Fibrinolysis in a lipid environment: modulation through release of free fatty acids

Background: Thrombolysis is conventionally regarded as dissolution of the fibrin matrix of thrombi by plasmin, but the structure of clots in vivo includes additional constituents (proteins, phospholipids) that modulate their solubilization. Objective: We examined the presence of free fatty acids in thrombi and their effects on distinct stages of fibrinolysis (plasminogen activation, plasmin activity). Methods and Results: Using the fluorescent probe acrylodated intestinal fatty acid-binding protein, variable quantities (up to millimolar concentrations) of free fatty acids were demonstrated in surgically removed human thrombi. Oleic acid at relevant concentrations reversibly inhibits more than 90% of the amidolytic activity of plasmin on a synthetic substrate (Spectrozyme PL), but only partially inhibits its fibrinolytic activity measured using turbidimetry. Chromogenic assays detecting the generated plasmin activity show that plasminogen activation by tissue-type plasminogen activator (t-PA) is completely blocked by oleic acid in the fluid phase, but is accelerated on a fibrin matrix. A recombinant derivative of t-PA (reteplase) develops higher fibrin specificity in the presence of oleic acid, because both the inhibition of plasminogen activation in free solution and its enhancement on fibrin template are stronger than with wild-type t-PA. Conclusion: Through the stimulation of plasminogen activation on a fibrin template and the inhibition of plasminogen activators and plasmin in the fluid phase, free fatty acids confine the action of fibrinolytic proteases to the site of clotting, where they partially oppose the thrombolytic barrier function of phospholipids

SlowMo, a digital therapy targeting reasoning in paranoia, versus treatment as usual in the treatment of people who fear harm from others: study protocol for a randomised controlled trial

Background: Paranoia is one of the most common symptoms of schizophrenia-spectrum disorders, and is associated with significant distress and disruption to the person’s life. Developing more effective and accessible psychological interventions for paranoia is a clinical priority. Our research team has approached this challenge in two main ways: firstly, by adopting an interventionist causal approach to increase effectiveness and secondly, by incorporating user-centred inclusive design methods to enhance accessibility and usability. Our resultant new digital intervention, SlowMo, intensively targets a reasoning style associated with paranoia, fast thinking, characterised by jumping to conclusions and belief inflexibility. It consists of an easy-to-use, enjoyable and memorable digital interface. An interactive web-based app facilitates delivery of face-to-face meetings which is then synchronised with an innovative mobile app for use in daily life. Methods/Design: We aim to test the clinical efficacy of SlowMo over 24 weeks to determine the mechanisms through which it reduces paranoia, and to identify participant characteristics that moderate its effectiveness. In a parallel-group randomised controlled trial, with 1:1 allocation, 360 participants with distressing persecutory beliefs will be independently randomised to receive either the SlowMo intervention added to treatment as usual (TAU) or TAU, using randomly varying permuted blocks, stratified by paranoia severity and site. Research workers will be blind to therapy allocation. The primary outcome is paranoia severity over 24 weeks; our hypothesised mechanism of change is reasoning; moderators include negative symptoms and working memory; and secondary outcomes include wellbeing, quality of life, and service use. The accessibility, usability and acceptability of the digital platform will be assessed. Discussion: SlowMo has been developed as the first blended digital therapy to target fears of harm from others through an inclusive design approach. In addition to testing its efficacy, this trial will add to our understanding of psychological mechanisms in paranoia. The study will examine the usability and adherence of a novel digital therapy, including an app for self-management, in a large sample of people affected by severe mental health difficulties

Re-visiting Meltsner: Policy Advice Systems and the Multi-Dimensional Nature of Professional Policy Analysis

10.2139/ssrn.15462511-2

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

The effects of unavoidable shocks on a multiple schedule having an avoidance component

Two dogs were maintained on a multiple schedule having both a food reinforced and an avoidance component (Mult VI 1′ S(Δ) Avoid(SS20 RS20) S(Δ)). The effects of superimposing an Estes-Skinner procedure for delivering unavoidable shocks on all components of the multiple schedule were observed. The buzzer-shock pairing of the Estes-Skinner procedure produced an increased rate of responding on the avoidance component of the schedule and also on the S(Δ) components. No persistent change in rate was observed on the food component during the pre-shock stimulus. Control performances on all components could be regained by either extinguishing or eliminating the buzzer-shock pairing. Extinction of the avoidance responding had little effect on the increased rates of responding produced by the Estes-Skinner procedure on the S(Δ) and avoidance extinction components and did not lead to a conditioned suppression of the food reinforced responding. Rate of responding during the pre-shock stimulus was observed to be relatively independent of changes in the maintaining schedules. Responding during the pre-shock stimulus could be conditioned and maintained after an extensive history of avoidance extinction

The effects of electroconvulsive shock on the action of a reinforcing stimulus

Three experiments sought to evaluate the effect of electroconvulsive shock on the action of a reinforcing stimulus. In all experiments behavior was maintained on a 2 min variable interval schedule for food reinforcement. Foot shock at the termination of a buzzer stimulus served as the reinforcing stimulus for conditioned suppression during the ensuing buzzer interval. Omission of foot shock at the termination of the buzzer stimulus was followed by normal responding (no conditioned suppression) during the next buzzer interval. In Exp I electroconvulsive shock followed foot shock at varying time intervals. In the first subsidiary experiment electroconvulsive shock followed an unreinforced buzzer stimulus at varying time intervals. In the second subsidiary experiment electroconvulsive shock followed foot shock at varying time intervals and an additional buzzer stimulus was sounded between the termination of foot shock and the onset of electroconvulsive shock. These three experiments demonstrated that electroconvulsive shock invariably abolished the effects of the reinforcing stimulus if it followed conditioning by no more than 10.0 sec and never had an effect if it followed conditioning by 12.5 sec or more; electroconvulsive shock was not acting as a reinforcing stimulus in this situation

Effects of chlorpromazine on appetitive and aversive components of a multiple schedule

A multiple schedule having both an appetitive and an avoidance component was maintained in two dogs to create a complex behavioral base line for observing the effects of chlorpromazine. Both soluble and “Spansule” chlorpromazine generated similar functions relating drug dose to measures of behavioral output. Although the dose ranges and the drugging procedures differed markedly for the different preparations of CPZ, the functions generated were comparable. There was no evidence that chlorpromazine had a differential depressing effect as a function of type of reinforcement. At low doses, rates of responding on the food-reinforced components increased slightly, whereas rates on the avoidance components remained relatively unchanged. At higher doses, both components showed an approximately equal depression of responding. These results are discussed with reference to some of the logical and experimental difficulties inherent in making comparisons across components of a multiple schedule and across schedules in general