Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from model animals. To assess the structure-function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometer scale. In our datasets retinal ganglion cell dendrites degenerate early in human glaucoma, with remodeling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure-function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma

Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions

We summarize here the results presented and subsequent discussion from the meeting on Integrating Hebbian and Homeostatic Plasticity at the Royal Society in April 2016. We first outline the major themes and results presented at the meeting. We next provide a synopsis of the outstanding questions that emerged from the discussion at the end of the meeting and finally suggest potential directions of research that we believe are most promising to develop an understanding of how these two forms of plasticity interact to facilitate functional changes in the brain.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'

Quality of health care around the time of childbirth during the COVID-19 pandemic: Results from the IMAgiNE EURO study in Norway and trends over time

Objective: To describe maternal perception of the quality of maternal and newborn care (QMNC) in facilities in Norway during the first year of COVID-19 pandemic. Methods: Women who gave birth in a Norwegian facility from March 1, 2020, to October 28, 2021, filled out a structured online questionnaire based on 40 WHO standards-based quality measures. Quantile regression analysis was performed to assess changes in QMNC index over time. Results: Among 3326 women included, 3085 experienced labor. Of those, 1799 (58.3%) reported that their partner could not be present as much as needed, 918 (29.8%) noted inadequate staff numbers, 183 (43.6%) lacked a consent request for instrumental vaginal birth (IVB), 1067 (34.6%) reported inadequate communication from staff, 78 (18.6%) reported fundal pressure during IVB, 670 (21.7%) reported that they were not treated with dignity, and 249 (8.1%) reported experiencing abuse. The QMNC index increased gradually over time (3.68 points per month, 95% CI, 2.83– 4.53 for the median), with the domains of COVID-19 reorganizational changes and experience of care displaying the greatest increases, while provision of care was stable over time. Conclusion: Although several measures showed high QMNC in Norway during the first year of the COVID-19 pandemic, and a gradual improvement over time, several findings suggest that gaps in QMNC exist. These gaps should be addressed and monitored

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Funding Information: Researchers were funded by investment from the European Regional Development Fund (ERDF) and the European Social Fund (ESF) Convergence Programme for Cornwall and the Isles of Scilly [J.T.]; European Research Council (ERC) [grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F., A.R.W.], [ERC Consolidator Grant, ERC-2014-CoG-648916 to V.W.V.J.], [P.R.N.]; University of Bergen, KG Jebsen and Helse Vest [P.R.N.]; Wellcome Trust Senior Investigator Awards [A.T.H. (WT098395), M.I.M. (WT098381)]; National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611–10219); Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150) [R.M.F., R.N.B.]; 4-year studentship (Grant Code: WT083431MF) [R.C.R]; the European Research Council under the European Union’s Seventh Framework Programme (FP/2007– 2013)/ERC Grant Agreement (grant number 669545; Develop Obese) [D.A.L.]; US National Institute of Health (grant: R01 DK10324) [D.A.L, C.L.R]; Wellcome Trust GWAS grant (WT088806) [D.A.L] and NIHR Senior Investigator Award (NF-SI-0611–10196) [D.A.L]; Wellcome Trust Institutional Strategic Support Award (WT097835MF) [M.A.T.]; The Diabetes Research and Wellness Foundation Non-Clinical Fellowship [J.T.]; Australian National Health and Medical Research Council Early Career Fellowship (APP1104818) [N.M.W.]; Daniel B. Burke Endowed Chair for Diabetes Research [S.F.A.G.]; UK Medical Research Council Unit grants MC_UU_12013_5 [R.C.R, L.P, S.R, C.L.R, D.M.E., D.A.L.] and MC_UU_12013_4 [D.M.E.]; Medical Research Council (grant: MR/M005070/1) [M.N.W., S.E.J.]; Australian Research Council Future Fellowship (FT130101709) [D.M.E] and (FT110100548) [S.E.M.]; NIHR Oxford Biomedical Research Centre (BRC); Oak Foundation Fellowship and Novo Nordisk Foundation (12955) [B.F.]; FRQS research scholar and Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics– Canadian Institute of Health Research (CIHR) [MFH]; CIHR— Frederick Banting and Charles Best Canada Graduate Scholarships [C.A.]; FRQS [L.B.]; Netherlands Organization for Health Research and Development (ZonMw–VIDI 016.136.361) [V.W.V.J.]; National Institute on Aging (R01AG29451) [J.M.M.]; 2010–2011 PRIN funds of the University of Ferrara—Holder: Prof. Guido Barbujani, Supervisor: Prof. Chiara Scapoli—and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists, ‘5 per mille’ contribution assigned to the University of Ferrara, income tax return year 2009 and the ENGAGE Exchange and Mobility Program for ENGAGE training funds, ENGAGE project, grant agreement HEALTH-F4–2007-201413 [L.M.]; ESRC (RES-060–23-0011) [C.L.R.]; National Institute of Health Research ([S.D., M.I.M.], Senior Investigator Award (NF-SI-0611–10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M]. For study-specific funding, please see Supplementary Material. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF). Funding Information: We are extremely grateful to the participants and families who contributed to all of the studies and the teams of investigators involved in each one. These include interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This research has been conducted using the UK Biobank Resource (Application numbers 7036 and 12703). For additional study-specific acknowledgements, please see Supplementary Material. Conflict of Interest statement. D.A.L. has received support from Roche Diagnostics and Medtronic for biomarker research unrelated to the work presented here. Funding Researchers were funded by investment from the European Regional Development Fund (ERDF) and the European Social Fund (ESF) Convergence Programme for Cornwall and the Isles of Scilly [J.T.]; European Research Council (ERC) [grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F., A.R.W.], [ERC Consolidator Grant, ERC-2014-CoG-648916 to V.W.V.J.], [P.R.N.]; University of Bergen, KG Jebsen and Helse Vest [P.R.N.]; Wellcome Trust Senior Investigator Awards [A.T.H. (WT098395), M.I.M. (WT098381)]; National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219); Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150) [R.M.F., R.N.B.]; 4-year studentship (Grant Code: WT083431MF) [R.C.R]; the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (grant number 669545; Develop Obese) [D.A.L.]; US National Institute of Health (grant: R01 DK10324) [D.A.L, C.L.R]; Wellcome Trust GWAS grant (WT088806) [D.A.L] and NIHR Senior Investigator Award (NF-SI-0611-10196) [D.A.L]; Wellcome Trust Institutional Strategic Support Award (WT097835MF) [M.A.T.]; The Diabetes Research and Wellness Foundation Non-Clinical Fellowship [J.T.]; Australian National Health and Medical Research Council Early Career Fellowship (APP1104818) [N.M.W.]; Daniel B. Burke Endowed Chair for Diabetes Research [S.F.A.G.]; UK Medical Research Council Unit grants MC_UU_12013_5 [R.C.R, L.P, S.R, C.L.R, D.M.E., D.A.L.] and MC_UU_12013_4 [D.M.E.]; Medical Research Council (grant: MR/M005070/1) [M.N.W., S.E.J.]; Australian Research Council Future Fellowship (FT130101709) [D.M.E] and (FT110100548) [S.E.M.]; NIHR Oxford Biomedical Research Centre (BRC); Oak Foundation Fellowship and Novo Nordisk Foundation (12955) [B.F.]; FRQS research scholar and Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics-Canadian Institute of Health Research (CIHR) [MFH]; CIHR-Frederick Banting and Charles Best Canada Graduate Scholarships [C.A.]; FRQS [L.B.]; Netherlands Organization for Health Research and Development (ZonMw-VIDI 016.136.361) [V.W.V.J.]; National Institute on Aging (R01AG29451) [J.M.M.]; 2010-2011 PRIN funds of the University of Ferrara-Holder: Prof. Guido Barbujani, Supervisor: Prof. Chiara Scapoli-and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists, '5 per mille' contribution assigned to the University of Ferrara, income tax return year 2009 and the ENGAGE Exchange and Mobility Program for ENGAGE training funds, ENGAGE project, grant agreement HEALTH-F4-2007-201413 [L.M.]; ESRC (RES-060-23-0011) [C.L.R.]; National Institute of Health Research ([S.D., M.I.M.], Senior Investigator Award (NFSI-0611-10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M]. For study-specific funding, please see Supplementary Material. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF). Publisher Copyright: © The Author(s) 2018.Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.Peer reviewe

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients

User characteristics and the effectiveness of inclusive design for older users of public access systems

Computer haben fast jeden Lebensbereich durchdrungen, was viele Vorteile - aber auch Herausforderungen - für ihre Nutzer mit sich bringt. Dies wird vor allem bei der Benutzung von Fahrkartenautomaten (FKA) oder anderer Technik im öffentlichen Raum deutlich, denn diese sollten spontan benutzbar sein, stellen gerade ältere Benutzer aber oft vor Probleme. Sind sie zu alt, um Technik zu benutzen? Diese Dissertation verfolgt zwei Ziele: Zum einen soll die Gebrauchstauglichkeit eines Fahrkartenautomaten (FKA) verbessert werden, indem zwei einander ergänzende Ansätze angewandt werden und die daraus entstehenden drei FKA-Varianten (Original, Video, Wizard) hinsichtlich der Kriterien der Gebrauchstauglichkeit Effektivität, Effizienz und Zufriedenstellung verglichen werden. Zum anderen wird der Einfluß des Alters und alterskorrelierter Benutzermerkmale auf die erfolgreiche Benutzung dieser funktional equivalenten FKA-Gestaltungsvarianten unter besonderer Berücksichtigung des Merkmals Computerwissen geschätzt. In einem zweifaktoriellen quasi-experimentellen Versuchsplan mit zwei (Alter: jung, alt) mal drei (experimentelle Bedingung: Kontrolle, Video, Wizard) Faktorstufen lösten 62 ältere (M=68 Jahre) und 62 jüngere (M=25 Jahre) Versuchsteilnehmer die selben elf Aufgaben: Die Kontrollgruppe nutzte einen simulierten FKA der BVG (Berliner Verkehrsbetriebe), die Videogruppe sah ein kurzes Instruktionsvideo bevor sie den selben FKA nutzte und die Wizardgruppe nutzte statt dessen eine umgestaltete graphische Benutzungsschnittstelle. Die Ergebnisse legen nahe, daß Technik im öffentlichen Raum durch die Integration einer minimalen Videoinstruktion oder eines aufgabenorientierten Wizards mit angemessenem Aufwand universell nutzbar gestaltet werden kann und daß nicht das chronologische Alter die erfolgreiche Nutzung des FKA beeinflußt, sondern altersbezogene Nutzermerkmale, welche gemessen werden können und sollten, um eine nutzungsgerechte Gestaltung zu ermöglichen.Computer technology has permeated almost every sphere of daily living, bringing about many advantages - and challenges - for its users. This becomes particularly apparent for older people’s use of public access systems like ticket vending machines (TVM), which should be „walk-up and use systems“ but often pose challenging problems for them. Are they too old to use IT? This thesis aims to (a) improve the usability of a ticket vending machine (TVM) following two different approaches (teach or design) and to compare the resulting three TVM designs (original, video, wizard) regarding the usability criteria effectiveness, efficiency and satisfaction, and to (b) estimate the impact of age and age-correlated user characteristics on the successful use of these functionally equivalent TVM designs with a special focus on computer literacy. In a two (young, old) by three (control, video, wizard) factorial quasi experimental research design, 62 older (M=68 years) and 62 younger (M=25 years) participants solved the same eleven tasks: The control group used a simulated TVM of the BVG (public transportation in Berlin, Germany), the video group watched a brief instructional video integrated into the same TVM before using it and the wizard group used a redesigned wizard interface instead. MANOVA indicates that video and wizard substantially improved TVM usability, increasing effectiveness for the older groups from 52% to 80% and 88% respectively. Hierarchical regression analysis revealed that user characteristics had a strong effect on effectiveness of BVG-TVM use, but a weaker effect in the video (36%) and wizard (5%) conditions (universal usability). Results suggest that integration of minimal video instruction or a task oriented wizard design can make public access systems truly universally usable with reasonable effort and that not chronological age itself predicts successful TVM use, but age related user characteristics, which can - and should - be measured and designed for

Myths About Older People’s Use of Information and Communication Technology

This paper discusses six myths common in the field of ‘human-computer interaction (HCI) and older people’. These myths are widespread among computer scientists, engineers and programmers, as well as among the general public and even older individuals themselves. We can define these myths as follows. (1) Just wait and see. Future generations of older people will use computers without problems. This myth differs from those following, as it may lead to a (dangerous) conclusion of avoidance and inactivity by integrating myths 2–6. If the other myths are accepted as being true and one assumes that the problems will eventually solve themselves, it might not seem worthwhile to expend any effort on ‘universal design’ for older people’s use of information and communication technology (ICT). However, we argue that if we do not actively and properly counteract these myths, we will perpetuate them and their grave consequences. (2) Older people are not interested in using computers. They are unaware of computer capabilities. (3) Older people consider computers as useless and unnecessary. (4) Older people lack the physical capabilities to use ICT. (5) Older people simply cannot understand interactive computing technology. (6) You can’t teach an old dog new tricks. The problem of HCI for older people is that they do not learn to use new technologies and interaction techniques. In discussing these myths, we demonstrate that each one contains a grain of truth. However, the myths are improperly overgeneralized and, therefore, often wrong. Such myths are problematic. Designers and engineers often accept them as truths and neglect older users and/or apply information and communication technologies in an age-discriminating manner. Furthermore, the myths are problematic as they lead older people to avoid computer usage (i.e. a self-fulfilling prophecy). We present evidence to support the notion that these myths may often be largely – although not completely – wrong. We then demonstrate how they can be counteracted through user-centered design, training and instruction.Peer Reviewe

The 'Ideal Homunculus':decoding neural population signals

Information processing in the nervous system involves the activity of large populations of neurons. It is possible, however, to interpret the activity of relatively small numbers of cells in terms of meaningful aspects of the environment. 'Bayesian inference' provides a systematic and effective method of combining information from multiple cells to accomplish this. It is not a model of a neural mechanism (neither are alternative methods, such as the population vector approach) but a tool for analysing neural signals. It does not require difficult assumptions about the nature of the dimensions underlying cell selectivity, about the distribution and tuning of cell responses or about the way in which information is transmitted and processed. It can be applied to any parameter of neural activity (for example, firing rate or temporal pattern). In this review we demonstrate the power of Bayesian analysis using examples of visual responses of neurons in primary visual and temporal cortices. We show that interaction between correlation in mean responses to different stimuli (signal) and correlation in response variability within stimuli (noise) can lead to marked improvement of stimulus discrimination using population responses.</p