Scoping review of interventions to de-implement potentially harmful non-steroidal anti-inflammatory drugs (NSAIDs) in healthcare settings.

OBJECTIVES: Potentially harmful non-steroidal anti-inflammatory drugs (NSAIDs) utilisation persists at undesirable rates worldwide. The purpose of this paper is to review the literature on interventions to de-implement potentially harmful NSAIDs in healthcare settings and to suggest directions for future research. DESIGN: Scoping review. DATA SOURCES: PubMed, CINAHL, Embase, Cochrane Central and Google Scholar (1 January 2000 to 31 May 2022). STUDY SELECTION: Studies reporting on the effectiveness of interventions to systematically reduce potentially harmful NSAID utilisation in healthcare settings. DATA EXTRACTION: Using Covidence systematic review software, we extracted study and intervention characteristics, including the effectiveness of interventions in reducing NSAID utilisation. RESULTS: From 7818 articles initially identified, 68 were included in the review. Most studies took place in European countries (45.6%) or the USA (35.3%), with randomised controlled trial as the most common design (55.9%). Interventions were largely clinician-facing (76.2%) and delivered in primary care (60.2%) but were rarely (14.9%) guided by an implementation model, framework or theory. Academic detailing, clinical decision support or electronic medical record interventions, performance reports and pharmacist review were frequent approaches employed. NSAID use was most commonly classified as potentially harmful based on patients' age (55.8%), history of gastrointestinal disorders (47.1%), or history of kidney disease (38.2%). Only 7.4% of interventions focused on over-the-counter (OTC) NSAIDs in addition to prescription. The majority of studies (76.2%) reported a reduction in the utilisation of potentially harmful NSAIDs. Few studies (5.9%) evaluated pain or quality of life following NSAIDs discontinuation. CONCLUSION: Many varied interventions to de-implement potentially harmful NSAIDs have been applied in healthcare settings worldwide. Based on these findings and identified knowledge gaps, further efforts to comprehensively evaluate the effectiveness of interventions and the combination of intervention characteristics associated with effective de-implementation are needed. In addition, future work should be guided by de-implementation theory, focus on OTC NSAIDs and incorporate patient-focused strategies and outcomes, including the evaluation of unintended consequences of the intervention.

A Scoping Review of Interventions to De-implement Potentially Harmful Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Healthcare Settings.

Objectives: Potentially harmful nonsteroidal anti-inflammatory drugs (NSAIDs) utilization persists at undesirable rates throughout the world. The purpose of this paper is to review the literature on interventions to de-implement potentially harmful NSAIDs in healthcare settings and to suggest directions for future research. Design: Scoping review. Data Sources: PubMed, CINAHL, Embase, Cochrane Central, and Google Scholar (2000-2022). Study Selection: Studies reporting on the effectiveness of interventions to systematically reduce potentially harmful NSAID utilization in healthcare settings. Data Extraction: Using Covidence systematic review software, we extracted study and intervention characteristics, including the effectiveness of interventions in reducing NSAID utilization. Results: From 7,818 articles initially identified, 68 were included in the review. Most studies took place in European countries (45.6%) or the U.S. (35.3%), with randomized controlled trial as the most common design (55.9%). The majority of studies (76.2%) reported a reduction in the utilization of potentially harmful NSAIDs. Interventions were largely clinician-facing (76.2%) and delivered in primary care (60.2%). Academic detailing, clinical decision support or electronic medical record interventions, performance reports, and pharmacist review were frequent approaches employed. NSAID use was most commonly classified as potentially harmful based on patients' age (55.8%) or history of gastrointestinal disorders (47.1%) or kidney disease (38.2%). Only 7.4% of interventions focused on over-the-counter NSAIDs in addition to prescription. Few studies (5.9%) evaluated pain or quality of life following NSAIDs discontinuation. Conclusion: Many varied interventions are effective in de-implementing potentially harmful NSAIDs in healthcare settings. Efforts to adapt, scale, and disseminate these interventions are needed. In addition, future interventions should address over-the-counter NSAIDs, which are broadly available and widely used. Evaluating unintended consequences of interventions, including patient-focused outcomes, is another important priority.

Do attachment-related differences in reflective functioning explain associations between expressed emotion and youth self-harm?

Youth self-harm is associated with poor health outcomes and attempted and completed suicide. Associations exist between self-harm and expressed emotion (EE), attachment insecurity, and reflective functioning (RF), but these associations are poorly understood. This study evaluates a mediation model in which perceived caregiver EE (pEE) exerts an indirect effect on youth self-harm through attachment insecurity and RF uncertainty. 461 participants aged 16-24 years completed an online survey. Statistical analyses revealed significant direct effects of pEE on attachment insecurity, and of RF uncertainty on self-harm; however, some direct effects were specific to pEE from female caregivers, and attachment insecurity in youth relationships with female caregivers. A significant direct effect of pEE on self-harm was found for pEE from male caregivers only. Significant indirect effects of pEE on self-harm through attachment anxiety and RF uncertainty were found only in relation to female caregivers. The findings encourage family-, attachment-, and mentalization-based approaches to preventing and treating youth self-harm, with a recommendation that caregivers are given adequate support, education, and skills-based training following youth disclosures of self-harm. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03614-w.

Reinforcer pathology in cocaine use disorder: Temporal window determines cocaine valuation.

AIMS: The Experimental Medicine Approach offers a unique perspective to determine clinical behavior change by engaging a target underlying the cause of a disorder. The present work engaged a novel target of addiction, Reinforcer Pathology, in two studies to test changes in behavior among individuals with cocaine use disorder. METHODS: In Study 1, n = 44 participants engaged the temporal window with episodic future thinking (EFT), a positive prospection exercise. Changes in temporal view and cocaine valuation were tested using delay discounting and behavioral economic demand, respectively. Additionally, a computational model assessed the relative reliance on the near- and far-sighted systems during EFT. In Study 2, n = 71 engaged the temporal window with a negatively-valenced hurricane scenario to test the opposite effects on window length and cocaine valuation. RESULTS: Results demonstrated systematic and symmetrical engagement of the behavioral target. Study 1 robustly replicated previous work, wherein EFT lengthened the temporal window and decreased cocaine valuation. Moreover, EFT increased the weighting of the modeled far-sighted system, increasing the relative impact of long-term discounting decisions. Study 2 produced opposite outcomes, shortened temporal window and increased cocaine valuation. CONCLUSIONS: This approximately equal and opposite reaction to the manipulations supports reinforcer pathology theory and implicates the temporal window over which rewards are valued as a target to be pushed and pulled to produce clinically meaningful behavior change. Using the Experimental Medicine Approach as a guide, future work should identify new potential interventions to engage reinforcer pathology and use the clinically relevant outcomes as a litmus test for mechanism.

The phenotype of recovery V: Does delay discounting predict the perceived risk of relapse among individuals in recovery from alcohol and drug use disorders.

BACKGROUND: Substance use recovery is a dynamic process. Relapse, often part of the recovery process, is a persistent problem for individuals seeking freedom from their harmful substance use and has become a focus of research on the improvement of recovery outcomes. Delay discounting is associated with substance use disorder severity, both its negative outcomes and the propensity to relapse. However, the association between delay discounting and perceived risk of relapse as measured by the Alcohol Warning of Relapse Questionnaire has not previously been examined in a population of individuals in long-term recovery from substance misuse. METHODS: In this study, using data collected from the International Quit and Recovery Registry, we investigated the association between delay discounting, self-reported time in recovery, and perceived risk of relapse. Data from 193 individuals self-reporting to be in recovery from harmful substance use were included in the study. RESULTS: Delay discounting rates were significantly negatively associated with length of recovery (p = 0.036) and positively with perceived risk of relapse (p = 0.027) even after controlling for age, gender, education, marital status, ethnicity, race, primary substance, and length in the registry. Moreover, a mediation analysis using Hayes' methods revealed that the association between the length of recovery and perceived relapse risk was partially mediated by delay discounting, accounting for 21.2% of the effect. CONCLUSIONS: Our finding supports previous characterizations of delay discounting as a candidate behavioral marker of substance misuse and may help to identify individuals at higher perceived risk of relapse in an extended recovery population.

Reinforcer pathology: Narrative of hurricane-associated loss increases delay discounting, demand, and consumption of highly palatable snacks in the obese.

Reinforcer pathology is derived from the integration of two measures: (a) self-control (i.e., delay discounting), and (b) reward valuation (i.e., behavioral economic demand). Narrative theory asserts that vividly imagining oneself in a hypothetical, yet realistic, scenario can acutely alter decision making, valuation of reinforcers such as food, and how much food is consumed. The present study measured changes in reinforcer pathology for highly palatable snacks following either a negative or neutral scenario in obese individuals. Participants (N = 48), with a body mass index of 30 or greater, rated their liking of 7 calorie-dense snack items and completed discounting and purchase demand tasks for their top-rated snack. Participants then read a randomly assigned hypothetical scenario (i.e., a devastating hurricane [negative] or minor storm [neutral]), completed the tasks again, and were given ad libitum access to their top 3 ranked snack foods. Results indicated that delay discounting, demand for participants' top-rated snack food, and negative affect all increased in the hurricane group compared with the minor storm group. The hurricane group also consumed more calories, even when hunger was standardized with a preload meal bar. Consistent with reinforcer pathology, these results suggest that vivid consideration of a devastating scenario constricts the temporal window and increases demand for hedonic snack foods among obese individuals. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Episodic future thinking reduces delay discounting and cigarette demand: an investigation of the good-subject effect.

Episodic future thinking (EFT), an intervention involving mental simulation of future events, has been shown to reduce both delay discounting and cigarette self-administration. In the present study, we extended these findings by showing that EFT in a web-based sample of smokers reduces delay discounting and intensity of demand for cigarettes (ad libitum consumption) in a hypothetical purchase task. No effect was observed on elasticity of demand (sensitivity to price) or cigarette craving. We also explored whether demand characteristics (specifically, the "good-subject" effect) might be responsible for observed effects. EFT participants were significantly better able than control participants to discern the experimental hypothesis. However, EFT participants were not better than controls at identifying whether they had been assigned to the experimental group and, likewise, showed no differences in attitudes about the experiment and experimenter. Importantly, effects of EFT on delay discounting and demand remained significant even when controlling for measures of demand characteristics, indicating that EFT's effects are independent of participants' perceptions about the experiment.

Discovery of a Series of Indazole TRPA1 Antagonists.

A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds.

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

The role of answer fluency and perceptual fluency in the monitoring and control of reasoning: reply to Oppenheimer, and Epley (2013).

In this reply, we provide an analysis of Alter et al. (2013) response to our earlier paper (Thompson et al., 2013). In that paper, we reported difficulty in replicating Alter, Oppenheimer, Epley, and Eyre's (2007) main finding, namely that a sense of disfluency produced by making stimuli difficult to perceive, increased accuracy on a variety of reasoning tasks. Alter, Oppenheimer, and Epley (2013) argue that we misunderstood the meaning of accuracy on these tasks, a claim that we reject. We argue and provide evidence that the tasks were not too difficult for our populations (such that no amount of "metacognitive unease" would promote correct responding) and point out that in many cases performance on our tasks was well above chance or on a par with Alter et al.'s (2007) participants. Finally, we reiterate our claim that the distinction between answer fluency (the ease with which an answer comes to mind) and perceptual fluency (the ease with which a problem can be read) is genuine, and argue that Thompson et al. (2013) provided evidence that these are distinct factors that have different downstream effects on cognitive processes.

The role of answer fluency and perceptual fluency as metacognitive cues for initiating analytic thinking.

Although widely studied in other domains, relatively little is known about the metacognitive processes that monitor and control behaviour during reasoning and decision-making. In this paper, we examined the conditions under which two fluency cues are used to monitor initial reasoning: answer fluency, or the speed with which the initial, intuitive answer is produced (Thompson, Prowse Turner, & Pennycook, 2011), and perceptual fluency, or the ease with which problems can be read (Alter, Oppenheimer, Epley, & Eyre, 2007). The first two experiments demonstrated that answer fluency reliably predicted Feeling of Rightness (FOR) judgments to conditional inferences and base rate problems, which subsequently predicted the amount of deliberate processing as measured by thinking time and answer changes; answer fluency also predicted retrospective confidence judgments (Experiment 3b). Moreover, the effect of answer fluency on reasoning was independent from the effect of perceptual fluency, establishing that these are empirically independent constructs. In five experiments with a variety of reasoning problems similar to those of Alter et al. (2007), we found no effect of perceptual fluency on FOR, retrospective confidence or accuracy; however, we did observe that participants spent more time thinking about hard to read stimuli, although this additional time did not result in answer changes. In our final two experiments, we found that perceptual disfluency increased accuracy on the CRT (Frederick, 2005), but only amongst participants of high cognitive ability. As Alter et al.'s samples were gathered from prestigious universities, collectively, the data to this point suggest that perceptual fluency prompts additional processing in general, but this processing may results in higher accuracy only for the most cognitively able.

In vitro and in vivo pharmacological characterisation of the potent and selective vasopressin V(1A) receptor antagonist 4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl-(3,5-difluoro-phenyl) methanone (PF-00738245).

The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin receptors plays an important role in disease conditions including polycystic kidney disease, congestive heart failure and dysmenorrhoea. The development of potent and selective vasopressin receptor ligands is needed to help dissect the function of the specific subtypes in disease pathogenesis. Here we report the pharmacological characterisation of PF-00738245 in in vitro binding and functional assays using cells expressing vasopressin V(1A), V(1B) or V2 receptors. PF-00738245 inhibited AVP binding to the recombinant human vasopressin V(1A) receptor (K(i)=2.85 nM) and blocked AVP-induced rat aortic ring and human myometrial contraction (pK(B)=7.35 and 8.62 respectively). PF-00738245 was selective for the vasopressin V(1A) receptor by demonstrating minimal binding to vasopressin V(1B) (3.6% inhibition at 10 µM) or functional activity at vasopressin V2 receptors (8.1% agonist and -8.4% antagonist activity at 10 µM) as well as the oxytocin receptor (46.3% antagonist activity at 10 µM). The in vivo pharmacological properties were tested orally in the rat and PF-00738245 dose dependently blocked the effect of AVP on a capsaicin-induced cutaneous flare response. Taken together the data support the use of PF-00738245 as a potent and selective vasopressin V(1A) receptor antagonist which may have utility in the treatment of disease conditions which are propagated by elevation in vasopressin V(1A) receptor signalling.

Intuition, reason, and metacognition.

Dual Process Theories (DPT) of reasoning posit that judgments are mediated by both fast, automatic processes and more deliberate, analytic ones. A critical, but unanswered question concerns the issue of monitoring and control: When do reasoners rely on the first, intuitive output and when do they engage more effortful thinking? We hypothesised that initial, intuitive answers are accompanied by a metacognitive experience, called the Feeling of Rightness (FOR), which can signal when additional analysis is needed. In separate experiments, reasoners completed one of four tasks: conditional reasoning (N=60), a three-term variant of conditional reasoning (N=48), problems used to measure base rate neglect (N=128), or a syllogistic reasoning task (N=64). For each task, participants were instructed to provide an initial, intuitive response to the problem along with an assessment of the rightness of that answer (FOR). They were then allowed as much time as needed to reconsider their initial answer and provide a final answer. In each experiment, we observed a robust relationship between the FOR and two measures of analytic thinking: low FOR was associated with longer rethinking times and an increased probability of answer change. In turn, FOR judgments were consistently predicted by the fluency with which the initial answer was produced, providing a link to the wider literature on metamemory. These data support a model in which a metacognitive judgment about a first, initial model determines the extent of analytic engagement.

Current concepts in assessment of microvascular endothelial function using laser Doppler imaging and iontophoresis.

Effective evaluation of endothelial function is a powerful tool for determining patients at risk of development and progression of cardiovascular disease. As an alternative to invasive tests of endothelial function, several noninvasive methods have been developed, including the use of laser Doppler flowmetry/imaging to measure cutaneous perfusion accompanied by iontophoresis of acetylcholine and sodium nitroprusside. It is clear from previous studies that this technique provides an easy, validated, and reproducible method for investigators to assess and monitor endothelial function in patients with a variety of pathologic conditions, but it may also be used to examine disease progression over time and responsiveness to treatment, thereby facilitating clinical trials. However, a standardization of protocols would help reduce the apparent controversy seen in the literature. With its increasing use by other groups, it is anticipated that further published studies will help to provide a better understanding of the development and progression of cardiovascular disease.