The effects of pathogens, parasites, and familiarity on alarm cell investment in fathead minnows, pimephales promelas

Fishes in the Superorder Ostariophysi have specialized epidermal club cells that contain an alarm substance. Damage to these cells causes the release of the alarm substance which can serve as a useful indicator of predation risk for nearby conspecifics. The majority of research involving alarm substances has investigated the roles that cues play in anti-predator contexts including learned predator avoidance. In this study I tested the effects of non-predatory stressors including pathogens, pathogen conditioned water, social dynamics, and skin-burrowing parasites on epidermal variables including alarm cell investment. In experiment 1, fathead minnows, Pimephales promelas, were exposed to different levels of the pathogenic water-mold, Saprolgenia ferax to determine the effect it would have on the epidermis. Minnows exposed to Saprolgenia had significantly more alarm cells than those exposed to the control solutions. The treatments had no effect on body condition, alarm cell size, mucous cell density, mucous cell size, or epidermal thickness. In experiment 2, social dynamics were manipulated by pairing minnows with either a familiar partner or an unfamiliar individual and exposing them to Saprolgenia ferax. The treatments had no effect on body condition, alarm cell density, alarm cell size, mucous cell density, mucous cell size, or epidermal thickness. In experiment 3, minnows were exposed to either Saprolgenia or Saprolgenia conditioned water to determine whether the physical presence of zoospores was required to induce a change in epidermal properties. The treatments had no effect on body condition, alarm cell density, alarm cell size, mucous cell density, mucous cell size, or epidermal thickness; suggesting that water conditioned by Saprolgenia may be sufficient to induce a change in alarm cell investment. In experiment 4, minnows were exposed to three different infection rates of skin burrowing parasites (trematode cercariae) to determine its effect on the epidermis. Minnows exposed to high levels of tramatode cercariae had significantly more alarm cells than those exposed to either low levels or those in the control treatment. The treatments had no effect on body condition, alarm cell size, mucous cell density, mucous cell size, or epidermal thickness. In experiment 5 and 6, cultures of Saprolegnia ferax were exposed to skin extracts from various fishes. S. ferax cultures exposed to fathead minnow skin extracts, which contain alarm cells showed the least amount of growth, while cultures exposed to swordtail skin extracts, which lack alarm cells, showed an intermediate amount of growth. Cultures exposed to fathead minnow skin extracts showed the least amount of growth compared to cultures exposed to either the synthetic alarm cue or the control. The results of these experiments suggest that disease does appear to influence alarm cell investment and there appears to be some property found in fathead minnow skin that inhibits S. ferax growth

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Pan-Canadian Evaluation of Irreversible Compression Ratios (“Lossy” Compression) for Development of National Guidelines

New technological advancements including multislice CT scanners and functional MRI, have dramatically increased the size and number of digital images generated by medical imaging departments. Despite the fact that the cost of storage is dropping, the savings are largely surpassed by the increasing volume of data being generated. While local area network bandwidth within a hospital is adequate for timely access to imaging data, efficiently moving the data between institutions requires wide area network bandwidth, which has a limited availability at a national level. A solution to address those issues is the use of lossy compression as long as there is no loss of relevant information. The goal of this study was to determine levels at which lossy compression can be confidently used in diagnostic imaging applications. In order to provide a fair assessment of existing compression tools, we tested and compared the two most commonly adopted DISCOM compression algorithms: JPEG and JPEG-2000. We conducted an extensive pan-Canadian evaluation of lossy compression applied to seven anatomical areas and five modalities using two recognized techniques: objective methods or diagnostic accuracy and subjective assessment based on Just Noticeable Difference. By incorporating both diagnostic accuracy and subjective evaluation techniques, enabled us to define a range of compression for each modality and body part tested. The results of our study suggest that at low levels of compression, there was no significant difference between the performance of lossy JPEG and lossy JPEG 2000, and that they are both appropriate to use for reporting on medical images. At higher levels, lossy JPEG proved to be more effective than JPEG 2000 in some cases, mainly neuro CT. More evaluation is required to assess the effect of compression on thin slice CT. We provide a table of recommended compression ratios for each modality and anatomical area investigated, to be integrated in the Canadian Association of Radiologists standard for the use of lossy compression in medical imaging

Epidermal ‘alarm substance’ cells of fishes maintained by non-alarm functions: possible defence against pathogens, parasites and UVB radiation

Many fishes possess specialized epidermal cells that are ruptured by the teeth of predators, thus reliably indicating the presence of an actively foraging predator. Understanding the evolution of these cells has intrigued evolutionary ecologists because the release of these alarm chemicals is not voluntary. Here, we show that predation pressure does not influence alarm cell production in fishes. Alarm cell production is stimulated by exposure to skin-penetrating pathogens (water moulds: Saprolegnia ferax and Saprolegnia parasitica), skin-penetrating parasites (larval trematodes: Teleorchis sp. and Uvulifer sp.) and correlated with exposure to UV radiation. Suppression of the immune system with environmentally relevant levels of Cd inhibits alarm cell production of fishes challenged with Saprolegnia. These data are the first evidence that alarm substance cells have an immune function against ubiquitous environmental challenges to epidermal integrity. Our results indicate that these specialized cells arose and are maintained by natural selection owing to selfish benefits unrelated to predator–prey interactions. Cell contents released when these cells are damaged in predator attacks have secondarily acquired an ecological role as alarm cues because selection favours receivers to detect and respond adaptively to public information about predation

parasites and UVB radiation non-alarm functions: possible defence against pathogens, Epidermal 'alarm substance' cells of fishes maintained by References Epidermal 'alarm substance' cells of fishes maintained by non-alarm functions: possible defence again

Many fishes possess specialized epidermal cells that are ruptured by the teeth of predators, thus reliably indicating the presence of an actively foraging predator. Understanding the evolution of these cells has intrigued evolutionary ecologists because the release of these alarm chemicals is not voluntary. Here, we show that predation pressure does not influence alarm cell production in fishes. Alarm cell production is stimulated by exposure to skin-penetrating pathogens (water moulds: Saprolegnia ferax and Saprolegnia parasitica), skin-penetrating parasites (larval trematodes: Teleorchis sp. and Uvulifer sp.) and correlated with exposure to UV radiation. Suppression of the immune system with environmentally relevant levels of Cd inhibits alarm cell production of fishes challenged with Saprolegnia. These data are the first evidence that alarm substance cells have an immune function against ubiquitous environmental challenges to epidermal integrity. Our results indicate that these specialized cells arose and are maintained by natural selection owing to selfish benefits unrelated to predator-prey interactions. Cell contents released when these cells are damaged in predator attacks have secondarily acquired an ecological role as alarm cues because selection favours receivers to detect and respond adaptively to public information about predation