Scalable Inference for Markov Processes with Intractable Likelihoods

Bayesian inference for Markov processes has become increasingly relevant in recent years. Problems of this type often have intractable likelihoods and prior knowledge about model rate parameters is often poor. Markov Chain Monte Carlo (MCMC) techniques can lead to exact inference in such models but in practice can suffer performance issues including long burn-in periods and poor mixing. On the other hand approximate Bayesian computation techniques can allow rapid exploration of a large parameter space but yield only approximate posterior distributions. Here we consider the combined use of approximate Bayesian computation (ABC) and MCMC techniques for improved computational efficiency while retaining exact inference on parallel hardware

Pavlovian drug discrimination with bupropion as a feature positive occasion setter: Substitution by methamphetamine and nicotine, but not cocaine

Bupropion can serve as a discriminative stimulus (SD) in an operant drug discrimination task, and a variety of stimulants substitute for the bupropion SD. There are no reports, however, of bupropion functioning as a Pavlovian occasion setter (i.e., feature positive modulator). The present experiment seeks to fill this gap in the literature by training bupropion in rats as a feature positive modulator that disambiguates when a light will be paired with sucrose. Specifically, on bupropion (10 mg/kg IP) sessions, offset of 15-sec cue lights were followed by brief delivery of liquid sucrose; saline sessions were similar except no sucrose was available. Rats readily acquired the discrimination with more conditioned responding to the light on bupropion sessions. Bupropion is approved for use as a smoking cessation aid, and more recently has drawn attention as a potential pharmacotherapy for cocaine and methamphetamine abuse. Accordingly, after discrimination training we tested the ability of cocaine (1 to 10 mg/kg), methamphetamine (0.1 to 1 mg/kg), and nicotine (0.00625 to 0.2 mg/kg) to substitute for the bupropion feature. Nicotine (0.05 mg/kg) and methamphetamine (0.3 mg/kg) substituted fully for bupropion; cocaine did not substitute. These results extend previous research on shared stimulus properties between bupropion and other stimulants to a Pavlovian occasion setting function. Further, this is the first report of nicotine and methamphetamine substitution for bupropion. The overlap in stimulus properties might explain the effectiveness of bupropion as a smoking cessation aid and highlight the possible utility of bupropion for treatment of stimulant use disorder

Vaccines to Combat Smoking

Background—Current U.S. FDA approved biological therapies for treating smoking target central nervous system processes. Although these therapies have had some success, relapse within a year is still high. Clearly additional strategies are needed to aid individuals in maintaining abstinence. Objective & Methods—We briefly discuss promising research using vaccines to combat smoking and then identify some potentially important directions for future research. Results & Conclusions—Immunization with a nicotine vaccine generates drug-specific antibodies that sequester some of the nicotine in peripheral circulation preventing it from entering the brain thus decreasing its addictive effects. Albeit promising, much more research is necessary to identify more efficacious vaccine designs and formulations, as well as optimal immunization regimens. A further understanding of the contributing factors to the substantial individual differences in immunogenicity to these vaccines and how to best use vaccines in combination with other treatment strategies will increase the success of intervention efforts

An investigation of bupropion substitution for the interoceptive stimulus effects of nicotine

smoking cessation aid has not been fully elucidated, studies have found that bupropion and nicotine share behavioral and neurophysiological properties suggesting that bupropion might serve as a substitute for nicotine. In fact, bupropion prompts nicotine-appropriate responding in operant and Pavlovian drug discrimination studies with rats. A majority of the literature examining this substitution pattern has been done with an operant paradigm. The present research extended this literature by further characterizing the behavioral and neuropharmacological properties underlying the substitution for a nicotine conditioned stimulus (CS). Examination of the dose-effect function and temporal dynamics of this substitution pattern showed that bupropion (20 mg/kg) produced conditioned responding similar to nicotine (0.4 mg base/kg) (ED50=9.9 mg/kg) at 15 and 30 min after injection and partially substituted 5 and 60 min post-injection. Bupropion produced a pattern of conditioned responding similar to nicotine during a 60-min extinction test. Additionally, it has been hypothesized that bupropion and nicotine have an overlapping dopaminergic mechanism. We tested the effects of bupropion pretreatment the nicotine dose-effect function and the ability of dopamine antagonist to block the substitution of bupropion for nicotine. Pretreatment with doses of bupropion that did not substitute for the nicotine stimulus (5 and 10 mg/kg) did not effect nicotine conditioned responding; pretreatment with 20 mg/kg attenuated nicotine-evoked responding. Pretreatment with the dopamine antagonists SCH-23390 and eticlopride blocked the substitution. Finally, S,S-hydroxybupropion, the major metabolite of bupropion in humans, did not substitute for the nicotine CS

Reference place conditioning procedure with cocaine: Increased sensitivity for measuring associatively motivated choice behavior in rats

Place conditioning is widely used to study the conditioned rewarding effects of drugs. In the standard version, one reward (cocaine) is compared to no reward (saline). A modified variant of this task, “reference-conditioning” procedure, compares two potentially rewarding stimuli (high versus low cocaine dose). There has been little research on the utility of this procedure. Experiment 1 used the standard protocol with saline administered before confinement to the reference compartment of a place-conditioning chamber. On alternating days, saline, 2.5, 5, 7.5, 10, or 20 mg/kg cocaine was administered before confinement to the opposite compartment. In Experiments 2 and 3, reference-compartment saline was replaced with 5 and 7.5 mg/kg cocaine, respectively. Relative to saline, 7.5–20 mg/kg cocaine had comparable conditioned rewarding effects (i.e., similar increase in time in paired compartment). When cocaine replaced saline, there was competition at doses lower than 7.5 mg/kg. Rats that received 7.5 versus 2.5 mg/kg spent similar time in each compartment, indicating competition. Competition was not seen with 5 versus 20 mg/kg; preference was for the 20 mg/kg compartment. Experiment 4 showed that the competition at 2.5 mg/kg was not due to reward sensitization—. The reference-conditioning procedure has increased sensitivity for measuring associatively-motivated choice behavior

Vaccines to Combat Smoking

Background—Current U.S. FDA approved biological therapies for treating smoking target central nervous system processes. Although these therapies have had some success, relapse within a year is still high. Clearly additional strategies are needed to aid individuals in maintaining abstinence. Objective & Methods—We briefly discuss promising research using vaccines to combat smoking and then identify some potentially important directions for future research. Results & Conclusions—Immunization with a nicotine vaccine generates drug-specific antibodies that sequester some of the nicotine in peripheral circulation preventing it from entering the brain thus decreasing its addictive effects. Albeit promising, much more research is necessary to identify more efficacious vaccine designs and formulations, as well as optimal immunization regimens. A further understanding of the contributing factors to the substantial individual differences in immunogenicity to these vaccines and how to best use vaccines in combination with other treatment strategies will increase the success of intervention efforts

Improving Holographic Search Algorithms using Sorted Pixel Selection

Traditional search algorithms for computer hologram generation such as Direct Search and Simulated Annealing offer some of the best hologram qualities at convergence when compared to rival approaches. Their slow generation times and high processing power requirements mean, however, that they see little use in performance critical applications. This paper presents the novel Sorted Pixel Selection (SPS) modification for Holographic Search Algorithms (HSAs) that offers Mean Square Error (MSE) reductions in the range of 14:7 19:2% for the test images used. SPS operates by substituting a weighted search selection procedure for traditional random pixel selection processes. While small, the improvements seen are observed consistently across a wide range of test cases and require limited overhead for implementatio

Gynecological trials frequently exclude people based on their symptoms rather than their condition: a systematic review of Cochrane reviews and their component trials

ObjectivesTo identify strategies used in recent randomized controlled trials (RCTs) and their associated Cochrane Reviews where patients with the same gynecological condition present with different symptoms but would plausibly benefit from a common intervention.Study design and settingWe searched the Cochrane library (February 2022) for reviews in polycystic ovarian syndrome (PCOS) and endometriosis. Reviews were included if the intervention was intended to treat all condition-specific symptoms. For each trial we recorded the strategy used and the number of potentially eligible participants excluded as a direct result of the chosen strategy. For each review we recorded the numbers of RCTs and participants excluded on the basis of symptoms experienced.ResultsThere were 89 distinct PCOS trials in 13 reviews, and 13 Endometriosis trials in 11 reviews. Most trials restricted their eligibility to participants with specific symptoms (55% PCOS, 46% endometriosis). The second most common strategy was to measure and analyze clinical outcomes that were not relevant to all participants (38% PCOS, 31% endometriosis). Reviews excluded 27% of trials in participants evaluating the same intervention in participants experiencing the same condition based on the outcomes measured in the trials.ConclusionMost gynecological trials exclude patients who could benefit from treatment or measure outcomes not relevant to all participants. We introduce a taxonomy to describe trial design strategies for conditions with heterogeneous symptoms