Short-duration Exposure Research Articles

Rapid Production of Micro- and Nanoplastics by Fragmentation of Expanded Polystyrene Exposed to Sunlight.

Expanded polystyrene (EPS) is a common plastic marine debris found in oceans worldwide. The unique "foamed" structure of EPS, which is composed of thin layers, is more vulnerable to fragmentation than bulk plastics. However, the production rate of micro- and nanoplastics by the fragmentation of EPS following sunlight exposure remains largely unknown. Here, we determined the fragmentation rate and weight loss of EPS in an outdoor weathering experiment that ran for 24 months. It took only 1 month for the weight of an EPS box to decline by 5% due to photodegradation, and approximately 6.7 × 107 micro- and nanoparticles/cm2 could be produced at a latitude of 34 °N. These results indicate that macro EPS debris can continually produce a massive number of particles within a relatively short exposure duration. The findings provide useful information to inform policymakers how rapidly to remove "likely fragmented" plastic litter from the environment.

Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not dose-proportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation pharmacokinetic mimic) or continuous exposure (oral pharmacokinetic mimic), nintedanib (1–100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response. Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice-daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalent-delivered lung exposure, QD short duration inhaled nintedanib (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1β) and soluble collagen). Comparatively, the increased inhaled lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited increased effect by further reducing silica-induced elastance, IL-1β and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced bronchoalveolar lavage fluid macrophage and neutrophil counts with oral achieving significance. In summary, pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.

Impact of Female Sex on Clinical Presentation and Ablation Outcomes in the CIRCA-DOSE Study.

This study sought to evaluate sex-specific differences in atrial fibrillation (AF) presentation and catheter ablation outcomes in the prospective, multicenter, randomized CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study. Similar to other cardiovascular conditions, significant sex-specific differences have been observed in the epidemiology, pathophysiology, presentation, and natural history of AF. Unfortunately, there are major gaps in our understanding of the pathophysiological basis for the observed sex-specific differences and their implications on therapy and prognosis. This study examined sex-specific differences in AF presentation, symptom severity and health-related quality of life, symptomatic and asymptomatic arrhythmia recurrence, AF burden, and health care utilization. Freedom from any atrial tachyarrhythmia and symptomatic atrial tachyarrhythmia were similar between male (hazard ratio: 1.18; 95% confidence interval: 0.85 to 1.64; p=0.39) and female patients (hazard ratio: 1.00; 95% confidence interval: 0.62 to 1.59; p=0.92). Post-ablation, the median AF burden (percentage time in AF) was 0.00% (interquartile range: 0.00% to 0.16%) in male patients and 0.00% (interquartile range: 0.00% to 0.17%) in female patients, with no difference observed between the sexes (p=0.30). Periprocedural complications occurred twice as frequently in female patients (3.5% vs. 7.0%; p=0.18). In comparison to male patients, female patients reported a significantly worse symptom score and quality of life at baseline and all follow-up intervals, but they derived similar magnitude of improvement post-ablation. There was no difference between male and female patients with respect to emergency department visits, hospitalization, cardioversion, or repeat ablation. When compared with male patients, female patients have significantly worse symptom scores and quality of life at baseline. Despite this, female patients with symptomatic paroxysmal AF derive similar benefit in freedom from recurrent arrhythmia and similar improvements in quality of life following AF ablation. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration [CIRCA-DOSE]; NCT01913522).

Impact of timing of the anorexigen sibutramine administration on reproductive end-points of male rats.

Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10mg/kg/d) or vehicle for 15days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.

Association of Atrial Fibrillation Episode Duration With Arrhythmia Recurrence Following Ablation

Contemporary guidelines recommend that atrial fibrillation (AF) be classified based on episode duration, with these categories forming the basis of therapeutic recommendations. While pragmatic, these classifications are not based on pathophysiologic processes and may not reflect clinical outcomes. To evaluate the association of baseline AF episode duration with post-AF ablation arrhythmia outcomes. The current study is a secondary analysis of a prospective, parallel-group, multicenter, single-masked randomized clinical trial (the Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration [CIRCA-DOSE] study), which took place at 8 Canadian centers. Between September 2014 and July 2017, 346 patients older than 18 years with symptomatic AF referred for first catheter ablation were enrolled. All patients received an implantable cardiac monitor at least 30 days before ablation. Data analysis was performed in September 2019. Before ablation, patients were classified based on their longest AF episode. Ablation consisted of circumferential pulmonary vein isolation using standard techniques. Time to first recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) following ablation and AF burden (percentage of time in AF) on preablation and postablation continuous rhythm monitoring. The study included 346 patients (mean [SD] age, 59 [10] years; 231 [67.7%] men). Overall, 263 patients (76.0%) had AF episode duration of less than 24 hours; 25 (7.2%), 24 to 48 hours; 40 (11.7%), 2 to 7 days; and 18 (5.2%), more than 7 days. Documented recurrence of any atrial tachyarrhythmia following ablation was significantly lower in patients with baseline AF episode duration of less than 24 continuous hours compared with those with longer AF episodes (24 hours vs 24-48 hours: hazard ratio [HR], 0.41; 95% CI, 0.21-0.80; P = .009; 24 hours vs 2-7 days: HR, 0.25; 95% CI, 0.14-0.45; P < .001; 24 hours vs >7 days: HR, 0.23; 95% CI, 0.09-0.55; P < .001). Patients with preablation AF episodes limited to less than 24 continuous hours had a significantly lower median (interquartile range) postablation AF burden (0% [0%-0.1%]) compared with those with AF preablation episodes lasting 2-7 days (0.1% [0%-1.0%]; P = .003) and those with AF preablation episodes lasting more than 7 days (1.0% [0%-5.4%]; P = .008). There was no significant difference in arrhythmia recurrence or AF burden between the 3 groups with a baseline AF episode duration of longer than 24 hours. In this study, patients with AF episodes limited to less than 24 continuous hours had a significantly lower incidence of arrhythmia recurrence following AF ablation. This suggests that current guidelines for classification of AF may not reflect clinical outcomes. ClinicalTrials.gov Identifier: NCT01913522.

The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) Study Results in Context.

The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration (CIRCA-DOSE) study was a multicentre, randomised, single-blinded trial that compared contact-force radiofrequency ablation and two different regimens of cryoballoon ablation. All patients received an implantable cardiac monitor for the purpose of continuous rhythm monitoring, with all arrhythmia events undergoing independent adjudication by a committee blinded to treatment allocation. The study demonstrated there were no significant differences between contact-force radiofrequency ablation and cryoballoon ablation with respect to recurrence of any atrial tachyarrhythmia, symptomatic atrial tachyarrhythmia, asymptomatic AF, symptomatic AF or AF burden. While the results of the CIRCA-DOSE study are reviewed here, this article focuses on considerations around the design of the study and places the observed outcomes in context.

1040-P: Ultra-Rapid Lispro (URLi) Accelerates Insulin Lispro Absorption and Insulin Action vs. Humalog (Lispro) Consistently across Study Populations: A Meta-analysis of Pharmacokinetic and Glucodynamic Data

URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This meta-analysis compared and assessed the consistency of the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with T1D or T2D. The analysis included 4 randomized, double-blind, crossover, single dose studies [healthy subjects (n=74), patients with T1D (n=80), and T2D (n=38)], evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog®. An 8 to10-h euglycemic clamp was conducted to assess pharmacodynamics. Meta-analysis showed a ∼5 min faster (95% CI:-5.38, -4.12 min) onset of appearance with URLi vs. Humalog. The early insulin exposure was ∼8 times greater (95% CI:6.63, 8.51) in first 15 min and 3 times greater (95% CI:2.74, 3.22) in the first 30 min after URLi vs. Humalog. URLi reduced the late insulin exposure after 3 hours by 43% (ratio 0.57; 95% CI:0.53, 0.60) and the duration of exposure by 68 min (95% CI:-76.86, -59.53 min) vs. Humalog. URLi had a faster onset of action occurring 10 min earlier (95% CI:-12.01, -8.64 min), and early action was increased 3-fold in the first 30 min (95% CI:2.72, 3.50 min) with URLi vs. Humalog. Late insulin action (glucose infused 4 h to end of the clamp) was reduced by 35% (ratio 0.65; 95% CI:0.61, 0.70) and duration of action was 44 min shorter with URLi (95% CI:-58.60, -29.02 min). Total exposure and glucose infused during the clamp was similar between URLi vs. Humalog across the dose range and in each study population. Across the studied dose range and study populations, URLi consistently had faster absorption, reduced late exposure, and an overall shorter exposure duration compared to Humalog. URLi demonstrated an earlier insulin action while reducing the late insulin action compared to Humalog across the studied dose range and study populations. Disclosure J. Leohr: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. K. Carter: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson &amp; Johnson, Novartis AG. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Ozone exposure, nitrogen addition and moderate drought dynamically interact to affect isoprene emission in poplar

Ozone (O3) pollution can induce changes in plant growth and metabolism, and in turn, affects isoprene emission (ISO), but the extent of these effects may be modified by co-occurring soil water and nitrogen (N) availability. To date, however, much less is known about the combined effects of two of these factors on isoprene emission from plants. We investigated for the first time the combined effects of O3 exposure (CF, charcoal-filtered air; EO3, non-filtered air plus 40 ppb of O3), N addition (N0, no additional N; N50, 50 kg ha−1 year−1 of N) and moderate drought (WW, well-watered; WR, 40% of WW irrigation) on photosynthetic carbon assimilation and ISO emission in hybrid poplar at both leaf- and plant-level over time. Consistent with leaf-level photosynthesis (Pnleaf) and ISO (ISOleaf) responses, plant-level ISO (ISOplant) responses to O3, N addition and moderate drought were more marked after long exposure (September) than short exposure duration (July). EO3 significantly decreased ISOleaf and Pnleaf, while WR and N50 significantly increased them. Although O3 and water interacted significantly to affect Pnleaf over the exposure duration, neither N50 nor WR mitigated the negative effects of EO3 on ISOleaf. When ISO was scaled up to the plant level, the WR-induced increase in ISOleaf under EO3 was offset by a reduction in total leaf area. By contrast, effects of EO3 on ISOplant were not changed by N addition. Our results highlight that the dynamic effects on ISO emission change over the exposure duration depending on involved co-occurring factors and evaluation scales.

Assessment of zebrafish embryo photomotor response sensitivity and phase-specific patterns following acute- and long-duration exposure to neurotoxic chemicals and chemical weapon precursors.

Zebrafish are an attractive model for chemical screening due to their adaptability to high‐throughput platforms and ability to display complex phenotypes in response to chemical exposure. The photomotor response (PMR) is an established and reproducible phenotype of the zebrafish embryo, observed 24 h post‐fertilization in response to a predefined sequence of light stimuli. In an effort to evaluate the sensitivity and effectiveness of the zebrafish embryo PMR assay for toxicity screening, we analyzed chemicals known to cause both neurological effects and developmental abnormalities, following both short (1 h) and long (16 h+) duration exposures. These include chemicals that inhibit aerobic respiration (eg, cyanide), acetyl cholinesterase inhibitors (organophosphates pesticides) and several chemical weapon precursor compounds with variable toxicity profiles and poorly understood mechanisms of toxicity. We observed notable concentration‐responsive, phase‐specific effects in the PMR after exposure to chemicals with a known mechanism of action. Chemicals with a more general toxicity profile (toxic chemical weapon precursors) appeared to reduce all phases of the PMR without a notable phase‐specific effect. Overall, 10 of 20 chemicals evaluated elicited an effect on the PMR response and eight of those 10 chemicals were picked up in both the short‐ and long‐duration assays. In addition, the patterns of response uniquely differentiated chemical weapon precursor effects from those elicited by inhibitors of aerobic respiration and organophosphates. By providing a rapid screening test for neurobehavioral effects, the zebrafish PMR test could help identify potential mechanisms of action and target compounds for more detailed follow‐on toxicological evaluations.Approved for public release: distribution unlimited.

LO42: A systematic review of short-term use of therapeutic opioids for children and future opioid use disorders

Introduction: Despite an overall decline in opioid prescriptions in Canada, healthcare visits, hospitalizations, and deaths due to opioid-related harms continue to rise for children. Clinicians urgently require high quality synthesized evidence to inform personalized decisions regarding opioid use for children. The objective of this systematic review was to examine the association between short-term therapeutic exposure to opioids and development of opioid use disorder. Methods: A medical librarian conducted a comprehensive search of 10 databases from inception to May 2019. Two authors independently assessed studies for inclusion. Studies were eligible if they reported primary research in English or French, and study participants had short (&lt;14 days) or non-specific duration of therapeutic exposure to opioids before age 18 years. Primary outcome was the development of an opioid use disorder; secondary outcomes included opioid addiction, dependence, misuse, and abuse. Data extraction involved two independent reviewers utilizing a standardized form. Methodological quality was assessed using the NIH tools for observational studies. Results are described narratively. Results: The search identified 4,072 unique citations; 82 were selected for review, and 17 were included (3 retrospective cohort, 4 prospective cohort, and 10 cross-sectional). All studies took place in the USA. A total of 1,562,503 participants were analyzed. Nine studies were administered in schools, 3 used administrative data. While most settings were non-specific, 1 study examined opioid use in dentistry, 1 in trauma, and 1 in organized sports. One comparative study showed an association between short-term therapeutic use and opioid misuse. Two studies showed opioid related adverse events (e.g., overdose) among cohorts exposed to short-term use. The remaining 14 studies did not specify duration of exposure; therefore, confirming whether misuse was due to short-term therapeutic exposure was not possible. Conclusion: A small number of studies in this review suggest an association between short-term opioid use and opioid misuse; however, further analysis is underway with consideration of methodological limitations of the individual studies (final results pending). Careful consideration of the risk and benefits of short-term opioid use should be undertaken prior to prescribing opioids. PROSPERO Registration Number: 122681.

Phytosanitary irradiation: Does modified atmosphere packaging or controlled atmosphere storage creating a low oxygen environment threaten treatment efficacy?

Phytosanitary irradiation treatment is used to control insects in fresh commodities so that the commodities can be safely exported to pest-free areas. The goal of phytosanitary irradiation is to prevent reproduction. Modified atmosphere packaging (MAP) and controlled atmosphere (CA) storage creating a low oxygen environment are used to preserve the quality of fruits and vegetables. Low oxygen is known to be radioprotective in insects and other organisms. This raises the question of whether MAP or CA may reduce the efficacy of phytosanitary irradiation treatments. IPPC regulations prohibit the application of phytosanitary irradiation for fruits and vegetables under modified atmospheres. Studies used to support this restriction have typically used unrealistic conditions, particularly with the use of severe hypoxia or anoxia and short duration exposures after irradiation (≤2 h hold time under low oxygen). Results from these studies have been extrapolated to suggest phytosanitary irradiation may be compromised by MAP or CA. Although low oxygen radioprotection in insects has been demonstrated for various biological parameters such as adult emergence, flight ability, mating success, and fertility, to date no studies have shown that irradiation of insects at approved doses under modified atmospheres results in treatment failure, i.e., allows successful reproduction. Recent studies using commercially relevant conditions show that MAP may improve control due to the toxic effect of extended exposures to low O2 and high CO2 to insects. Regulatory restrictions on the use of MAP and CA during irradiation treatment should be reviewed and reconsidered. In the absence of data showing treatment failure due to modified atmospheres, current regulatory restrictions are not scientifically justified.

Innate inflammatory response to acute inhalation exposure of riot control agent oleoresin capsicum in female rats: An interplay between neutrophil mobilization and inflammatory markers

Aim: The use of oleoresin capsicum (OC) sprays, due to their irreversible health effects has now grown into a matter of heated debate. In the present study, the early phase pulmonary events involving chemotactic and inflammatory mediators after short-exposure duration to OC have been presented.Materials and methods: Female Wistar rats used in the evaluation of respiratory parameters at 1 h, 3 h, and 24 h post-exposure, were sacrificed for the evaluation of blood cell counts, BALF cytokine estimation, lung capillary leakage, study of oxidative stress and histopathology of the lungs.Results: Results confirmed a dose-dependent effect of OC exposure on serum clinical chemistry and hematological parameters. Subsequent upregulation of IL-l and TNF-α indicated lung’s responses to acute oxidant-induced injury and inflammation after OC exposure. Significant alterations in the pulmonary levels of reactive oxygen intermediates were seen following the inhalation of OC. Infiltration of polymorphonuclear leukocytes, mostly neutrophils, into the site of infection was evident in the cytocentrifuged samples of BALF. Histological samples of rat lung sections revealed the recruitment of inflammatory cells in the airways and around blood vessels in the subepithelium of conducting airways.Conclusion: Results of the present study demonstrated that, exposure to OC spray may mitigate inflammatory response and development of acute lung injury in rats. However, it can be concluded that although OC spray causes pulmonary hazards in the aforementioned concentrations, it can be used as a non-lethal riot control agent in minimal concentration. Understanding the in-depth mechanism of action in the molecular and receptor level will help in developing effective antagonist against OC.

Effect of Louisiana sweet crude oil on a Pacific coral, Pocillopora damicornis

Recent oil spill responses such as the Deepwater Horizon event have underscored the need for crude oil ecotoxicological threshold data for shallow water corals to assist in natural resource damage assessments. We determined the toxicity of a mechanically agitated oil-seawater mixture (high-energy water-accommodated fraction, HEWAF) of a sweet crude oil on a branched stony coral, Pocillopora damicornis. We report the results of two experiments: a 96 h static renewal exposure experiment and a “pulse-chase” experiment of three short-term exposure durations followed by a recovery period in artificial seawater. Five endpoints were used to determine ecotoxicological values: 1) algal symbiont chlorophyll fluorescence, 2) a tissue regeneration assay and a visual health metric with three endpoints: 3) tissue integrity, 4) tissue color, and 5) polyp behavior. The sum of 50 entrained polycyclic aromatic hydrocarbons (tPAH50) was used as a proxy for oil exposure. For the 96 h exposure dose response experiment, dark-adapted maximum quantum yield (Fv/Fm) of the dinoflagellate symbionts was least affected by crude oil (EC50 = 913 μg/L tPAH50); light-adapted effective quantum yield (EQY) was more sensitive (EC50 = 428 μg/L tPAH50). In the health assessment, polyp behavior (EC50 = 27 μg/L tPAH50) was more sensitive than tissue integrity (EC50 = 806 μg/L tPAH50) or tissue color (EC50 = 926 μg/L tPAH50). Tissue regeneration proved to be a particularly sensitive measurement for toxicity effects (EC50 = 10 μg/L tPAH50). Short duration (6−24 h) exposures using 503 μg/L tPAH50 (average concentration) resulted in negative impacts to P. damicornis and its symbionts. Recovery of chlorophyll a fluorescence levels for 6−24 h oil exposures was observed in a few hours (Fv/Fm) to several days (EQY) following recovery in fresh seawater. The coral health assessments for tissue integrity and tissue color were not affected following short-term oil exposure durations, but the 96 h treatment duration resulted in significant decreases for both. A reduction in polyp behavior (extension) was observed for all treatment durations, with recovery observed for the short-term (6−24 h) exposures within 1–2 days following placement in fresh seawater. Wounded and intact fragments exposed to oil treatments were particularly sensitive, with significant delays observed in tissue regeneration. Estimating ecotoxicological values for P. damicornis exposed to crude oil HEWAFs provides a basis for natural resource damage assessments for oil spills in reef ecosystems. These data, when combined with ecotoxicological values for other coral reef species, will contribute to the development of species sensitivity models.

Ethanol metabolism: The good, the bad, and the ugly

Throughout the world, ethanol is both an important commercial commodity and a source of major medical and social problems. Ethanol readily passes through biological membranes and distributes throughout the body. It is oxidized, first to acetaldehyde and then to acetate, and finally by the citric acid cycle in virtually all tissues. The oxidation of ethanol is irreversible and unregulated, making the rate dependent only on local concentration and enzyme activity. This unregulated input of reducing equivalents increases reduction of both cytoplasmic and intramitochondrial NAD and, through the latter, cellular energy state {[ATP]/([ADP][Pi])}. In brain, this increase in energy state stimulates dopaminergic neural activity signalling reward and a sense of well being, while suppressing glutamatergic neural activity signalling anxiety and unease. These positive responses to ethanol ingestion are important to social alcohol consumption. Importantly, decreased free [AMP] decreases AMP-dependent protein kinase (AMPK) activity, an important regulator of cellular energy metabolism. Oxidation of substrates used for energy metabolism in the absence of ethanol is down regulated to accommodate the input from ethanol. In liver, chronic ethanol metabolism results in fatty liver and general metabolic dysfunction. In brain, transport of other oxidizable metabolites through the blood-brain barrier and the enzymes for their oxidation are both down regulated. For exposures of short duration, ethanol induced regulatory changes are rapid and reversible, recovering completely when the concentrations of ethanol and acetate fall again. Longer periods of ethanol exposure and associated chronic suppression of AMPK activity activates regulatory mechanisms, including gene expression, that operate over longer time scales, both in onset and reversal. If chronic alcohol consumption is abruptly ended, metabolism is no longer able to respond rapidly enough to compensate. Glutamatergic neural activity adapts to chronic dysregulation of glutamate metabolism and suppression of glutamatergic neural activity by increasing excitatory and decreasing inhibitory amino acid receptors. A point is reached (ethanol dependence) where withdrawal of ethanol results in significant metabolic energy depletion in neurons and other brain cells as well as hyperexcitation of the glutamatergic system. The extent and regional specificity of energy depletion in the brain, combined with hyperactivity of the glutamatergic neuronal system, largely determines the severity of withdrawal symptoms.

Prevalence and clinical impact of spontaneous and adenosine-induced pulmonary vein reconduction in the Contact-Force vs. Cryoballoon Atrial Fibrillation Ablation (CIRCA-DOSE) study

Use of intraprocedural observation and pharmacologic challenges have been proposed as means to differentiate permanent pulmonary vein (PV)-left atrial conduction block from inadequate ablation lesions. The purpose of this study was to determine the prevalence and clinical impact of spontaneous and adenosine-provoked reconnection using contemporary atrial fibrillation (AF) ablation technologies. The CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study enrolled 346 patients with paroxysmal AF and randomized them to contact force-guided radiofrequency ablation (CF-RF) or cryoballoon ablation. Patients underwent provocative testing with adenosine after a 20-minute observation period. All patients received an implantable cardiac monitor for arrhythmia monitoring. Spontaneous reconnection was observed in 5.4% of PVs (71/1318) during the 20-minute postprocedure observation period, and dormant conduction was elicited in 5.7% of PVs (75/1318). Both spontaneous reconnection and dormant conduction were more common after CF-RF compared to cryoballoon ablation (P=.03 and P <.0001, respectively). Acute PV reconnection (spontaneous or adenosine-provoked) was associated with a significantly higher incidence of recurrent atrial tachyarrhythmia in the cryoballoon group (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.44-3.96; P = .0007) but not in the CF-RF group (HR 1.47; 95% CI 0.84-2.58; P = .16). In the absence of acute reconnection, the freedom from recurrent arrhythmia did not differ between groups (HR 0.95; 95% CI 0.6057-1.495; P = .83). Patients without spontaneous or adenosine-provoked reconnection had better outcomes compared to those with acute PV reconnection, suggesting that efforts should be directed toward ensuring an ideal ablation lesion at the first attempt in order to achieve durable PV isolation.

P684 The effect of tofacitinib on serum lipids and cardiovascular safety in patients with ulcerative colitis: updated results from the tofacitinib ulcerative colitis clinical programme

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, the majority of patients did not have cardiovascular (CV) risk factors at baseline (BL), and increases in lipid levels occurred primarily during induction and remained elevated to Week 61 during maintenance; lipid ratios were relatively unchanged.1 Here, we present updated results of lipid levels in the ongoing, open-label, long-term extension (OLE) study (NCT01470612) and major adverse CV events (MACE) in the Phase 3/OLE tofacitinib UC clinical programme. Methods Lipid levels were assessed at multiple time points, and changes from OLE study BL to Month 48 in the OLE study were evaluated. Lipid-lowering agent (LLA) use (proportion of patients) and adjudicated MACE (proportion of patients and incidence rate [IR; unique patients with events per 100 patient-years] with 95% confidence interval [CI]) were reported in patients with UC in two Phase 3, 8-week, placebo-controlled induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a Phase 3, 52-week, placebo-controlled maintenance study (OCTAVE Sustain; NCT01458574) and the OLE study (data as of May 2019; database not locked). Results No major changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, LDL-c:HDL-c and TC:HDL-c from OLE study BL were observed at Month 48 of the OLE study (Table). In the Phase 3/OLE programme (n = 1124), 7.7% of patients had a new LLA added and 1.9% of patients had their LLA dose increased. Seven MACE were reported (IR 0.26; 95% CI 0.11, 0.54; 2654.66 patient-years); the IR has remained stable since Dec 2016 (IR 0.24; 95% CI 0.07, 0.62).1 Reported MACE was one each of myocardial infarction, acute myocardial infarction, acute coronary syndrome, cerebrovascular accident, haemorrhagic stroke, cerebellar haemorrhage and aortic dissection. Both myocardial infarction events and the acute coronary syndrome event led to temporary tofacitinib discontinuation; the haemorrhagic stroke, cerebrovascular accident and cerebellar haemorrhage led to permanent tofacitinib discontinuation; and the aortic dissection resulted in death. Of the seven patients with MACE, five had CV risk factors at BL. Conclusion At Month 48 of the OLE study, lipid levels and ratios remained generally unchanged from OLE study BL following tofacitinib treatment. MACE were infrequent, with the IR remaining stable since the previous report.1 Limitations include low patient numbers and short tofacitinib exposure duration. Longer-term observation studies will further assess risk. Reference

The effect of varying danger controllability on attention to threat messages

SummaryThe objective of this study is to determine whether attention toward fear messages is affected by variation in the controllability of the associated danger. There is no consensus regarding the effectiveness of fear appeals in driving adaptive behaviour, and it may be the case that threat messages fail to capture attention if the associated danger is not explicitly controllable. One hundred and sixty undergraduate university students completed a computer task that involved exposure to threat cues signalling a danger (money loss). In high control blocks, attending to threat cues provided a high chance of avoiding the danger, whereas in low control blocks, attending to threat cues provided little chance of avoiding the danger. Attentional capture by threat was measured. A mixed‐design analysis of variance showed there was greater attentional capture by threat cues in high control blocks compared with low control blocks. This effect was observed with a short stimulus exposure duration and was magnified with a long exposure duration. Fear appeals could capture attention to a greater degree if the danger related to the threat message was communicated as being controllable. This has significant practical implications for the implementation of fear appeals.

The Influence of Blue Light in Maintaining Alertness in Tropical Country: A Preliminary Study

Several studies have discussed the influence of blue light on cognitive activity. This study aims to determine the effectiveness of blue light in increasing alertness at night in tropical countries. Twelve healthy young males joined in this study. All participants were asked to do a monotonous activity that is reading activity. The experiment was a within-subject design with the independent variable is lighting condition (normal light and blue light) and duration of exposure (30 minutes and 60 minutes). Electroencephalography (EEG) signals were recorded continuously during the experiment. Alertness was measured based on theta, alpha, and beta activity. The result is the light condition not significantly affected the theta (F (1,11) = 0.608, ρ = 0.452), alpha (F (1,11) = 1.561, ρ = 0.237), and beta (F (1,11) = 0.608, ρ = 0.700) activity. This shows that blue light is not effective in increasing alertness at night in the tropical country both in short and long duration of exposure.

Effects of lighting on ECG, visual performance and psychology of the elderly

Research has explored the effects of illuminance and correlated color temperature (CCT) of indoor lighting on visual performance, mood and physiological parameters of the elderly. Yet, these investigations did not render a consistent finding on visual and non-visual effects of lighting from a holistic perspective. The present study systemically explored the comprehensive effects of illuminance (300 lx, 500 lx, 750 lx, 1000 lx and 1500 lx) and CCT (3000 K, 5000 K and 6500 K) on electrocardiogram (ECG), visual performance and subjective mood of the elderly. The findings revealed that the ECG indicators of the elderly did not change significantly under most lighting conditions though the heart rate was more sensitive to light than waveform time. In addition, an increase in CCT elicited statistically significant benefits on task performance, however, participants' task performance was not significantly enhanced with the increase of illuminance, and the light of 750 lx seemed to be the most unfavorable for the visual task of the elderly. Furthermore, the participants’ subjective appraisals were inclined to be positive and satisfactory and were not significantly different between different lighting conditions. The results of this study showed that short duration (i.e. 20 min) of light exposure had little effect on the physiological rhythm of the elderly, but it did affect the visual performance and psychological feelings of the elderly. Therefore, in the places where the elderly stay for a short time, the first consideration of lighting design should be to meet the visual and psychological needs of the elderly.

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure.

IntroductionLong-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis.MethodsIntegrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies.ResultsTotal ixekizumab exposure was 17,003.4 p-y (N = 5898); 2749 patients had ≥ 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2–7.0/100 p-y); serious infections (range 1.3–1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to 0.2/100 p-y in years 4–5); other malignancies (range 0.4–0.6/100 p-y); inflammatory bowel disease including ulcerative colitis and Crohn’s disease (IR 0.2/100 p-y); and major adverse cardiovascular events (MACE) (range 0.3–0.7/100 p-y). Candidiasis was reported in 327 patients (IR 1.9/100 p-y), with the majority identified as mucocutaneous. The rate of injection site reactions was 15.5/100 p-y during year 1 and 2.0–2.3/100 p-y by years 3–5.ConclusionsThe decrease in rates of TEAEs and the stable rates of SAEs, other malignancies and MACE during up to 5 years of ixekizumab dosing are consistent with previous reports describing a favorable safety profile of ixekizumab following shorter durations of exposure.FundingEli Lilly and Company.