fat oxidation and attenuate postprandial increases in plasma triglycerides. This suggests that "exercise resistance" occurs in individuals taking approximately 5000 or fewer steps per day, whereas 8500 steps per day protects against exercise resistance in fat metabolism. It seems that fat metabolism is influenced more by the inhibitory effects of inactivity than by the stimulating effects derived from 1 h of moderate-intensity running.
Published: 2020

34. Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia

Author: Donna L. McPhie, Hae-Young Kim, Gun-Hoo Park, Peiyan Ni, Yiren Qin, Sangmi Chung, Joseph T. Coyle, Zhicheng Shao, Derek T Le, James M. Park, Haneul Noh, Chiderah P Abani, Weihua Huang, Hualin S. Xi, Dongxin Liu, Changhong Yin, Joy S. Park, Cameron P Beaudreault, Bruce M. Cohen, Sasha Z Gonzalez, Thomas A. Lanz, and Youxin Guan
Subjects: Adult, Male, 0301 basic medicine, Induced Pluripotent Stem Cells, Gene Expression, Glutamic Acid, Biology, Article, Transcriptome, Young Adult, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, Immune system, Interneurons, Gene expression, medicine, Humans, Induced pluripotent stem cell, gamma-Aminobutyric Acid, Cerebral Cortex, Microglia, General Neuroscience, Middle Aged, medicine.disease, Coculture Techniques, Mitochondria, Metabolic pathway, 030104 developmental biology, medicine.anatomical_structure, nervous system, Schizophrenia, Encephalitis, Neuroscience, 030217 neurology & neurosurgery
Abstract: The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.
Published: 2020

35. Acupuncture versus placebo acupuncture for in vitro fertilisation: a systematic review and meta-analysis

Author: Hiba Ali, Sinan Tekin, Phillip Lie, Meaghan E. Coyle, Michelle Kotlyarsky, Katherine Abdel-Nour, Thilini Thrimawithana, and Ieva Stupans
Subjects: Adult, Male, medicine.medical_specialty, In vitro fertilisation, business.industry, medicine.medical_treatment, Acupuncture Therapy, Pregnancy Outcome, Fertilization in Vitro, General Medicine, Placebo Effect, Placebo acupuncture, Complementary and alternative medicine, Pregnancy, Meta-analysis, Internal medicine, medicine, Acupuncture, Humans, Female, Neurology (clinical), business, Infertility, Female, Randomized Controlled Trials as Topic
Abstract: Objective: To evaluate the efficacy of acupuncture compared to placebo acupuncture for women undergoing in vitro fertilisation (IVF) in a systematic review and meta-analysis. Methods: A search was conducted in seven English-language biomedical databases from their inception to 3 April 2019 to identify studies evaluating acupuncture as an adjunct to IVF treatment. Randomised controlled trials (RCTs) that compared acupuncture with placebo acupuncture using a non-invasive placebo acupuncture device in women undergoing a fresh or frozen IVF cycle were eligible, as were studies that tested placebo acupuncture as the intervention. Outcomes were clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, live birth rate and adverse events. Results: Eight RCTs involving 3607 women were included. Studies were judged to be low risk for most of the risk of bias domains. Acupuncture around the time of embryo transfer was not significantly different to placebo acupuncture in terms of the clinical pregnancy rate (6 RCTs, 2473 women, risk ratio (RR) = 0.99 (95% confidence interval (CI) = 0.88, 1.11), I2 = 51%, moderate certainty evidence), ongoing pregnancy rate (4 RCTs, 1459 women, RR = 0.88 (95% CI = 0.75, 1.02), I2 = 50%, moderate certainty evidence), miscarriage rate (4 RCTs, 502 women, RR = 1.23 (95% CI = 0.89, 1.71), I2 = 30%, high certainty evidence) or live birth rate (4 RCTs, 1835 women, RR = 0.87 (95% CI = 0.75, 1.01), I2 = 0%, high certainty evidence). Outcomes with placebo acupuncture were not significantly different to usual care. Adverse events relating to acupuncture, such as discomfort and bruising, were mild to moderate. Conclusion: Acupuncture administered around the time of embryo transfer did not have a statistically significant effect on IVF outcomes compared with placebo acupuncture.
Published: 2020

36. A Mixed-Methods Analysis of Barriers to and Facilitators of Human Papillomavirus Vaccination Among Adolescents in Montana

Author: Matthew F. Daley, Beth Jones, Sophia R. Newcomer, Emily Coyle, Timothy Schehl, and James C. Caringi
Subjects: Male, Parents, Rural Population, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, Vaccination Coverage, Adolescent, Attitude of Health Personnel, Intention, Environment, Mixed methods analysis, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Environmental health, medicine, Humans, Papillomavirus Vaccines, 030212 general & internal medicine, Montana, Immunization Programs, business.industry, Research, Rural health, Public health, Papillomavirus Infections, Public Health, Environmental and Occupational Health, United States, Human papillomavirus vaccination, Vaccination, Socioeconomic Factors, Infectious disease (medical specialty), Female, Rural area, business, Adolescent health
Abstract: Objectives Human papillomavirus (HPV) vaccination rates among adolescents are lower in rural areas than in urban areas of the United States. The objective of this study was to identify barriers to and facilitators of adolescent HPV vaccination in Montana, a large, primarily rural state. Methods Using a mixed-methods design, we integrated quantitative analyses of Montana’s National Immunization Survey–Teen (NIS-Teen) data from 2013-2017 with qualitative data collected at a statewide meeting in October 2018 and from stakeholder interviews conducted from October 2018 through June 2019. Using NIS-Teen data, we identified trends and estimated adjusted prevalence ratios (aPRs) to identify factors associated with vaccine uptake. Using directed content analysis of qualitative data, we identified themes related to vaccine uptake. Results In Montana, initiation of the HPV vaccine series among adolescents aged 13-17 increased from 34.4% in 2013 to 65.5% in 2017. We identified 6 themes related to HPV vaccination from qualitative analyses, including medical providers’ recommendation style as a facilitator of vaccination and parental vaccine hesitancy as a barrier to vaccination. In NIS-Teen 2017 data (n = 326 adolescents), receiving a medical provider recommendation was significantly associated with series initiation (aPR = 2.3; 95% CI, 1.5-3.6). Among parents who did not intend to initiate the vaccine series for their adolescent within 12 months (n = 71), vaccine safety was the top concern (aPR = 24.5%; 95% CI, 12.1%-36.9%). Conclusions HPV vaccination rates have increased in Montana but remain lower than rates for other adolescent vaccines. Future work should focus on reducing missed opportunities, increasing parents’ knowledge of and confidence in vaccination, and training medical providers on addressing common vaccine concerns.
Published: 2020

37. Increased protease activated receptors in the colon of patients with Hirschsprung's disease

Author: Anne Marie O'Donnell, Christian Tomuschat, Prem Puri, and David Coyle
Subjects: Male, Colon, Receptors, Proteinase-Activated, Motility, Immunofluorescence, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Western blot, 030225 pediatrics, medicine, Humans, Protease-activated receptor, Hirschsprung Disease, Receptor, Hirschsprung's disease, Intestinal permeability, medicine.diagnostic_test, business.industry, Infant, General Medicine, medicine.disease, Molecular biology, Interstitial cell of Cajal, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, symbols, Female, Surgery, business
Abstract: PURPOSE The pathophysiology of Hirschsprung's associated enterocolitis (HAEC) is not understood. Abnormal intestinal motility and altered intestinal epithelial barrier function have been suggested to play a key role in the causation of HAEC. Protease-activated receptors (PARs) 1 and 2, have been implicated in inflammatory reactions, intestinal permeability and modulation of motility in the gut. METHODS We investigated PAR-1 and PAR-2 protein expression in aganglionic and ganglionic regions of patients with Hirschsprung's Disease (HSCR) (n = 10) versus normal control colon (n = 10). Protein distribution was assessed by using immunofluorescence and confocal microscopy. Gene and protein expression were quantified using quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and densitometry. RESULTS qPCR and Western blot analysis revealed that PAR-1 and PAR-2 expression was significantly increased in ganglionic and aganglionic bowel in HSCR compared to controls (p
Published: 2020

38. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Author: Graeme J. Hankey, Maree L. Hackett, Osvaldo P. Almeida, Leon Flicker, Gillian E. Mead, Martin S. Dennis, Christopher Etherton-Beer, Andrew H. Ford, Laurent Billot, Stephen Jan, Thomas Lung, Veronica Murray, Erik Lundström, Craig S. Anderson, Robert Herbert, Gregory Carter, Geoffrey A. Donnan, Huy-Thang Nguyen, John Gommans, Qilong Yi, Qiang Li, Severine Bompoint, Sarah Barrett, Anne Claxton, Julia O'Dea, Michelle Tang, Clare Williams, Shenae Peterson, Christie Drummond, Uyen-Ha Hong, Linh-Thi My Le, Tram-Thi Bich Ngo, Yen-Bao Mai, Huyen-Thanh Han, Nhu-Quynh Truong, Huong-Thi Nguyen, Hai-Thanh Ngo, Thi Binh Nguyen, Oanh-Thi Kieu Ha, Trang-Le Huyen Nguyen, Richard I. Lindley, Peter New, Andrew Lee, Thanh-Trung Tran, Loan-Tran Truc Mai Le, Thuy-Le Vu Kieu, Sang-Van Nguyen, Thuy-Anh Diem Nguyen, Tam-Nhat Dang, Hanh-Thi Truc Phan, Loan-Thi Ngoc Vo, Mai-Hue Nguyen, Hanh-Cao Dang, Hong-Thi Tran, Linh-Thi Cam Dam, Trinh-Thi Kim Ngo, Thai-Nguyen Thanh Pham, Binh-Nguyen Pham, Nha-Thi Thanh Dao, Huong-Thi Bich Nguyen, Linh-Thi Cam Le, Chi-Minh Do, Huy-Quoc Huynh, Giau-Thi Kim Tran, Oanh-Thi Le, Ly-Thi Khanh Tran, Chinh-Dinh Duong, Duong-Van Kieu, Na Le, Hoa-Ngoc Nguyen, Binh-Van Le, Long-Thanh Nguyen, Long-Van Nguyen, Tuan-Quoc Dinh, Tan-Van Vo, Tram-Ngoc Bui, Uyen-Thi To Hoang, Hien-Thi Bich Nguyen, Ha-Thi Thu Nguyen, Nga-Thuy Lam, Khanh-Kim Le, Phuong-Thanh Trinh, Hop-Quang Huynh, Thao-Thi Thu Nguyen, Huyen-Ngoc Lu, Tham-Hong Pham, Sam-Hoanh Nguyen, Ninh-Hong Le, Giang-Truong Nguyen, Bich-Thi Doan, Sung-Phuoc Pham, Duong-Huu Luong, Ha-Van Mai, Thuc-Van Tran, Phuong-Thi Do, Hoai-Thi Le, Chi-Van Nguyen, Phuong-Doan Nguyen, Ton-Duy Mai, Phuong-Viet Dao, Dung-Tien Nguyen, Dai-Quoc Khuong, Trung-Xuan Vuong, Lan-Tuong Vu, Ngoc-Duc Ngo, Hanh-Hong Dang, Phuong-Thai Truong, Ngan-Thi Le, Hoa-Van Hoang, Chung-Quang Do, Minh-Thao Nguyen, Anh-Hai Dam, Quynh-Nhu Le, Ngoc-Hoang Nguyen, Tuyen-Van Nguyen, Toan-Dinh Le, Ha-Thi Hai Dinh, Cuong-Van Pham, Khanh-Thi Ngoc Thach, Linh-Hai Nguyen, Loan-Thi Nguyen, Vien-Chi Le, Phuong-Hong Tran, Tai-Anh Nguyen, Tuan-Van Le, Luyen-Van Truong, Tue-Chau Bui, Ngoc-Xuan Huynh, Lap-Van Dinh, An-Gia Pham, Trang-Thi Huyen Le, Vy-Tuong Nguyen, Yen-Hai Nguyen, Thang-Ba Nguyen, Huy Thai, Quyen-Thi Ngoc Pham, Khoa-Duy Dao, Quoc-Nguyen Bao Pham, Thuong-Thi Huyen Dang, Huong-Huynh To Dinh, Trang-Mai Tong, Thuy-Thi Vu, Si-Tri Le, Tai-Ngoc Tran, Phuong-Hoai Tran, Ngoc-Thuy Nhu Dinh, Binh-Thanh Nguyen, Vinh-Phuong Do, Anh-Ngoc Nguyen, Binh-Thi Thanh Nguyen, David Blacker, Lindsey Bunce, Ai Ling Tan, Darshan Ghia, Gillian Edmonds, Nicole O'Loughlin, Megan Ewing, Kerri-Ann Whittaker, Lorralee Deane, Yash Gawarikar, Brett Jones, Maria Lopez, Koushik Nagesh, Emma Siracusa, Stephen Davis, Amy McDonald, Jess Tsoleridis, Rachael McCoy, David Jackson, Gab Silver, Timothy R. Bates, Amanda Boudville, Lynda Southwell, Dennis Cordato, Alan J. McDougall, Cecilia Cappelen-Smith, Zeljka Calic, Shabeel Askar, Qi Cheng, Raymond Kumar, Richard Geraghty, Maree Duroux, Megan Ratcliffe, Samantha Shone, Cassandra McLennan, Ramesh Sahathevan, Casey Hair, Stanley Levy, Beverley Macdonald, Benjamin Nham, Louise Rigney, Dev Nathani, Sumana Gopinath, Vishal Patel, Abul Mamun, Benjamin Trewin, Chun Phua, Ho Choong, Lauren Tarrant, Kerry Boyle, Luisa Hewitt, Monique Hourn, Amanda Masterson, Kim Oakley, Karen Ruddell, Colette Sanctuary, Kimberley Veitch, Camelia Burdusel, Lina Lee, Gary Cheuk, Jeremy Christley, Tabitha Hartwell, Craig Davenport, Kate Hickey, Rosanna Robertson, Michelle Carr, Sam Akbari, Hannah Coyle, Megan O'Neill, Cameron Redpath, Caroline Roberts, Marjan Tabesh, Toni Withiel, Kapila Abeysuriya, Andrew Granger, Angela Abraham, Chermaine Chua, Dung Do Nguyen, Vathani Surendran, Melissa Daines, David Shivlal, Mudassar Latif, Noreen Mughal, Patricia Morgan, Martin Krause, Miriam Priglinger, Ehsan E. Shandiz, Susan Day, Lay Kho, Michael Pollack, Judith Dunne, Helen Baines, Merridie Rees, Jenni White, Aicuratiya Withanage, Candice Delcourt, Cheryl Carcel, Alejandra Malavera, Amy Kunchok, Elizabeth Ray, Elizabeth Pepper, Emily Duckett, Sally Ormond, Andrew Moey, Timothy Kleinig, Vanessa Maxwell, Chantal Baldwin, Wilson Vallat, Deborah Field, Romesh Markus, Kirsty Page, Danielle Wheelwright, Sam Bolitho, Steven Faux, Fix Sangvatanakul, Alexis Brown, Susan Walker, Jennifer Massey, Hillary Hayes, Pesi Katrak, Annie Winker, Alessandro Zagami, Alanah Bailey, Sarah Mccormack, Andrew Murray, Mark Rollason, Christopher Taylor, Fintan O'Rourke, Ye Min Kuang, Heike Burnet, Yvonne Liu, Aileen Wu, Diana Ramirez, Tissa Wijeratne, Sherisse Celestino, Essie Low, Cynthia Chen, Jennifer Bergqvist, Andrew Evans, Queenie Leung, Martin Jude, Rachael McQueen, Katherine Mohr, Latitia Kernaghan, Paul Stockle, Boon L. Tan, Sara Laubscher, Diana Schmid, Melissa Spooner, Bhavesh Lallu, Bronwen Pepperell, John Chalissery, Karim Mahawish, Susan DeCaigney, Paula Broughton, Karen Knight, Veronica Duque, Harry McNaughton, Jeremy Lanford, Vivian Fu, and Lai-Kin Wong
Subjects: Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Population, Placebo-controlled study, Placebo, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Modified Rankin Scale, Fluoxetine, Internal medicine, medicine, Humans, 030212 general & internal medicine, education, Stroke, Aged, education.field_of_study, business.industry, B790, Recovery of Function, Odds ratio, Middle Aged, medicine.disease, Clinical trial, Treatment Outcome, Female, Neurology (clinical), Stroke recovery, business, Selective Serotonin Reuptake Inhibitors, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.
Published: 2020

39. Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing

Author: Sriram Balasubramanian, Quratulain Qureshi, Christopher Rushton, Miguel Alcaide, Nicole Thomas, Krysta M. Coyle, Bruno M. Grande, Prasath Pararajalingam, Barbara Meissner, Joseph M. Connors, Diego Villa, Ryan D. Morin, Constantine S. Tam, Randy D. Gascoyne, David W. Scott, Graham W. Slack, Christian Steidl, Nathalie A. Johnson, Timothy E. Audas, Marco A. Marra, Sarah E. Arthur, Rishu Agarwal, Andrew J. Mungall, Merrill Boyle, Sarah-Jane Dawson, and Georg Lenz
Subjects: Adult, Male, 0301 basic medicine, Genotype, Immunology, Lymphoma, Mantle-Cell, Biology, medicine.disease_cause, Biochemistry, Genome, Heterogeneous-Nuclear Ribonucleoproteins, 03 medical and health sciences, Exon, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Genetic Predisposition to Disease, Gene, Exome, Exome sequencing, Aged, Aged, 80 and over, Mutation, Whole Genome Sequencing, Cell Biology, Hematology, Middle Aged, medicine.disease, Lymphoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Female, Mantle cell lymphoma
Abstract: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
Published: 2020

40. Duration of adhesion of swallowed alginates to distal oesophageal mucosa: implications for topical therapy of oesophageal diseases

Author: Daniel Sifrim, Cathal Coyle, Shirley Sonmez, and Philip Woodland
Subjects: Adult, Male, medicine.medical_specialty, Esophageal Mucosa, Alginates, Administration, Topical, medicine.medical_treatment, Administration, Oral, Placebo, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Heartburn, In vivo, Internal medicine, medicine, Mucoadhesion, Humans, Pharmacology (medical), 030212 general & internal medicine, Saline, Hepatology, Oesophageal Mucosa, business.industry, Adhesiveness, Middle Aged, Catheter, Female, 030211 gastroenterology & hepatology, medicine.symptom, business, Ex vivo
Abstract: BACKGROUND We have previously shown, ex vivo, that alginate solutions can have a topical protective effect on oesophageal mucosal biopsies exposed to simulated gastric juice. Oesophageal mucosal impedance can measure the duration of mucosal adherence of ionic solutions since the impedance drops when the solution is present, and rises to baseline as the solution clears. AIM To investigate the in vivo duration of adhesion of swallowed alginate solution to distal oesophageal mucosa. METHODS We studied 20 healthy volunteers and 10 patients with heartburn. A pH-impedance catheter was inserted, and baseline distal channel oesophageal impedance measured. Healthy volunteers received 10 mL of either sodium alginate (Gaviscon Advance), Gaviscon placebo (no alginate) or viscous slurry (saline mixed with sucralose), given in a randomised, single-blinded order over three visits. Patients received either sodium alginate or placebo on two visits. Initial impedance drop was measured, then 1-minute mean impedance was measured each minute until ≥75% recovery to baseline. RESULTS In healthy volunteers, sodium alginate adhered to the oesophageal mucosa for longer than placebo or viscous slurry (10.4 [8.7] minutes vs 1.1 [1.6] vs 3.6 [4.0], P
Published: 2020

41. Condom Use and Error Experience Among Young Adolescents: Implications for Classroom Instruction

Author: Elizabeth Baumler, Kari Kesler, Mia Barrett, Karin K. Coyle, B. A. Laris, Pamela M. Anderson, and Andrea Gerber
Subjects: Male, Nursing (miscellaneous), Adolescent, Sexual Behavior, Psychological intervention, law.invention, Condoms, Condom, Randomized controlled trial, law, Humans, Students, Curriculum, Reproductive health, Schools, business.industry, Public Health, Environmental and Occupational Health, virus diseases, United States, Health promotion, Adolescent Behavior, Female, Health education, Parental consent, business, Psychology, Clinical psychology
Abstract: We examine condom failure and use error experienced by high school youth in two regions of the United States. Data are from a baseline survey of a randomized controlled trial to evaluate FLASH, a sexual health education curriculum for high school students. Participants were 1,597 ninth- or 10th-grade students in health class who had parental consent and who assented to participate in the study. This study examines condom use behavior among students who reported vaginal or anal sex at baseline. Of the 222 participants who reported having vaginal or anal sex in the 3 months prior to baseline survey, 180 of them reported using a condom at least once. Of these youth, 70.6% reported that they did not squeeze the tip of the condom before sex, 25.0% of youth reported that they did not roll the condom all the way down to the base of the penis, and 49.4% reported that they did not hold the base of the penis when pulling out; 36.9% reported experiencing condom breakage or slippage. The frequency of condom error and/or failure reported by young adolescents in this study indicates a need for further education on potential condom use errors with an emphasis on the correct steps for using a condom to prevent condom failure. High rates of error and failure suggest an opportunity for educators to tailor preexisting condom use interventions to further reinforce the skills necessary for effective condom use and to educate on what to do in the event of condom failure.
Published: 2020

42. Socio‐Ecological Factors Associated With Students' Perceived Impact of an Evidence‐Based Sexual Health Education Curriculum

Author: Melissa F. Peskin, Elizabeth Baumler, Susan Tortolero Emery, Ross Shegog, Belinda F Hernandez, Christine Markham, B. A. Laris, Kimberly Baker, Melanie Thiel, Robert C. Addy, and Karin K. Coyle
Subjects: Male, Evidence-based practice, Adolescent, Sexual Behavior, Teaching method, Decision Making, education, Human sexuality, Sex Education, Proxy (climate), Education, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Humans, 030212 general & internal medicine, Sexual health education, Students, Curriculum, Reproductive health, Self-efficacy, Schools, business.industry, Public Health, Environmental and Occupational Health, Philosophy, Female, business, Psychology, Program Evaluation, Clinical psychology
Abstract: Background Although schools often implement evidence-based sexual health education programs to address sexual and reproductive health disparities, multiple factors may influence program effectiveness. Methods Using student-reported perceived impact measures as a proxy for program effectiveness, we employed a socio-ecological approach to examine student, teacher, school, and district factors associated with greater perceived impact of It's Your Game (IYG), an evidence-based middle school sexual health education program. The student sample was 58.7% female, 51.8% Hispanic, mean age 13.2 years, from 73 middle schools. We assessed students' (N = 4531) perceived impact of IYG on healthy decision-making (α = 0.75) and sexual communication (α = 0.71); satisfaction with IYG activities and teacher; and demographics. We assessed teachers' (N = 56) self-efficacy to teach IYG, perceived administrative support, implementation barriers, and demographics. School and district data were abstracted from state records. We used multilevel logistic regression to estimate associations between independent variables and student-reported perceived impact. Results In final multivariate models, students' demographics (sex, β = 0.06, SE = 0.015), satisfaction with IYG (β = 0.21, SE = 0.012), and their IYG teacher (β = 0.18, SE = 0.013) (all p = .000) were significantly associated with perceived impact on healthy decision-making. Similar findings resulted for sexual communication. No other variables were significantly associated with perceived impact. Conclusions Helping schools select age-appropriate, culturally relevant programs, and facilitate supportive learning environments may enhance the perceived impact of sexual health education programs.
Published: 2020

43. Real-time 3D movement correction for two-photon imaging in behaving animals

Author: Paul Anthony Kirkby, Theo Koimtzis, Antoine M. Valera, R. Angus Silver, George Konstantinou, Geoffrey J. Evans, Chiara Baragli, Hana Roš, Sameer A Punde, Isaac H. Bianco, Joanna Yn Lau, Boris Marin, K. M. Naga Srinivas Nadella, Diccon Coyle, Thomas J. Younts, and Victoria A. Griffiths
Subjects: Male, Laser scanning, Computer science, Movement, Field of view, Tracking (particle physics), Biochemistry, Article, Photostimulation, law.invention, Mice, 03 medical and health sciences, Imaging, Three-Dimensional, Two-photon excitation microscopy, law, Microscopy, Animals, Molecular Biology, Zebrafish, 030304 developmental biology, 0303 health sciences, Cell Biology, Mice, Inbred C57BL, Functional imaging, Lens (optics), Microscopy, Fluorescence, Multiphoton, Female, Neuroscience, Biotechnology
Abstract: Two-photon microscopy is widely used to investigate brain function across multiple spatial scales. However, measurements of neural activity are compromised by brain movement in behaving animals. Brain motion-induced artefacts are typically corrected using post-hoc processing of 2D images, but this approach is slow and does not correct for axial movements. Moreover, the deleterious effects of brain movement on high speed imaging of small regions of interest and photostimulation cannot be corrected post-hoc. To address this problem, we combined random access 3D laser scanning using an acousto-optic lens and rapid closed-loop FPGA processing to track 3D brain movement and correct motion artifacts in real-time at up to 1 kHz. Our recordings from synapses, dendrites and large neuronal populations in behaving mice and zebrafish demonstrate real-time movement corrected 3D two-photon imaging with sub-micrometer precision., Editor summary: Real-time 3D movement correction by tracking a fluorescent bead in the field of view enables functional imaging with 3D two-photon random access microscopy in behaving mice and zebrafish.
Published: 2020

44. Assessment of neurogenic bowel symptoms with the bowel dysfunction score in children with spina bifida: a prospective case–control study

Author: M Doyle, David Coyle, E Aldridge, C Gibbons, S Cascio, and Cynthia White
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Longitudinal study, Pediatrics, Constipation, Adolescent, Bowel management, 03 medical and health sciences, 0302 clinical medicine, Neurogenic Bowel, Quality of life, Surveys and Questionnaires, 030225 pediatrics, Pediatric surgery, medicine, Humans, Child, Spinal Dysraphism, business.industry, Spina bifida, General Medicine, medicine.disease, Pediatric urology, nervous system diseases, Child, Preschool, Pediatrics, Perinatology and Child Health, Quality of Life, Female, 030211 gastroenterology & hepatology, Surgery, medicine.symptom, business
Abstract: To compare the quality of life (QoL) in children with spina bifida with a control group of their peers using a validated questionnaire, the Neurogenic Bowel Dysfunction Score (NBDS). The NBDS questionnaire was prospectively distributed to children attending a multi-disciplinary Spina Bifida clinic and healthy controls attending pediatric urology clinics. A score (out of 41) was assigned to each child based on their responses to the validated questionnaire. A lower score indicates better bowel function-related quality of life. SPSS software (v.25) was used for all statistical analysis. There were 98 respondents to the questionnaire, 48 children with spina bifida and 50 controls. The average age of respondents was 7.88 years (3–16 years). Of those with Spina Bifida, 33 (69%) were on retrograde rectal irrigations, [19 (58%) Peristeen® system, 11 (33%) tube rectal irrigations, and 3 (9%) Willis system], 6 (12%) were on laxatives, and 9 (19%) were on no treatment. The median NBDS for Spina Bifida patients was significantly higher 13.5 (2–32) compared to the control group 2 (0–26, p
Published: 2020

45. Neurologists’ perspectives on medical cannabis for pediatric drug-resistant epilepsy in Canada: A qualitative interview study

Author: Tammy Clifford, Jesse Elliott, Bláthnaid McCoy, Doug Coyle, George A. Wells, Beth K. Potter, and Deirdre DeJean
Subjects: Adult, Male, Canada, Drug Resistant Epilepsy, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, Attitude of Health Personnel, Medical Marijuana, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Health care, medicine, Humans, Neurologists, Child, Qualitative Research, business.industry, Qualitative interviews, Treatment options, General Medicine, Middle Aged, medicine.disease, Pediatric drug, Neurology, Epilepsy in children, Family medicine, Medical cannabis, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Qualitative research
Abstract: Purpose To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy. Methods In this qualitative study, we interviewed neurologists who provide care to children with drug-resistant epilepsy in Canada. Through semi-structured telephone interviews, we sought participants’ views about and experiences with medical cannabis for the treatment of drug-resistant epilepsy in children. Here we present a thematic summary of the interviews. Results The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children’s care, including medical cannabis, others referred interested families to non-neurology health care professionals. Conclusion Our findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, in order to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.
Published: 2020

46. Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

Author: Alexander G Murley, Matthew A Rouse, Ian Coyle-Gilchrist, Kamen A. Tsvetanov, Alicia Wilcox, Julie Wiggins, Matthew A. Lambon Ralph, P. Simon Jones, Win Li, Claire J. Lansdall, Patricia Vázquez Rodríguez, James B. Rowe, Karalyn Patterson, Murley, Alexander [0000-0003-0813-0670], Rouse, Matthew [0000-0002-3157-4301], Jones, Simon [0000-0001-9695-0702], Tsvetanov, Kamen A. [0000-0002-3178-6363], Patterson, Karalyn [0000-0003-1927-7424], Lambon Ralph, Matthew [0000-0001-5907-2488], Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: Male, Pediatrics, medicine.medical_specialty, Semantic dementia, frontotemporal dementia, Progressive supranuclear palsy, Primary progressive aphasia, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Epidemiology, medicine, Humans, Aged, 030304 developmental biology, Cerebral atrophy, Principal Component Analysis, 0303 health sciences, business.industry, Brain morphometry, Original Articles, progressive supranuclear palsy, corticobasal syndrome, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Black or African American, Phenotype, semantic dementia, Etiology, primary progressive aphasia, Dementia, Female, Neurology (clinical), Frontotemporal Lobar Degeneration, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: See Piguet (doi:10.1093/brain/awaa119) for a scientific commentary on this article. Murley et al. report the results of a transdiagnostic study of clinical phenotype and brain atrophy in frontotemporal lobar degeneration syndromes, showing that these syndromes exist on a multidimensional spectrum, rather than as discrete entities., The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.
Published: 2020

47. Development and Validation of Person-Centered Cut-Points for the Figure-of-8-Walk Test of Mobility in Community-Dwelling Older Adults

Author: Subashan Perera, Valerie Shuman, Jennifer S. Brach, Peter C. Coyle, and Jessie M. VanSwearingen
Subjects: Male, Aging, medicine.medical_specialty, Psychometrics, THE JOURNAL OF GERONTOLOGY: Medical Sciences, Poison control, Walk Test, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Injury prevention, medicine, Humans, 030212 general & internal medicine, Geriatric Assessment, Motor skill, Aged, Balance (ability), Aged, 80 and over, Receiver operating characteristic, business.industry, Emergency department, Test (assessment), Preferred walking speed, Motor Skills, Female, Independent Living, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Background The Figure-of-8-Walk test (F8WT) is a performance measure of the motor skill of walking. Unlike walking speed over a straight path, it captures curved path walking, which is essential to real-world activity, but meaningful cut-points have yet to be developed for the F8WT. Methods A secondary analysis of 421 community-dwelling older adults (mean age 80.7 ± 7.8), who participated in a community-based exercise clinical trial, was performed. Area under receiver operating characteristic curves (AUROCC) were calculated using baseline data, with F8WT performance discriminating different self-reported global mobility and balance dichotomies. Cut-points for the F8WT were chosen to optimize sensitivity and specificity. For validation, F8WT cut-points were applied to postintervention F8WT data. Participants were called monthly for 12 months after intervention completion to record self-reported incident falls, emergency department visits, and hospitalizations; risks of the outcomes were compared between those who performed well and poorly on the F8WT. Results F8WT performance times of ≤9.09 seconds and ≤9.27 seconds can discriminate those with excellent (sensitivity = 0.647; specificity = 0.654) and excellent/very good global mobility (sensitivity = 0.649; specificity = 0.648), respectively. A total number of steps ≤17 on the F8WT can discriminate those with excellent/very good/good global balance (sensitivity = 0.646; specificity = 0.608). Compared to those who performed poorly, those who performed well had a lower incidence of negative outcomes: F8WT time ≤9.09 seconds = 46%–59% lower; F8WT time ≤9.27 seconds = 46%–56% lower; F8WT steps ≤17 = 44%–50% lower. Conclusions Clinicians may consider these preliminary cut-points to aid in their clinical decision making, but further study is needed for definitive recommendations.
Published: 2020

48. A Transcriptomic Approach to Elucidate the Mechanisms of Gefitinib-Induced Toxicity in Healthy Human Intestinal Organoids

Author: Daniela Rodrigues, Bram Herpers, Sofia Ferreira, Heeseung Jo, Ciarán Fisher, Luke Coyle, Seung-Wook Chung, Jos C. S. Kleinjans, Danyel G. J. Jennen, Theo M. de Kok, Toxicogenomics, RS: GROW - R1 - Prevention, RS: FSE MaCSBio, RS: FPN MaCSBio, and RS: FHML MaCSBio
Subjects: Male, PREDICTION, CELL LUNG-CANCER, gefitinib, molecular mechanisms, Antineoplastic Agents, Apoptosis, METABOLISM, Catalysis, Inorganic Chemistry, human intestinal organoids, transcriptomics, toxicity, TYROSINE KINASE INHIBITORS, Humans, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, TISSUE DISTRIBUTION, Aged, Cell Proliferation, STRESS-MEDIATED INJURY, Organic Chemistry, Cell Cycle, ADENOCARCINOMA, General Medicine, IN-VITRO, Computer Science Applications, ErbB Receptors, Intestines, Organoids, Drug Resistance, Neoplasm, Quinazolines, Tumor Suppressor Protein p53, Transcriptome, RESISTANCE, Signal Transduction, DRUG-INTERACTIONS
Abstract: Gefitinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the epidermal growth factor receptor (EGFR), hampering cell growth and proliferation. Due to its action, gefitinib has been used in the treatment of cancers that present abnormally increased expression of EGFR. However, side effects from gefitinib therapy may occur, among which diarrhoea is most common, that can lead to interruption of the planned therapy in the more severe cases. The mechanisms underlying intestinal toxicity induced by gefitinib are not well understood. Therefore, this study aims at providing insight into these mechanisms based on transcriptomic responses induced in vitro. A 3D culture of healthy human colon and small intestine (SI) organoids was exposed to 0.1, 1, 10 and 30 µM of gefitinib, for a maximum of three days. These drug concentrations were selected using physiologically-based pharmacokinetic simulation considering patient dosing regimens. Samples were used for the analysis of viability and caspase 3/7 activation, image-based analysis of structural changes, as well as RNA isolation and sequencing via high-throughput techniques. Differential gene expression analysis showed that gefitinib perturbed signal transduction pathways, apoptosis, cell cycle, FOXO-mediated transcription, p53 signalling pathway, and metabolic pathways. Remarkably, opposite expression patterns of genes associated with metabolism of lipids and cholesterol biosynthesis were observed in colon versus SI organoids in response to gefitinib. These differences in the organoids’ responses could be linked to increased activated protein kinase (AMPK) activity in colon, which can influence the sensitivity of the colon to the drug. Therefore, this study sheds light on how gefitinib induces toxicity in intestinal organoids and provides an avenue towards the development of a potential tool for drug screening and development.
Published: 2022
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49. Chronic androgen excess in female mice does not impact luteinizing hormone pulse frequency or putative GABAergic inputs to GnRH neurons

Author: Chris S. Coyle, Melanie Prescott, David J Handelsman, Kirsty A. Walters, and Rebecca E. Campbell
Subjects: Male, Neurons, Endocrine and Autonomic Systems, Endocrinology, Diabetes and Metabolism, Dihydrotestosterone, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Cellular and Molecular Neuroscience, Mice, Endocrinology, Pregnancy, Prenatal Exposure Delayed Effects, Androgens, Animals, Humans, Female, Hyperandrogenism, Polycystic Ovary Syndrome
Abstract: Polycystic ovary syndrome (PCOS) is associated with androgen excess and, frequently, hyperactive pulsatile luteinizing hormone (LH) secretion. Although the origins of PCOS are unclear, evidence from pre-clinical models implicates androgen signalling in the brain in the development of PCOS pathophysiology. Chronic exposure of female mice to dihydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic impairments that are ameliorated by selective androgen receptor (AR) loss from the brain. This suggests centrally driven mechanisms in hyperandrogen-mediated PCOS-like pathophysiology that remain to be defined. Acute prenatal DHT exposure can also model the hyperandrogenism of PCOS, and this is accompanied by increased LH pulse frequency and increased GABAergic innervation of gonadotrophin-releasing hormone (GnRH) neurons. We aimed to determine the impact of chronic exposure of female mice to DHT, which models the hyperandrogenism of PCOS, on pulsatile LH secretion and putative GABAergic input to GnRH neurons. To do this, GnRH-green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day 21 (n = 6 or 7 per group). Serial tail-tip blood sampling was used to measure LH dynamics and perfusion-fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP-labelled GnRH neurons. As expected, chronic DHT resulted in acyclicity and significantly increased body weight. However, no differences in LH pulse frequency or the density of VGAT appositions to GnRH neurons were identified between ovary-intact DHT-treated females and controls. Chronic DHT exposure significantly increased the number of AR expressing cells in the hypothalamus, whereas oestrogen receptor α-expressing neuron number was unchanged. Therefore, although chronic DHT exposure from 3 weeks of age increases AR expressing neurons in the brain, the GnRH neuronal network changes and hyperactive LH secretion associated with prenatal androgen excess are not evident. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.
Published: 2022

50. A 6-mRNA host response classifier in whole blood predicts outcomes in COVID-19 and other acute viral infections

Author: Ljubomir Buturovic, Hong Zheng, Benjamin Tang, Kevin Lai, Win Sen Kuan, Mark Gillett, Rahul Santram, Maryam Shojaei, Raquel Almansa, Jose Ángel Nieto, Sonsoles Muñoz, Carmen Herrero, Nikolaos Antonakos, Panayiotis Koufargyris, Marina Kontogiorgi, Georgia Damoraki, Oliver Liesenfeld, James Wacker, Uros Midic, Roland Luethy, David Rawling, Melissa Remmel, Sabrina Coyle, Yiran E. Liu, Aditya M. Rao, Denis Dermadi, Jiaying Toh, Lara Murphy Jones, Michele Donato, Purvesh Khatri, Evangelos J. Giamarellos-Bourboulis, and Timothy E. Sweeney
Subjects: Male, Multidisciplinary, Molecular medicine, Statistical methods, SARS-CoV-2, Science, COVID-19, Middle Aged, Article, Coronavirus, Prognostic markers, Gene Expression Regulation, Viral infection, Predictive Value of Tests, Machine learning, Acute Disease, Medicine, Infectious diseases, Humans, Female, RNA, Messenger, Retrospective Studies
Abstract: Predicting the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19. We developed a logistic regression-based classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N = 705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs. We selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.94 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N = 97) and retrospectively (N = 100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay. With further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.
Published: 2022

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