Developing an experimental challenge model for gill disease caused by gelatinous zooplankton

Harmful zooplankton, such as jellyfish or cnidarians, play an important role in gill disease development, but there is a lack of scientific and technical understanding of the interactions between gelatinous zooplankton and fish gills that can only be obtained through a lab-based challenge model using lab-reared organisms. Such a model does not exist, so we set out to develop one. We were able to produce a pre-determined quantity of gelatinous zooplankton at a pre-determined point in time, transport them, and challenge salmon with these live gelatinous zooplankton, and present initial results. Currently we are optimizing the model. When developed further, the model is intended to be used as a tool to improve understanding of the role of gelatinous zooplankton in gill disease, identify host responses and assess techniques to mitigate the effects of gelatinous zooplankton on gill health

Developing an experimental challenge model for gill disease caused by gelatinous zooplankton

Harmful zooplankton, such as jellyfish or cnidarians, play an important role in gill disease development, but there is a lack of scientific and technical understanding of the interactions between gelatinous zooplankton and fish gills that can only be obtained through a lab-based challenge model using lab-reared organisms. Such a model does not exist, so we set out to develop one. We were able to produce a pre-determined quantity of gelatinous zooplankton at a pre-determined point in time, transport them, and challenge salmon with these live gelatinous zooplankton, and present initial results. Currently we are optimizing the model. When developed further, the model is intended to be used as a tool to improve understanding of the role of gelatinous zooplankton in gill disease, identify host responses and assess techniques to mitigate the effects of gelatinous zooplankton on gill health

Developing an experimental challenge model for gill disease caused by gelatinous zooplankton

Harmful zooplankton, such as jellyfish or cnidarians, play an important role in gill disease development, but there is a lack of scientific and technical understanding of the interactions between gelatinous zooplankton and fish gills that can only be obtained through a lab-based challenge model using lab-reared organisms. Such a model does not exist, so we set out to develop one. We were able to produce a pre-determined quantity of gelatinous zooplankton at a pre-determined point in time, transport them, and challenge salmon with these live gelatinous zooplankton, and present initial results. Currently we are optimizing the model. When developed further, the model is intended to be used as a tool to improve understanding of the role of gelatinous zooplankton in gill disease, identify host responses and assess techniques to mitigate the effects of gelatinous zooplankton on gill health

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.  Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).  Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.  Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker

Association of Age with Mortality and Virological and Immunological Response to Antiretroviral Therapy in Rural South African Adults

OBJECTIVE: To assess whether treatment outcomes vary with age for adults receiving antiretroviral therapy (ART) in a large rural HIV treatment cohort. DESIGN: Retrospective cohort analysis using data from a public HIV Treatment & Care Programme. METHODS: Adults initiating ART 1(st) August 2004-31(st) October 2009 were stratified by age at initiation: young adults (16-24 years) mid-age adults (25-49 years) and older (≥50 years) adults. Kaplan-Meier survival analysis was used to estimate mortality rates and age and person-time stratified Cox regression to determine factors associated with mortality. Changes in CD4 cell counts were quantified using a piecewise linear model based on follow-up CD4 cell counts measured at six-monthly time points. RESULTS: 8846 adults were included, 808 (9.1%) young adults; 7119 (80.5%) mid-age adults and 919 (10.4%) older adults, with 997 deaths over 14,778 person-years of follow-up. Adjusting for baseline characteristics, older adults had 32% excess mortality (p = 0.004) compared to those aged 25-49 years. Overall mortality rates (MR) per 100 person-years were 6.18 (95% CI 4.90-7.78); 6.55 (95% CI 6.11-7.02) and 8.69 (95% CI 7.34-10.28) for young, mid-age and older adults respectively. In the first year on ART, for older compared to both young and mid-aged adults, MR per 100 person-years were significantly higher; 0-3 months (MR: 27.1 vs 17.17 and 21.36) and 3-12 months (MR: 9.5 vs 4.02 and 6.02) respectively. CD4 count reconstitution was lower, despite better virological response in the older adults. There were no significant differences in MR after 1 year of ART. Baseline markers of advanced disease were independently associated with very early mortality (0-3 months) whilst immunological and virological responses were associated with mortality after 12 months. CONCLUSIONS: Early ART initiation and improving clinical care of older adults are required to reduce high early mortality and enhance immunologic recovery, particularly in the initial phases of ART

Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis

Background The public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods Using a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. Results The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions Advances in the treatment of COVID-19 to date have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority