The Human Electro-oculogram: Interaction of Light and Alcohol

PURPOSE. To investigate the production of the voltage changes evoked in the retinal pigment epithelium (RPE) by light and alcohol and the interaction of these agents. METHODS. The eye movement potential in humans was intermittently recorded to standard horizontal excursions for long periods during which either retinal illumination was altered or ethyl alcohol was administered by the oral, intragastric, or intravenous route. In other experiments, both light and alcohol were administered. RESULTS. Alcohol and light produced near identical corneofundal voltage changes (positive and then negative) over more than 40 minutes. Differences in timing between alcohol and light increases are explicable by the delays in alcohol absorption. Weak background light suppressed the effect of light steps, and low levels of background alcohol suppressed the response to subsequent doses. Backgrounds of one agent did not affect the voltage changes caused by the other. Minimal alcohol effects were seen after administration of 1 g orally or 270 mg intravenously-that is, doses that produced undetectable changes in breath alcohol. The semisaturating oral dose was approximately 20 mg/kg. CONCLUSIONS. Alcohol and light act through separate pathways to form a final common pathway inside the RPE cell that is responsible for triggering the timing of the slow oscillatory changes of EOG voltage. The sensitivity and duration with which alcohol affects the RPE are comparable with the effect of melatonin or dopamine, although only the former interacts with light similarly to alcohol. Transient modulation of the acetylcholine (Ach) neuronal receptor occurs at similar sensitivity, but all other known actions of alcohol require higher concentrations than this RPE action. (Invest Ophthalmol Vis Sci. 2000;41:2722-2729 S ince the original descriptions of the electro-oculogram (EOG) in humans, 1-4 intraretinal microelectrode recordings 5-10 have elucidated the underlying mechanisms. Light adaptation of the retina changes the quantity of an unknown substance or substances, probably produced by photoreceptors, that diffuses to the apical processes of the retinal pigment epithelium (RPE) where it binds to membrane-bound chemical receptors. These then liberate an intracellular second messenger that ultimately depolarizes the basolateral surface of the RPE cells, causing a light-induced increase in the corneofundal potential (hereafter termed light rise), by increasing the chloride conductance. 11 The external and internal transmitters are unknown, as is the relationship between the transmitter concentration and the stereotyped voltage changes. Thus, the time course of the concentration changes of the external or the internal transmitter may determine the timing of the light rise and the subsequent oscillations. The EOG remains a useful clinical test, 12-18 because it offers an overview of the functioning of photoreceptors, subretinal space, and RPE, but because light is used to provoke the voltage changes, retinal and RPE dysfunction cannot be separated. Therefore, other agents, such as bicarbonate ions, acetazolamide, and hyperosmotic solutions, which act directly on the RPE, have been investigated. 18 -22 All have been found to cause a slow decrease in corneofundal potential. Previous experiments METHODS Subjects Three students aged 20 to 25 years and the authors (seventh decade) gave informed consent, and the experimental protocols complied with the Helsinki declaration. Recording Techniques Five-millimeter chloride-coated silver disc electrodes were placed on each temple, near the lateral canthi, and a similar earth electrode was placed on the forehead. The recording was bitemporal (i.e., the voltages were generated by both eyes). Standard 30°horizontal eye movements were made at two per From the Applie

A Utility Framework for COVID-19 Online Forward Triage Tools: A Swiss Telehealth Case Study.

The SARS-CoV-2 pandemic caused a surge in online tools commonly known as symptom checkers. The purpose of these symptom checkers was mostly to reduce the health system burden by providing worried people with testing criteria, where to test and how to self-care. Technical, usability and organizational challenges with regard to online forward triage tools have also been reported. Very few of these online forward triage tools have been evaluated. Evidence for decision frameworks may be of particular value in a pandemic setting where time frames are restricted, uncertainties are ubiquitous and the evidence base is changing rapidly. The objective was to develop a framework to evaluate the utility of COVID-19 online forward triage tools. The development of the online forward triage tool utility framework was conducted in three phases. The process was guided by the socio-ecological framework for adherence that states that patient (individual), societal and broader structural factors affect adherence to the tool. In a further step, pragmatic incorporation of themes on the utility of online forward triage tools that emerged from our study as well as from the literature was performed. Seven criteria emerged; tool accessibility, reliability as an information source, medical decision-making aid, allaying fear and anxiety, health system burden reduction, onward forward transmission reduction and systems thinking (usefulness in capacity building, planning and resource allocation, e.g., tests and personal protective equipment). This framework is intended to be a starting point and a generic tool that can be adapted to other online forward triage tools beyond COVID-19. A COVID-19 online forward triage tool meeting all seven criteria can be regarded as fit for purpose. How useful an OFTT is depends on its context and purpose

The Electro-oculographic Responses to Alcohol and Light in a Series of Patients with Retinitis Pigmentosa

PURPOSE. Alcohol produces changes in the electro-oculogram (EOG) similar to those caused by light, but indirect evidence indicates that alcohol directly affects the retinal pigment epithelium (RPE). An investigation of the alcohol-induced increase (termed the alcohol rise in this study) in patients with disease of the photoreceptors was therefore of interest. METHODS. Standard EOGs were recorded after oral administration of alcohol in a group of patients with retinitis pigmentosa (RP). RESULTS. The average response of 17 patients to alcohol was a slow decrease of potential, which contrasts with the normal alcohol rise. In patients with considerable residual peripheral field, alcohol produced a small increase of voltage, followed by a prolonged decrease. The slower decrease in the EOG voltage was evident in patients with small fields and could be seen even in those who had lost all visual function. Light caused small increments of EOG voltage (termed light rises), again related to the field size. CONCLUSIONS. It is probable that the intracellular signaling system that causes the alcohol and light rises is lost in RP. (Invest Ophthalmol Vis Sci. 2000;41:2730 -2734 T he light-induced increase (termed light rise in this study) of the EOG is produced by the liberation of an unknown substance from the retina, which has been shown to affect second-messenger systems in the apical membrane of the RPE. 1,2 Results in a companion study 3 demonstrated that small oral doses of alcohol produce an effect on the EOG that is indistinguishable from that evoked by light, except for a delay due to the time required to absorb alcohol from the gut. The interactions between alcohol and light were investigated, and the inference from the results was that alcohol (similar to other agents) is able to alter the basolateral conductance of the RPE by a pathway that probably involves second messengers, but not the retina. 5 Because many of the photoreceptors in such retinas are nonfunctional, the failure to release a light rise substance is not surprising, and the EOG light rise is known to be greatly reduced. METHODS Seventeen patients were recruited by contacting the British Retinitis Pigmentosa Society, by letter and on its Web sites, and asking for volunteers, who were then given a written explanation of the proposed test, so they could provide informed consent. All the patients were under the care of specialist eye departments. One patient was excluded because he had bilateral cataract extraction with ocular implants. We did not accept patients under 18 years of age or those with other systemic conditions. The age range was between 22 and 74 years. The work was performed in accordance with the Declaration of Helsinki. Standard EOG recordings of 30°horizontal eye movements were made as described in a previous article, 3 except in the case of patients with very reduced vision, when the patients made extreme eye movements that were measured as 90°. The (ethyl) alcohol was administered after subjects fasted for more than 12 hours (0.3 g/kg, 20% wt/vol in water, drunk in 15 seconds). Other clinical tests (fields, electroretinograms [ERGs]) were performed in a standard fashion in patients with the best preserved vision to confirm clinical diagnoses. ERGs were elicited by equipment (a LED-powered miniganzfeld stimulus) similar to that already described

Effects and utility of an online forward triage tool during the SARS-CoV-2 pandemic: a mixed method study and patient perspectives, Switzerland.

OBJECTIVE To assess the effects (quantitatively) and the utility (qualitatively) of a COVID-19 online forward triage tool (OFTT) in a pandemic context. DESIGN A mixed method sequential explanatory study was employed. Quantitative data of all OFTT users, between 2 March 2020 and 12 May 2020, were collected. Second, qualitative data were collected through key informant interviews (n=19) to explain the quantitative findings, explore tool utility, user experience and elicit recommendations. SETTING The working group e-emergency medicine at the emergency department developed an OFTT, which was made available online. PARTICIPANTS Participants included all users above the age of 18 that used the OFTT between 2 March 2020 and 12 May 2020. INTERVENTION An OFTT that displayed the current test recommendations of the Federal Office of Public Health on whether someone needed testing for COVID-19 or not. No diagnosis was provided. RESULTS In the study period, 6272 users consulted our OFTT; 40.2% (1626/4049) would have contacted a healthcare provider had the tool not existed. 560 participants consented to a follow-up survey and provided a valid email address. 31.4% (176/560) participants returned a complete follow-up questionnaire. 84.7% (149/176) followed the recommendations given. 41.5% (73/176) reported that their fear was allayed after using the tool. Qualitatively, seven overarching themes emerged namely (1) accessibility of tool, (2) user-friendliness of tool, (3) utility of tool as an information source, (4) utility of tool in allaying fear and anxiety, (5) utility of tool in medical decision-making (6) utility of tool in reducing the potential for onward transmissions and (7) utility of tool in reducing health system burden. CONCLUSION Our findings demonstrated that a COVID-19 OFTT does not only reduce the health system burden but can also serve as an information source, reduce anxiety and fear, reduce potential for cross infections and facilitate medical decision-making

Use of telehealth and outcomes before a visit to the emergency department: a cross-sectional study on walk-in patients in Switzerland

AIMS OF THE STUDY An increasing number of patients are using telehealth before contacting the healthcare system. If we are to optimise future telehealth strategies and adequately respond to patient needs, we need to know more about the frequency and characteristics of telehealth use. Our objectives were (i) to investigate whether patients use telehealth before consulting the emergency department (ED), (ii) to compare patients with and without use of telehealth, and (iii) to investigate adherence, confidence and satisfaction. MATERIALS AND METHODS A survey was conducted among ED walk-in patients at a tertiary university hospital in Switzerland. Eligible patients were questioned about their use of telehealth before current presentation, during 30 shifts from 23 October to 15 December 2019. RESULTS A total of 183 (43.9%) of 417 surveyed patients used telehealth, with the telephone being the most commonly used modality, especially among elderly patients. Patients using telehealth were more likely to be male (53.5%, p = 0.001) and were similar in age to non-users. Telehealth users tended to be better educated. Telehealth was predominantly used for semi-urgent non-traumatic diseases that did not lead to hospitalisation. All age groups expressed satisfaction with telehealth, trusted the recommendations and adhered to them. The main reason for "non-use" of telehealth was lack of knowledge. CONCLUSIONS Lack of knowledge about telehealth opportunities and barriers in specific patient groups should be addressed to include all patients, and thus to exploit telehealth’s many advantages

The Utility of an Online Forward Triage Tool During the SARS-CoV-2 Pandemic: Health Care Provider and Health Authority Perspectives.

Introduction The SARS CoV-2 pandemic poses major challenges not only to patients but also to health care professionals and policy-makers, with rapidly changing, sometimes complex, recommendations, and guidelines to the population. Online forward triage tools (OFTT) got a major boost from the pandemic as they helped with the implementation and monitoring of recommendations. Methods A multiphase mixed method sequential explanatory study design was employed. Quantitative data were collected first and informed the qualitative interview guides. Video interviews were held with key informants (health care providers and health authorities) between 2 September and 10 December 2020. Audio-recordings were transcribed verbatim, coded thematically and compared with patient perspectives (framework). Objectives To explore the perspectives of health care providers and authorities in Canton Bern on the utility of a COVID-19 OFTT, as well as elicit recommendations for telehealth in future. Results The following themes emerged; (i) accessibility (ii) health system burden reduction (iii) utility in preventing onward transmission (iv) utility in allaying fear and anxiety (v) medical decision-making utility (vi) utility as information source (vii) utility in planning and systems thinking. The health care providers and health authorities further provided insights on potential barriers and facilitators of telehealth in future. Conclusion Similar to patients, health care providers acknowledge the potential and utility of the COVID-19 OFTT particularly as an information source and in reducing the health system burden. Data privacy, doctor-patient relationship, resistance to change, regulatory, and mandate issues, and lack of systems thinking were revealed as barriers to COVID-19 OFTT utility

Globular Cluster Abundances from High-Resolution, Integrated-Light Spectroscopy. III. The Large Magellanic Cloud: Fe and Ages

In this paper we refine our method for the abundance analysis of high resolution spectroscopy of the integrated light of unresolved globular clusters (GCs). This method was previously demonstrated for the analysis of old ($>$10 Gyr) Milky Way GCs. Here we extend the technique to young clusters using a training set of 9 GCs in the Large Magellanic Cloud (LMC). Depending on the signal-to-noise ratio of the data, we use 20-100 Fe lines per cluster to successfully constrain the ages of old clusters to within a $\sim$5 Gyr range, the ages of $\sim$2 Gyr clusters to a 1-2 Gyr range, and the ages of the youngest clusters (0.05-1 Gyr) to a $\sim$200 Myr range. We also demonstrate that we can measure [Fe/H] in clusters with any age less than 12 Gyrs with similar or only slightly larger uncertainties (0.1-0.25 dex) than those obtained for old Milky Way GCs (0.1 dex); the slightly larger uncertainties are due to the rapid evolution in stellar populations at these ages. In this paper, we present only Fe abundances and ages. In the next paper in this series, we present our complete analysis of the $\sim 20$ elements for which we are able to measure abundances. For several of the clusters in this sample, there are no high resolution abundances in the literature from individual member stars; our results are the first detailed chemical abundances available. The spectra used in this paper were obtained at Las Campanas with the echelle on the du Pont Telescope and with the MIKE spectrograph on the Magellan Clay Telescope.Comment: 34 pages, accepted for publication in Ap

Discovery of Precursor LBV Outbursts in Two Recent Optical Transients: The Fitfully Variable Missing Links UGC 2773-OT and SN 2009ip

We present progenitor-star detections, light curves, and optical spectra of SN2009ip and the 2009 optical transient in UGC2773 (U2773-OT), which were not genuine SNe. Precursor variability in the decade before outburst indicates that both of the progenitor stars were LBVs. Their pre-outburst light curves resemble the S Doradus phases that preceded giant eruptions of eta Carinae and SN1954J (V12 in NGC2403), with intermediate progenitor luminosities. HST detections a decade before discovery indicate that the SN2009ip and U2773-OT progenitors were supergiants with likely initial masses of 50-80 Msun and \ga20 Msun, respectively. Both outbursts had spectra befitting known LBVs, although in different physical states. SN 2009ip exhibited a hot LBV spectrum with characteristic speeds of 550 km/s, plus faster material up to 5000 km/s, resembling the slow Homunculus and fast blast wave of eta Carinae. U2773-OT shows a forest of narrow absorption and emission lines comparable to that of S Dor in its cool state, plus [CaII] emission and an IR excess indicative of dust, similar to SN2008S and N300-OT. [CaII] emission is probably tied to a dusty pre-outburst environment, and not the outburst mechanism. SN2009ip and U2773-OT may provide a critical link between historical LBV eruptions, while U2773-OT may provide a link between LBVs and SN2008S and N300-OT. Future searches will uncover more examples of precursor LBV variability of this kind, providing key clues that may help unravel the instability driving LBVs.Comment: 18 pages, 13 Figures, accepted AJ. added significant material while revising after referee repor

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1.

BACKGROUND: Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery. RESULTS: Using the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients. CONCLUSIONS: These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging