Stability of finite difference deconvolution I: theoretical analysis

Analysis of the stability of finite difference deconvolution (FDD) shows that it is dependent on the characteristics of the unit impulse response function and the sampling schedule of the input response function, and that stability properties are improved when the cumulative amount function is directly estimated rather than the rate function. The estimated input rate for an intravenous (iv) unit impulse response function and the release rate for an oral solution unit impulse response function are unstable for any sampling schedule of the input response function. However, for an iv unit impulse response function, the estimated cumulative amount absorbed is stable for any sampling schedule of the response function. For an oral unit impulse response function, the estimated cumulative amount released is unstable for all the sampling points of the input response function located before the time of the maximum of the oral unit impulse response function, but it can be made stable if an appropriately designed sampling schedule of the input response function is used. In addition, the theoretical basis for choosing a sampling schedule to overcome the instability of FDD has been established. © 1998 John Wiley & Sons, Ltd.     

新冠肺炎隔离病房内医务人员应激(压力)反应与心理韧性现状及相关性研究

目的:探讨新冠肺炎隔离病房内医务人员应激(压力)反应与心理韧性的状况及其相关性.方法:采用应激(压力)反应问卷、心理韧性量表对成都市某三甲传染病医院98名新型冠状病毒隔离病房内医务人员进行调查,应用Pearson相关分析研究两者的相关性.结果:新型冠状病毒隔离病房内医务人员的应激(压力)反应与心理韧性总分在性别、年龄、...     

Placebo Response and Its Predictors in Attention Deficit Hyperactivity Disorder: A Meta-Analysis and Comparison of Meta-Regression and MetaForest

BackgroundHigh placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication–placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response.MethodsA systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design–, intervention–, and patient–related covariates in predicting placebo response was studied by means of meta-regression and MetaForest.ResultsNinety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was −8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R² = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world.ConclusionsStrong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world.     

海洛因依赖者纳曲酮治疗过程中意外催瘾的研究

目的:探讨海洛因依赖者纳曲酮抗复吸治疗中意外催瘾的作用。方法:对49例应用纳曲酮抗复吸治疗的海洛因依赖者随访6个月,了解患者意外催瘾经历,以及意外催瘾对患者偷吸、脱毒后操守率及服用纳曲酮保持率的影响。结果:27例(55.1%)有意外催瘾的经历;与无意外催瘾组比较,在1-4周内,有意外催瘾组的偷吸人数少(P<0.05,P<0.01),2-25周的操守率高(P<0.05);Cox回归分析发现,稽延性戒断症状、患者孤独、沉闷情绪及家庭经济困难是纳曲酮治疗保持率的风险因素。结论:意外催瘾具有厌恶疗法样作用,对应用纳曲酮抗复吸治疗的海洛因依赖者的抗偷吸和抗复吸具有积极意义。     

Meta‐analysis: the effects of placebo treatment on gastro‐oesophageal reflux disease

Aliment Pharmacol Ther 2010; 32: 29–42

Summary

Background There appears to be a significant placebo response rate in clinical trials for gastro‐oesophageal reflux disease. Little is known about the determinants and the circumstances associated with placebo response in the treatment of gastro‐oesophageal reflux disease (GERD). Aims To estimate the magnitude of the placebo response rate in randomized controlled trials for GERD and to identify factors that influence this response. Methods A meta‐analysis of randomized, double‐blind, placebo‐controlled trials, published in English language, which included >20 patients with GERD, treated with either a proton pump inhibitor or H₂‐receptor antagonist for at least 2 weeks. Medline, Cochrane and EMBASE databases were searched, considering only studies that reported a global response for ‘heartburn’. Results A total of 24 studies included 9989 patients with GERD. The pooled odds ratio (OR) for response to active treatment vs. placebo was 3.71 (95% CI: 2.78–4.96). The pooled estimate of the overall placebo response was 18.85% (range 2.94%–47.06%). Patients with erosive oesophagitis had a non‐significantly lower placebo response rate than patients without it (11.87% and 18.31%, respectively; P = 0.246). Placebo response was significantly lower in studies of PPI therapy vs. studies of H₂ RAs ( 14.51% vs. 24.69%, respectively; P = 0.05). Conclusions The placebo response rate in randomized controlled trials for GERD is substantial. A lower placebo response was associated with the testing of PPIs, but not the presence of erosive oesophagitis.     

Enhancing response inhibition by incentive: comparison of adolescents with and without substance use disorder

Effective response inhibition is a key component of recovery from addiction. Some research suggests that response inhibition can be enhanced through reward contingencies. We examined the effect of monetary incentive on response inhibition among adolescents with and without substance use disorder (SUD) using a fast event-related fMRI antisaccade reward task. The fMRI task permits investigation of how reward (monetary incentive) might modulate inhibitory control during three task phases: cue presentation (reward or neutral trial), response preparation, and response execution. Adolescents with lifetime SUD (n=12; 100% marijuana use disorder) were gender and age-matched to healthy controls (n=12). Monetary incentive facilitated inhibitory control for SUD adolescents; for healthy controls, the difference in error rate for neutral and reward trials was not significant. There were no significant differences in behavioral performance between groups across reward and neutral trials, however, group differences in regional brain activation were identified. During the response preparation phase of reward trials, SUD adolescents, compared to controls, showed increased activation of prefrontal and oculomotor control (e.g., frontal eye field) areas, brain regions that have been associated with effective response inhibition. Results indicate differences in brain activation between SUD and control youth when preparing to inhibit a prepotent response in the context of reward, and support a possible role for incentives in enhancing response inhibition among youth with SUD.     

Comparative effects of nitrendipine and verapamil on neuroeffector transmission in the rabbit ear artery

The purpose of the present study was to evaluate and compare the effects of the calcium antagonists nitrendipine and verapamil on nerve-evoked constrictions and on norepinephrine (NE) release in the isolated, perfused rabbit ear artery. The response of the ear artery to nerve stimulation consists of an early phasic constriction (P response) and a late, slow-developing tonic constriction (T response). Both calcium antagonists were much more potent in causing inhibition of the T than P responses. For nitrendipine the EC50 (6.6 +/- 2.3 X 10(-8)M) for inhibition of T response was 450 times lower than the EC50 for inhibition of P response. Verapamil exhibited less selectivity for T response: the EC50 for inhibition of T response was 17 times lower than the EC50 for inhibition of the P response. Nitrendipine (3.3 X 10(7) to 3.3 X 10(-5) M) did not alter the nerve-evoked release of [3H]NE from arteries preincubated with [3H]NE. Verapamil at 3.3 X 10(-6) and 3.3 X 10(-5)M enhanced both spontaneous and nerve-evoked [3H]NE release.     

A parametric description of amphetamine's effect on response rate: changes in reinforcement efficacy and response topography

A mathematical model was used to describe the effects of amphetamine on the rate of a reinforced response in the rat. The model provides measures of reinforcement efficacy and response topography for behavior maintained by variable-interval reinforcement schedules. In this study the measured behavior was a lever press, the reinforcer was water, and the variable-interval schedules provided five different rates of reinforcement, ranging from about 20 to 660/h. In each session the rats were exposed to each of the five schedules, and as reinforcement rate increased, the rate of lever pressing increased in a negatively accelerated manner that was closely approximated by the equation for a rectangular hyperbola. Amphetamine changed response rate and the parameters of the best-fitting hyperbolas. The 0.25-1.0-mg/kg doses increased response rate, and the parameter changes supported the interpretation that the increases were due primarily to an increase in reinforcement efficacy. The 2.0- and 3.0-mg/kg doses decreased response rates maintained by low reinforcement rates and increased response rates maintained by high reinforcement rates, and the parameter changes supported the interpretation that at higher doses amphetamine produced counteracting changes in reinforcement efficacy and response topography: reinforcement efficacy decreased, whereas response topography changed so as to increase response rates.     

Study on the mechanism of potential response of a ketamine‐sensitive membrane electrode

The response mechanism of a simple device for the rapid detection of ketamine with ‘in the field’ capabilities is investigated. The mechanism is a membranous ketamine ionic selective electrode (ISE) with partly carboxylated PVC as matrix and ortho‐nitrophenyloctyl ether (o‐NPOE) as plasticizer. The experimental results reveal that the inclusion of the plasticizer in the membrane significantly increased the response. A mechanism is proposed where the infiltration of a target species into the membrane is capable of producing a superior response. This response process is non‐selective for species with similar molecular structure and size. This new research addresses some omissions and misapprehension in the literature where the mechanism was reported as an ion‐exchange‐induced response. In this research the ion‐exchange‐induced response was measurable after the elimination of the infiltration‐induced response extending to lower concentration ranges and thus providing the potential for better sensitivity and selectivity. Copyright © 2010 John Wiley & Sons, Ltd.     

Crotapotin induced modification of T lymphocyte proliferative response through interference with PGE2 synthesis.

The immunosuppressive property has been demonstrated for the venom of the Crotalus durissus terrificus. Using a simple, novel method for obtaining crotapotin and phospholipase A2 isoforms from venom, it was possible to demonstrate that the addition of crotapotin to cultures of isolated lymphocytes resulted in a significant inhibition of the cellular proliferative response to Concanavalin A. This reduction in blastogenic response of lymphocytes is accompanied by a significant increase in the production of PGE2 by macrophages. This effect on the innate immune response suggests that this compound may modify the subsequent adaptative immune response.     

Clomipramine concentration as a predictor of delayed response: a naturalistic study

Objectives: The aim of the present study was to characterise onset of response to clomipramine treatment in a naturalistic setting and to investigate the relationship between concentration and delayed response, postulated to reflect drug-specific response to antidepressant therapy. Methods: Ninety-eight depressed patients were prescribed clomipramine in an open flexible manner and followed for depressive symptoms (Montgomery-Åsberg depression scale) over a maximum 12 weeks follow-up period. All patients had at least one concentration measurement for therapeutic drug monitoring purpose. Results: Firstly, survival analysis revealed a probability of 15.4% for patients not to show 50% improvement over baseline by week 12, and thus to be considered as non-responders. Median time to onset of response was 31 days for responders, indicating a relatively high probability of delayed response under routine treatment. Secondly, pattern analysis indicated a significant association between early and abrupt response on the one hand and delayed and gradual response on the other. A tendency towards an association between delayed and persistent response was also observed. Finally, receiver operating characteristics analysis allowed identification of a highly significant lower threshold of 230?ng?·?ml^?1 for the sum of clomipramine and desmethyl-clomipramine, as measured at week 3, with respect to response from week 3 onward. Predictive values were 68.8% and 81.0% for concentrations above and below this threshold to predict delayed response and non-response, respectively. Thresholds were 55?ng?·?ml^?1 for parent compound and 180?ng?·?ml^?1 for metabolite. Conclusion: This approach supports the hypothesis that delayed response may be concentration dependent and thus may reflect true drug effect. As a consequence, monitoring clomipramine concentration about 3 weeks after initiation of therapy may valuably contribute to help clinicians decide about the adequacy of ongoing therapy.     

新生儿接种乙型肝炎疫苗后无(低)应答率及再免效果分析

目的探究新生儿接种乙型肝炎疫苗后无(低)应答率及再免效果。方法对我中心接种的1301名新生儿乙型肝炎疫苗接种以及应答情况进行检测。结果有231例新生儿出现低(无)免疫应答,低应答主要与新生儿的体质量以及母亲的感染情况有明显相关性(P<0.05)。结论对新生儿进行疫苗接种后对其进行应答检测,并对低应答新生儿及时进行再免疫,提高其免疫效果。     

Zero interaction response surfaces, interaction functions and difference response surfaces for combinations of biologically active agents.

In the field of combination experiments there is wide-spread confusion over definitions, terminology and methods for the evaluation of interaction between biologically active agents. According to our view the widely used isobole approach is the method of choice. In this contribution it is shown how the combination of the classical isobole approach with response surface modeling and computer graphics leads to powerful new methods for the assessment of interaction of biologically active agents. In particular, zero interaction response surfaces, difference response surfaces and interaction functions are proposed. Zero interaction response surfaces represent surfaces which display zero interaction in the whole dose range. Difference response surfaces display the difference between an actual response surface and the corresponding zero interaction response surface. Interaction functions are a generalization of the index of interaction, which describe the dose dependence of this quantity.     

Translational aspects of pharmacological research into anxiety disorders: the stress-induced hyperthermia (SIH) paradigm

In anxiety research, the search for models with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is often challenging. This review describes the stress-induced hyperthermia (SIH) paradigm, a model that studies the activation of the autonomic nervous system in response to stress by measuring body temperature. The reproducible and robust SIH response, combined with ease of testing, make the SIH paradigm very suitable for drug screening. We will review the current knowledge on the neurobiology of the SIH response, discuss the role of GABA_A and serotonin (5-HT) pharmacology, as well as how the SIH response relates to infectious fever. Furthermore, we will present novel data on the SIH response variance across different mice and their sensitivity to anxiolytic drugs. The SIH response is an autonomic stress response that can be successfully studied at the level of its physiology, pharmacology, neurobiology and genetics and possesses excellent animal-to-human translational properties.     

Lymphotoxin alpha gene in Crohn's disease patients: absence of implication in the response to infliximab in a large cohort study

A haplotype in the lymphotoxin alpha (LTA) gene has been associated with a lack of response to infliximab in a small cohort of Crohn's disease (CD) patients. The present study aimed to confirm the implication of this haplotype in the response to infliximab in a larger cohort of Caucasian patients. The response to the first infusion with infliximab was evaluated in 214 Caucasian patients with either luminal (n=150) or fistulising (n=64) CD. Clinical response was based on the decrease in CD Activity Index (luminal) or on the evolution in the fistula discharge (fistulising). Biological response was assessed in 139 patients who had elevated C-reactive protein (CRP) before treatment and for whom CRP values were also available after treatment. A positive biological response was defined as a decrease in CRP of at least 25%. The patients were genotyped for six polymorphisms in the LTA gene. A positive clinical response was present in 65.4% of the patients and a positive biological response was observed in 80.6% of the patients. No association was found with any of the studied polymorphisms, nor with the previously published LTA haplotype and the response to infliximab. We could not confirm an association between the LTA locus and clinical or biological response to infliximab in a large cohort of CD patients.     

Synthesis and Structure Elucidation of 5-Aminomethinimino-3-methyl-4-isoxazolecarboxylic Acid Phenylamides and Their Immunological Activity

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4 . The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response ( 4d ), humoral immune response ( 4a ), or cellular immune response ( 4c ). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.     

Extremely low doses of X-radiation can induce adaptive responses in mouse prostate

The pKZ1 mouse chromosomal inversion assay is the only assay that has detected modulation of a mutagenic endpoint after single whole body X-irradiation with doses lower than 1 mGy. A non-linear dose response for chromosomal inversion has been observed in spleen and prostate between 0.001 mGy and 10 mGy, with doses between 0.005-0.01 mGy causing an increase in inversions and doses between 1-10 mGy causing a reduction below spontaneous inversion frequency. An adaptive response is a decreased biological effect induced by a low radiation dose. Adaptive responses contradict the linear-no-threshold model of risk estimation. We demonstrated that very low (0.001 mGy, 0.01 mGy, 1 mGy and 10 mGy) doses of X-radiation induced a chromosomal inversion adaptive response as measured by a reduction in the frequency of subsequent high dose (1000 mGy) induced inversions in prostate. These are the lowest X-radiation doses reported to induce an adaptive response for any endpoint. Adaptive response experiments were also performed where the high dose was administered four hours prior to a low dose of 0.01 mGy or 10 mGy In both cases an adaptive response was observed. Identification of the modifying factors involved in the adaptive response may provide candidates for radioprotection.     

Predicting Low Dose Effects for Chemicals in High Through-Put Studies

High through-put studies commonly use automated systems with 96-well plates in which multiple chemicals are tested at multiple doses using log-2 dose increments after a suitable incubation period. There are typically multiple (ranging from five to eleven) doses on each chemical, and occasionally plate replications of the dose-response studies. The target endpoint for such studies is typically the LC50, but for some chemicals, there may be multiple doses below a benchmark dose where there is no apparent adverse response relative to control response. We show how an estimation approach can lead to clearly interpretable results about response in the low dose region using data from a high throughput study of 2189 chemicals on yeast. Accurate estimates can be obtained of response for study chemicals by using best linear unbiased predictors (BLUPs) in a mixed model, and summarized via plots with expected response (assuming no low-dose effect) with confidence intervals for response below the benchmark dose for each chemical, providing an informative summary of response at low doses. We conclude that this approach can provide valuable insights that would be missed if the observational data were only considered through the lens of statistical methods appropriate for experimental studies.     

Effects of specific dopamine lesions and dopamine receptor sensitivity on angiotensin II- and carbachol-induced thirst in rats

A study was made of the effects of manipulating brain dopaminergic activity upon drinking induced by intracerebroventricular administration of angiotensin II or carbachol. Non-specific lesions induced by injecting 6-hydroxydopamine (6-OHDA) into the cerebroventricles caused a significant reduction in angiotensin-induced thirst without affecting carbachol drinking. Specific 6-OHDA-induced lesions of the dopaminergic nigro-striatal pathway also attenuated the angiotensin-induced response, while unilateral lesions reduced and bilateral lesions almost completely abolished the effect. Again, the response to carbachol was unaffected. Chronic haloperidol treatment increased behavioural responses to the dopamine agonist apomorphine and significantly stimulated angiotensin-induced drinking without affecting response to carbachol. These studies provide support for the hypothesis that a dopaminergic event is involved in the angiotensin-induced thirst response and point to the need for a functioning dopaminergic nigro-striatal pathway for the full expression of this response.     

Exposure–Response modeling of anti-depressant treatments: the confounding role of placebo effect

Emerging evidence indicates that the selection of patients and the selection of recruitment centers in placebo-controlled, randomized clinical trials (RCTs) in depression have a substantial impact on the probability of observing a treatment effect of a novel medication. The objective of this work was to evaluate the role of placebo in characterizing the exposure–response relationship and proposes a new methodology based on band-pass filtering for assessing the relationship between drug exposure, level of clinical response conditioned to the level of placebo response, and the potency of the antidepressant drug evaluated. Clinical trial simulation (CTS) was used to demonstrate that the conventional analyses of data generated in multi-centre RCTs including centres exhibiting heterogeneous placebo response can lead to contradictory and inappropriate assessment of the exposure–response relationship. To address this issue, a novel modelling approach has been developed for establishing the exposure–response relationship by using a pharmacodynamic model accounting for the placebo effect. The proposed model demonstrated that the expected drug related treatment effect in a placebo-controlled RCT can be predicted as a function of the dose, the drug potency and the level of placebo response when data from informative recruitment centres are considered. With this novel approach, a more accurate estimate of the dose/exposure response can be derived and more informed go/no-go decisions can be made in developing drugs for psychiatric disorders.