Onset and Decline Rates of Marine Heatwaves: Global Trends, Seasonal Forecasts and Marine Management

Changing ocean conditions due to anthropogenic climate change, particularly the increasing severity and frequency of extreme events, are a growing concern for a range of marine sectors. Here we explore the global trends in marine heatwaves (MHWs), specifically onset and decline rates, two metrics which describe how quickly a MHW will emerge or disappear from a location. These rates determine the reaction window—the start of a MHW event to peak MHW temperatures—and the coping window—time from peak temperatures to the end of an event—two important time periods relevant to a marine decision-maker. We show that MHW onset and decline rates are fastest in dynamic ocean regions and that overall, the global trend in onset rate is greater than the global trend in decline rate. We map ocean regions where these rates are changing together with forecast skill from a seasonal dynamical model (ACCESS-S). This analysis highlights areas where the length of the preparation window for impending MHWs is increased by using forecasts, and areas where marine decision-makers should be prepared for rapid responses based on realtime observations as MHWs evolve. In regions such as south Africa and Kerguelen, northwest Atlantic, northwest Pacific, southwest South Atlantic and off Australian east coast where rapid median onset and decline rates are observed, there is also a positive trend in onset and decline rates i.e., MHWs are developing and declining more rapidly. This will be a concern for many decision-makers operating in these regions.

Cerebellar Disorders and Ataxias: Acquired Disorders

Disorders of the cerebellum or its connections can result in ataxia characterized by imbalance and incoordination of gait, limbs, speech, and eye movements. The pathologic changes may be confined to the cerebellum or simultaneously affect other parts of the central nervous system or peripheral nervous system. Ataxias are generally classified as acquired, inherited, or sporadic. The differential diagnosis is broad and daunting. However, a detailed history and examination can rapidly narrow the list. Key information includes age at onset; rate of disease progression; family history; presence of pure cerebellar syndrome or other neurologic signs; other systemic features; and imaging findings.

Estimation of the Onset Rate and the Number of Asymptomatic Patients of COVID-19 From the Proportion of Untraceable Patients

A simple method is devised to estimate the onset rate of COVID-19 from the proportion of untraceable patients tested positive, which allows us to obtain the number of asymptomatic patients, the number of infectious patients and the effective reproduction number. The recent data in Tokyo indicate that there are about six times as many infectious patients in the city as the daily confirmed new cases. It is shown that a quarantine measure on non-symptomatic patients is critically important in controlling the pandemic.

Estimation of the onset rate and the number of asymptomatic patients of COVID-19 from the proportion of untraceable patients

A simple method is devised to estimate the onset rate of COVID-19 from the proportion of untraceable patients tested positive, which allows us to obtain the number of asymptomatic patients, the number of infectious patients and the effective reproduction number. The recent data in Tokyo indicate that there are about six times as many infectious patients in the city as the daily confirmed new cases. It is shown that a quarantine measure on non-symptomatic patients is critically important in controlling the pandemic.

Compound-specific, concentration-independent biophysical properties of sodium channel inhibitor mechanism of action

We have developed an automated patch-clamp protocol that allows high information content screening of sodium channel inhibitor compounds. We have observed that individual compounds had their specific signature patterns of inhibition, which were manifested irrespective of the concentration. Our aim in this study was to quantify these properties. Primary biophysical data, such as onset rate, the shift of the half inactivation voltage, or the delay of recovery from inactivation, are concentration-dependent. We wanted to derive compound-specific properties, therefore, we had to neutralize the effect of concentration. This study describes how this is done, and shows how compound-specific properties reflect the mechanism of action, including binding dynamics, cooperativity, and interaction with the membrane phase. We illustrate the method using four well-known sodium channel inhibitor compounds, riluzole, lidocaine, benzocaine, and bupivacaine. Compound-specific biophysical properties may also serve as a basis for deriving parameters for kinetic modeling of drug action. We discuss how knowledge about the mechanism of action may help to predict the frequency-dependence of individual compounds, as well as their potential persistent current component selectivity. The analysis method described in this study, together with the experimental protocol described in the accompanying paper, allows screening for inhibitor compounds with specific kinetic properties, or with specific mechanisms of inhibition.

POS0517 A LONGITUDINAL STUDY OF SARCOPENIA, LOCOMOTIVE SYNDROME, AND FRAILTY IN PATIENTS WITH RHEUMATOID ARTHRITIS: FROM THE CHIKARA STUDY

Background:Rheumatoid arthritis (RA) patients have a high frequency of sarcopenia, and they commonly have reduced physical function. We previously reported that the prevalence of sarcopenia was 28%, that of frailty was 18.9%, and that of pre-frailty was 38.9% in RA patients1,2, and 13.2% of RA patients developed sarcopenia within a year 3.Objectives:To investigate the risk factors for new onset of sarcopenia, locomotive syndrome, and frailty in patients with RA and the course of each disease.Methods:Two-year follow-up data from the rural group of the prospective, observational CHIKARA study were used. Sarcopenia was diagnosed using the criteria of the Asian Working Group for Sarcopenia 2014, locomotive syndrome was diagnosed using locomotive 5, and frailty was diagnosed using the basic checklist. New onset of the disease over the 2-year follow-up period was studied, excluding cases that had the disease at baseline. Improvement was defined as cases with disease at baseline that no longer met the diagnostic criteria after 2 years. Differences in the characteristics of each disease were tested using the Chi-squared test and the paired t-test.Results:The 81 patients with RA (82.7% female) had mean age 66.9±11.5 years, mean DAS28-ESR 2.9±1.2, methotrexate use in 81.5% (with a dose of 9.9±2.7 mg/week), and glucocorticoid (GC) use in 22.2% (with a dose of 3.1±1.7 mg/week). The baseline prevalence was 44.4% for sarcopenia, 35.8% for locomotive syndrome, and 25.9% for frailty, and the new onset rate was 4.4% for sarcopenia, 15.4% for locomotive syndrome, and 13.3% for frailty. Of the patients with each disease at baseline, 36.1% had sarcopenia, 20.7% had locomotive syndrome, and 33.3% had frailty, and of those with each disease at 2 years, 36.1% had sarcopenia, 20.7% had locomotive syndrome, and 33.3% had frailty. The new onset sarcopenia and locomotive syndrome groups had significantly higher rates of GC use (p=0.036, p=0.007, paired t-test) and significantly higher doses (p=0.01, p=0.001, paired t-test) than the groups without new onset sarcopenia and locomotive syndrome. High baseline disease activity was an independent predictor of new onset of locomotive syndrome on multivariate logistic regression analysis (OR=3.21, p=0.015).Conclusion:The new onset rates at 2 years were 4.4% for sarcopenia, 15.4% for locomotive syndrome, and 13.3% for frailty. In the new onset sarcopenia and locomotive syndrome groups, both GC use and dosage were significantly higher.References:[1]Tada M, et al. Matrix metalloprotease 3 is associated with sarcopenia in rheumatoid arthritis - results from the CHIKARA study. Int J Rheum Dis. 2018 Nov;21(11):1962-1969.[2]Tada M, et al. Correlation between frailty and disease activity in patients with rheumatoid arthritis: Data from the CHIKARA study. Geriatr Gerontol Int. 2019 Dec;19(12):1220-1225.[3]Yamada Y, et al. Glucocorticoid use is an independent risk factor for developing sarcopenia in patients with rheumatoid arthritis: from the CHIKARA study. Clin Rheumatol. 2020 Jun;39(6):1757-1764.Disclosure of Interests:None declared

Onset rate and intensity of signs of organophosphate poisoning related to paraoxon dose and survival in rats

Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning. Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period. Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously) and PR of atropine was 2.73. Dose-dependent, piloerection occurred more often (p = 0.009) and at higher intensity (p = 0.016) at higher doses. Fasciculations, tremor, seizures and ataxia occurred significantly earlier at higher doses of paraoxon (p = 0.015, 0.002, 0.021 and 0.016, respectively), as well as the intensity of seizure, tremor and fasciculation. Piloerection (p = 0.002) and seizures occurred more frequently (p = 0.009) in non-survivors. Fasciculations, tremor, seizures and ataxia occurred significantly earlier and at higher intensity in non-survivors (p < 0.001, for all parameters), as well as dyspnoea (p = 0.009 and p = 0.048). In atropine-protected rats, nicotinic effects persevered, so they were the prognostic parameter of the severity of the poisoning. Conclusion: Seizures and fasciculations followed by tremor were strong prognostic parameters of the probability of lethal outcome of paraoxon poisoning. Also, the mentioned poisoning signs were with their intensity and speed of occurrence in a clear positive correlation with the administered dose of paraoxon. Even at high doses of paraoxon, atropine blocked the muscarinic (but not nicotinic) effects and somewhat mitigated the CNS toxic effects.

Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy

Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.