Intrinsically photosensitive retinal ganglion cells (ipRGCs) are inner retinal photoreceptors that mediate non-image-forming visual functions, e.g. pupillary constriction, regulation of pineal melatonin release, and circadian photoentrainment. Five types of ipRGCs were recently discovered in mouse, but whether they exist in other mammals remained unknown. We report that the rat also has five types of ipRGCs, whose morphologies match those of mouse ipRGCs; this is the first demonstration of all five cell types in a non-mouse species. Through immunostaining and λmax measurements, we showed that melanopsin is likely the photopigment of all rat ipRGCs. The various cell types exhibited diverse spontaneous spike rates, with the M1 type spiking the least and M4 spiking the most, just like we had observed for their mouse counterparts. Also similar to mouse, all ipRGCs in rat generated not only sluggish intrinsic photoresponses but also fast, synaptically driven ones. However, we noticed two significant differences between these species. First, whereas we learned previously that all mouse ipRGCs had equally sustained synaptic light responses, rat M1 cells’ synaptic photoresponses were far more transient than those of M2–M5. Since M1 cells provide all input to the circadian clock, this rat-versus-mouse discrepancy could explain the difference in photoentrainment threshold between mouse and other species. Second, rat ipRGCs’ melanopsin-based spiking photoresponses could be classified into three varieties, but only two were discerned for mouse ipRGCs. This correlation of spiking photoresponses with cell types will help researchers classify ipRGCs in multielectrode-array (MEA) spike recordings.

Rationale: The Epic Deterioration Index (EDI) is a proprietary prediction model implemented in over 100 U.S. hospitals that was widely used to support medical decision-making during the coronavirus disease (COVID-19) pandemic. The EDI has not been independently evaluated, and other proprietary models have been shown to be biased against vulnerable populations. Objectives: To independently evaluate the EDI in hospitalized patients with COVID-19 overall and in disproportionately affected subgroups. Methods: We studied adult patients admitted with COVID-19 to units other than the intensive care unit at a large academic medical center from March 9 through May 20, 2020. We used the EDI, calculated at 15-minute intervals, to predict a composite outcome of intensive care unit–level care, mechanical ventilation, or in-hospital death. In a subset of patients hospitalized for at least 48 hours, we also evaluated the ability of the EDI to identify patients at low risk of experiencing this composite outcome during their remaining hospitalization. Results: Among 392 COVID-19 hospitalizations meeting inclusion criteria, 103 (26%) met the composite outcome. The median age of the cohort was 64 (interquartile range, 53–75) with 168 (43%) Black patients and 169 (43%) women. The area under the receiver-operating characteristic curve of the EDI was 0.79 (95% confidence interval, 0.74–0.84). EDI predictions did not differ by race or sex. When exploring clinically relevant thresholds of the EDI, we found patients who met or exceeded an EDI of 68.8 made up 14% of the study cohort and had a 74% probability of experiencing the composite outcome during their hospitalization with a sensitivity of 39% and a median lead time of 24 hours from when this threshold was first exceeded. Among the 286 patients hospitalized for at least 48 hours who had not experienced the composite outcome, 14 (13%) never exceeded an EDI of 37.9, with a negative predictive value of 90% and a sensitivity above this threshold of 91%. Conclusions: We found the EDI identifies small subsets of high-risk and low-risk patients with COVID-19 with good discrimination, although its clinical use as an early warning system is limited by low sensitivity. These findings highlight the importance of independent evaluation of proprietary models before widespread operational use among patients with COVID-19.

Introduction:The coronavirus disease 2019 pandemic is straining the capacity of U.S. healthcare systems. Accurately identifying subgroups of hospitalized COVID-19 patients at high-and low-risk for complications would assist in directing resources.Objective: To validate the Epic Deterioration Index (EDI), a predictive model implemented in over 100 U.S. hospitals that has been recently promoted for use in COVID-19 patients. Methods:We studied adult patients admitted with COVID-19 to non-ICU level care at a large academic medical center from March 9 through April 7, 2020. We used the EDI, calculated at 15-minute intervals, to predict a composite adverse outcome of ICU-level care, mechanical ventilation, or death during the hospitalization. In a subset of patients hospitalized for at least 48 hours, we also evaluated the ability of the EDI (range 0-100) to identify patients at low risk of experiencing this composite outcome during their remaining hospitalization. We evaluated model discrimination and calibration using both raw EDI scores and their slopes.Results: Among 174 COVID-19 patients meeting inclusion criteria, 61 (35%) experienced the composite outcome. Area under the receiver-operating-characteristic curve (AUC) of the EDI was 0.76 (95% CI 0.68-0.84). Patients who met or exceeded an EDI of 64.8 made up 17% of the study cohort and had an 80% probability of experiencing the outcome during their hospitalization with a median lead time of 28 hours from when the threshold was first exceeded to the outcome. Employing the EDI slope lowered the AUCs to 0.68 (95% CI 0.60-0.77) and 0.67 (95% CI 0.59-0.75) for slopes calculated over 4 and 8 hours, respectively. In a subset of 109 patients hospitalized for at least 48 hours and who had not experienced the composite outcome, 14 (13%) patients who never exceeded an EDI of 37.9 had a 93% probability of not experiencing the outcome throughout the rest of their hospitalization, suggesting low risk.

SUMMARY Retinal neurons exhibit sustained vs. transient light responses, which are thought to encode low- and high-frequency stimuli respectively. This dichotomy has been recognized since the earliest intracellular recordings from the 1960s, but the underlying mechanisms are not yet fully understood. We report that in the ganglion cell layer of rat retinas, all spiking amacrine interneurons with sustained ON photoresponses receive gap-junction input from intrinsically photosensitive retinal ganglion cells (ipRGCs), recently discovered photoreceptors that specialize in prolonged irradiance detection. We have identified three morphological varieties of such ipRGC-driven displaced amacrine cells: 1) monostratified cells with dendrites terminating exclusively in sublamina S5 of the inner plexiform layer; 2) bistratified cells with dendrites in both S1 and S5; and 3) polyaxonal cells with dendrites and axons stratifying in S5. Most of these amacrine cells are wide-field, although some are medium-field. The three classes respond to light differently, suggesting they probably perform diverse functions. These results demonstrate that ipRGCs are a major source of tonic visual information within the retina and exert widespread intraretinal influence. They also add to recent evidence that ganglion cells signal not only to the brain.