There are other essential goals in clinical trial design as well. For instance, a well-designed trial will have a sample size that provides adequate statistical power to detect a clinically meaningful effect. An antidepressant trial, for example, must be designed to detect an effect of about .40 standard deviation units (ie, Cohen’s d=.40) and that requires about 100 participants per

treatment group for 80% statistical power for a t-est with a two-tailed alpha-level of .05. However, there is a tradeoff between power and feasibility. Recruitment of 100 per group is only feasible if compatible with both the budget and Inhibitors,research,lifescience,medical the study site patient flow. Furthermore, a trial must be designed such that the false-positive rate (ie, Type I error) is acceptable; the convention is 0.05. This is because false-positive treatments, of course, do not reduce suffering in patients. Finally, the design must be applicable. That is, Inhibitors,research,lifescience,medical the recruited sample should yield results Inhibitors,research,lifescience,medical that generalize to the target patient population; ie, that for which the indication is sought. A well-designed and well-implemented RCT is the gold standard for treatment evaluation. This is because the groups tend to be well-balanced at baseline,

and therefore subsequent group différences can be attributed to treatment effects, providing strong internal validity. However, there are limitations of results from RCTs for psychiatric Inhibitors,research,lifescience,medical disorders. For example, trials for mood disorder interventions typically involve short-term treatment (4 to 12 weeks) despite the chronic nature of the disorders. Furthermore,

Inhibitors,research,lifescience,medical the samples tend to be highly- selected and that restricts the generalizability (ie, external validity) of the results. For instance, it has been shown that RCTs for major depression evaluate treatment in rarefied samples, excluding as many as 85% of those who are Batimastat screened.3 The exclusions are, for example, based on illness severity (too severe or not severe Olaparib purchase enough) and safety risk (eg, suicidality, concomitant medication, or psychosis). Therefore the results do not inform the treatment of patients who have such features. Finally, the attrition poses a serious threat to the internal validity of a clinical trial. The attrition rates in antidepressant trials range from 30% to 40% and they are higher for antipsychotics, ranging from 50% to 60%:’ Self-selection of this type (ie, attrition) and of this magnitude severely compromises randomization. Features of design and analysis that reduce the impact of attrition on RCTs of psychotropics have been discussed in detail elsewhere.

A direct comparison of 0.5- and 100-Hz activation patterns revealed no significant differences between frequencies. The block-by-block analysis, performed to understand

the pattern of deactivation for each stimulation time period over the experimental run, revealed that the majority of the blocks for both 0.5 and 100 Hz demonstrated a reliable pattern of deactivation Inhibitors,research,lifescience,medical during “on” and relative activation during baseline (Fig. 3). Figure 3 Time course of activation/deactivation block-by-block, averaged for regions for which there was overlap from all 11 participants’ leave-one-subject-out group activation maps (see Fig. S1). ROI analysis We found no differences in mean thalamic activity when the device was “on” versus baseline for either the 0.5- or 100-Hz CES. Current intensity regression Inhibitors,research,lifescience,medical A voxel-wise analysis using current as a regressor revealed positive associations between current and activation for 100-Hz but not 0.5-Hz stimulation. Regions included right/left posterior cingulate cortex, left superior selleck kinase inhibitor parietal lobule, left angular gyrus, left supramarginal gyrus, and left lateral occipital cortex (Table S2). There were no significant associations with brain deactivation in any www.selleckchem.com/products/FTY720.html region. Inhibitors,research,lifescience,medical This pattern for current intensity therefore differed from what was found in the “on” versus baseline analyses, suggesting that cortical deactivation may depend more on frequency than intensity of stimulation.

PPI analysis (Fig. 4 and Table 2) Figure 4 Regions of altered connectivity with the posterior cingulate seed

within the default mode network associated with 100-Hz stimulation. Regions of increased connectivity are depicted in yellow–orange and decreased connectivity Inhibitors,research,lifescience,medical are depicted in blue–light … Table 2 Regions of altered functional connectivity associated with CES stimulation at 100 Hz between the bilateral posterior cingulate gyrus (seed region) and other regions within the default mode network. Inhibitors,research,lifescience,medical Z scores and MNI coordinates for local maxima (x, y, … For the DMN analysis, 100 Hz was associated with increased connectivity between the posterior cingulate AV-951 cortex seed and the left planum temporale, bilateral postcentral gyrus, and bilateral anterior supramarginal gyrus (Fig. 4 and Table 2). A total of 100 Hz was also associated with decreased connectivity between the posterior cingulate cortex seed and the left posterior supramarginal gyrus, the left angular gyrus, and the left superior lateral occipital cortex. A total of 0.5 Hz was not associated with any significant changes in connectivity. For the SMN, neither 100-Hz nor 0.5-Hz stimulation was associated with any significant changes in connectivity. For the FPN, there were no significant alterations of connectivity detected for either frequency. Discussion Results from this study suggest that 0.5- and 100-Hz CES causes cortical brain deactivation in midline prefrontal and parietal regions.

The clinic-based nature of the programs, which mix stable patients and newly maintained patients, along with inadequate staffing, and minimal incentives for patient change, can lead to a culture of continued illicit drug use and chronic unemployment.94 In spite of many decades of improving and saving lives, methadone maintenance is often viewed

as perpetuating addiction or being immoral. The traditional method of withdrawal Inhibitors,research,lifescience,medical is decreasing the methadone dose rapidly until 30 mg is reached, and then slowly tapering from that, eg 5 mg/week or switching to clonidine.102,103 A more recent approach involves transferring the patient to buprenorphine/naloxone and then tapering as described in the section on discontinuing buprenorphine.103 Partial agonist maintenance Buprenorphine Buprenorphine, a Schedule III controlled substance, Inhibitors,research,lifescience,medical is a high affinity partial n-selleck chemical Sunitinib opioid agonist, k antagonist, and ORL-1 receptor agonist.104 Studies from 1980 on found it useful for treating opioid withdrawal and dependence.105-109 Office-based buprenorphine maintenance has already increased treatment availability for opioid-dependent selleck kinase inhibitor individuals and brought into treatment populations Inhibitors,research,lifescience,medical that had been unable or

unwilling to attend methadone maintenance clinics, eg, prescription opioid addicts. Prescription opioid addicts seeking office-based buprenorphine are likely to present different issues than heroin addicts applying for methadone maintenance.110 Primary-care physicians who have not treated opioid dependence will also present new challenges to the field. Anecdotal Inhibitors,research,lifescience,medical reports describe patients on buprenorphine

as feeling Inhibitors,research,lifescience,medical more clear-headed, more energetic, and more aware of emotions than on methadone maintenance.111 To diminish possible diversion to parenteral use, the recommended form of buprenorphine is a 4:1 combination with naloxone (Suboxone). The mono form (Subutex) is used for pregnant women and, at times, for induction. Federal regulations In 2002, the FDA approved buprenorphine for the treatment of opioid dependence in office-based practice. It was already being used for such treatment in other Entinostat countries. Physicians need to receive 8 hours of specialized training in person or online, and then apply for a waiver from the Department of Health and Human Services. They are limited to 30 patients on buprenorphine for the first year, and can then apply to increase the number to 100. Pharmacology Buprenorphine binds to the n receptor and activates it, but as the dose increases, there is a ceiling on some opioid agonist effects, such as respiratory depression, making it safer than a full agonist as far as overdose.

4,95% CI=2.6-11.3) compared with selleck chem inhibitor Individuals with neither insomnia or psychiatric disorders. The authors suggested that the early diagnosis and treatment of insomnia may prevent subsequent depression. In a longitudinal study of 979 young adults,24 insomnia increased the relative risk for depression fourfold (95% 0=2.2-7.0) over a 3-year period, even after controlling for baseline depression symptoms. In another longitudinal study in 591 young adults, depression and insomnia symptoms were assessed six times Inhibitors,research,lifescience,medical over 21 years.25 The presence of insomnia either with or without comorbid depression tended to be highly stable over time. Between

17% and 50% of cases without depression but Inhibitors,research,lifescience,medical with 2 weeks or more of insomnia in the past 6 months developed a major depressive episode at a subsequent time point. The presence of insomnia (without depression) and depression (without insomnia) were not longitudinally related to each other. Insomnia comorbid

with depression, however, was longitudinally related to having both. Two other studies have similarly selleck bio identified insomnia as a risk factor for depression over long follow-up periods. One study26 followed Inhibitors,research,lifescience,medical over 1000 male medical students for a median of 34 years (range 1-45). Both insomnia and difficulty sleeping under stress in medical school increased the risk for subsequent depression (relative risk and 95% CI, respectively, 1.9, 1.2-3.2 and 1.7, 1.1-2.5). Another study followed 1244 middle-aged adults for 12 years.27 Chronic insomnia was reported in a third of women and a quarter of men; three Inhibitors,research,lifescience,medical quarters of those with insomnia at baseline also had insomnia at the 12year follow-up. Only women who reported insomnia at baseline were significantly more likely to report feeling depressed at follow-up Inhibitors,research,lifescience,medical “(QR=4.1, 95% CI=2.1-7.2), whereas the relationship in men was not significant. (OR=1.3, 95% 0=0.8-2.3). Similar risk relationships have been identified in older

adults. In a study28 involving 147 older adults without, a prior history of mental illness, the presence of insomnia (scoring 1 or higher on any of the Hamilton Rating Scale for Depression sleep items) was assessed at two time points separated by 1 year. Participants with insomnia that persisted at both time points were more likely to develop a first episode of depression during the AV-951 1-year follow-up period (OR=6.9,95% 0=1.3-36.1) compared with participants who scored 0 on the three sleep items at both time points. In a larger longitudinal study of 524 older adults,29 sleep disturbances at baseline predicted depression 2 to 3 years later (odds ratio=3.2, 95% CI=1 .5-6.8), after adjusting for other risk factors. Individuals with persistent sleep disturbances were more likely to be depressed than individuals whose insomnia had resolved at follow-up or individuals who developed insomnia during follow-up.

47 The use of PDE5-Is will only be successful in post-RP patients who have had some type of nerve-sparing selleck Lapatinib procedure. It appears that the induction of neural NO as discussed previously contributes to its mechanism

of action. Preservation of smooth muscle content has been seen with these agents, which will prevent venous leak from developing. Early Inhibitors,research,lifescience,medical usage of these agents may not be as effective as long-term usage because of neuropraxia, which may resolve as late as 2 years after RP, although recent studies have suggested that early use of PDE5-Is, regardless of neuropraxia, improves long-term erectile recovery. Gene Therapy Advances in molecular Inhibitors,research,lifescience,medical biology have allowed transfer of genetic material to humans and other animals with the aid of vectors. This technology is now being expanded to a disease process

like ED. Currently, human trials with FK506, GPI-1046, and potassium channel gene therapy have just begun.27 George Christ, PhD, has classified gene therapy into two categories: increasing the supply of the erectile stimulus and decreasing the physiologic demand for the erectile tissue.27 Brain-derived neurotrophic factor (BDNF) has been shown to Inhibitors,research,lifescience,medical improve erection in rats using adeno-associated virus as a vector after cavernous nerve injury, which subsequently increases NO and NOS.27 Vascular endothelial growth factor (VEGF) has been shown to increase vascular supply in rat models.27 FK506 and GPI-1046 have been shown to selleck inhibitor accelerate nerve regeneration after crush injury in rat sciatic nerves by protecting neurons from chemotoxin-induced cell death.25,27 All these therapies have Inhibitors,research,lifescience,medical been shown to increase the supply of NO or the regeneration of nerves that supply

NO. Conversely, in the demand category RhoA and manipulation of potassium channels (hSlo) help to sensitize calcium relaxation of smooth muscle and potassium-related smooth muscle tone in the penis, which ultimately leads to improved erectile function. These gene factors show promise Inhibitors,research,lifescience,medical in animal studies and may be the future ED therapy in post-RP patients, yet randomized, controlled human studies need to be conducted because long-term side effects are unknown.27 Conclusions There are many factors that contribute to post-RP ED. Preoperatively, the patient’s Cilengitide age at the time of surgery, partner’s age, preoperative erectile function, and comorbidity profile should be assessed.9 Intraoperative factors that contribute to recovery of erectile function after RP are surgical approach and amount of nerve preservation and surgical expertise. Postoperative factors that contribute to recovery of erectile function after RP are time to erectile function assessment after surgery and ED treatment.9 This review concentrated on the latter.

These compounds are characterized by an aromatic ring which is condensed to a heterocyclic ring and attached to a second aromatic ring. An innovative therapeutic approach could be the use of natural plant polyphenol flavenoids, reported to have access to the brain and to possess multifunctional activities as iron chelators, radical scavengers, anti-inflammatory agents, and neuroprotectants.80–83 Figure 12 Structures of polyphenol flavenoids which in in-vitro and in-vivo studies have been shown

Inhibitors,research,lifescience,medical to have neuroprotective and cognitive enhancing activities in animal models of Parkinson’s and Alzheimer’s diseases. These compounds and their actions have been extensively reviewed.84 In particular, the major constituent of green tea catechin Crenolanib PDGFR inhibitor extract (-)-epigallocatechin-3-gallate (EGCG) (Figure 12) plays a major role in the prevention of selleck chemicals llc neurodegeneration in a variety of cellular and animal models of neurodegenerative diseases.85 This effect appears to be mediated through multiple pathways, including the participation of the pro-survival PKC and extracellular mitogen-activated Inhibitors,research,lifescience,medical protein kinase (MAPK) signaling and the Inhibitors,research,lifescience,medical promotion of neurite outgrowth.86 Structurally important features defining their chelating potential are the 3′,4′-dihydroxyl group in the B ring,80 as well as the gallate group87 which may neutralize ferric iron to form redox-inactive iron, thereby

protecting cells against oxidative damage.88 Recent studies have shown that prolonged administration Inhibitors,research,lifescience,medical of EGCG to mice induced a significant reduction in membrane-associated APP levels in hippocampus89 and in cerebral Aβ levels con-comitant with reduced β-amyloid plaques.90 This effect may be accounted for, in part, by the chelation of the intracellular free-iron labile pool, modulating APP mRNA translation via its IRE-type II,91 as has recently been described for other metal chelators, such as desferoxamine, clioquinol, and dimercaptopropanol.92,93

CONCLUSIONS PD and AD are complex diseases with multiple pathways which contribute Inhibitors,research,lifescience,medical to their etiology and finally cell death of DA, cholinergic, and other neurons. To address this multiplicity, Anacetrapib compounds that have more than one target in the cell death cascades are now investigated and designed. These drugs have the advantage of acting at several sites in the brain and neurons and possess not only neuroprotective but also neurorestorative activity. Their neuroprotective activity relies on activating the Bcl-2 antiapoptotic proteins while down-regulating the proapoptotic proteins through gene regulation. On the other hand the neurorestorative property of these compounds is associated with induction of neurotrophins such as BDNF, GDNF, and HIF (hypoxia-inducing factor). The feasibility of moving these drugs to market has been shown through the success of rasagiline, which has been shown to have neuroprotective activity and has made it to the market as a PD therapeutic.

Indeed, in their eyes, the inability to prove that God exists might even cast doubt on His existence. Because of their reverent attitude towards the power of logic, many Jewish philosophers devoted considerable effort to

arguments intended to prove that God exists. Although this subject is nowhere discussed in the Bible or in the Talmud, proofs for the existence of God are Inhibitors,research,lifescience,medical a major topic in the writings of prominent medieval Jewish philosophers. It is instructive to analyze these arguments and their shortcomings. Consider the most famous proof of all – the “prime mover argument.” We all experience in our daily lives the truism asserted by Aristotle: “There is no motion without a mover.” When I rearrange the living-room furniture under the watchful eye of my wife, I am painfully aware of the fact that the couch will not Inhibitors,research,lifescience,medical budge even one centimeter unless I push it, and the instant that I stop pushing, the couch ceases its motion. If I throw a ball, its motion persists momentarily even

after it leaves my hand because I have imparted some “impetus” to the ball. According to the widely accepted “HTC impetus theory,” the ball will continue to move until it uses up all its acquired impetus. Then, the ball will come to rest because “there is no motion without a mover.” Let us now turn our attention to the heavenly bodies, Inhibitors,research,lifescience,medical whose ceaseless motion can Inhibitors,research,lifescience,medical be selleck chemical observed day after day, year after year, century after century. What causes the ceaseless motion of the heavenly bodies? It must surely be a supernatural entity (God to the medieval theologian; Intelligent Designer in today’s terminology). The bubble burst in the seventeenth century, when Isaac Newton formulated his famous three laws of motion in the Principia, the most important book of science ever written. Newton’s law of inertia states, in contrast to Aristotle, that a moving body will continue to move forever unless some force causes it to stop.

In the above examples, the force that causes the furniture or the ball to stop moving Inhibitors,research,lifescience,medical is friction. However, if friction were not present, then the motion would persist forever. In the heavens, there is no friction. Therefore, according to the law of inertia, heavenly bodies will move forever without any agency being required to keep them moving. To complete the picture, Newton’s law of inertia predicts straight-line motion, whereas the orbit of the planets is an ellipse. This is due to Entinostat the gravitational attraction between the sun and the planets, which yields the observed elliptical orbits. Planetary motion is completely described by the laws of nature, without the need to invoke a supernatural entity. The “prime mover proof” for the existence of God is thus refuted. GOD OF THE GAPS The “prime mover proof” for the existence of God was based on a lack of knowledge of physics. This is an example of what is called the “God of the gaps.

58 In addition, the appreciation of the neurohumoral modulation of social download catalog processes (eg, oxytocin/vasopressin, endorphin, and dopamine systems) appears to many as a promising ground to understand psychiatric disorders and devise new effective medications.20 Current research in social cognition and social neuroscience is historically related to academic Inhibitors,research,lifescience,medical cognitive psychology whose theories and experimental paradigms provided fertile

ground for the early development of cognitive neuroscience in the beginning era of noninvasive human functional neuroimaging.59 Some academic social psychologists were also well positioned to take advantage of the new technologies.60 Typically these approaches have not been developed starting from an integrative theory of the self and self-awareness, and the struggle with the demands of human life. Conversely, scholars Inhibitors,research,lifescience,medical interested in psychodynamic approaches (structurally equipped and interested in developing a discourse on various aspects of the self and self-awareness in social interactions), Inhibitors,research,lifescience,medical have lagged behind in the development of experimental

approaches (but see the recent endeavor of the Society for Neuropsychoanalysis and related work).47,61 Therefore, historical contingencies and the global readiness of a field to embrace the new scientific outlets rather than cogency of psychological models and their potential applicability to the clinical reality influenced the research agenda in social neuroscience. One is left to wonder Inhibitors,research,lifescience,medical if cognitive sciences, as they seek an understanding

of the human mind and psychiatric phenomena, have reflected adequately on the nature of their object of inquiry. Essential conceptualizations Inhibitors,research,lifescience,medical have been excluded in the name of Ockham’s Razor (or lex parsimoniae, law of parsimony), in a way that tends to lead to an eliminativist reductionism. A valid object of research has been partially lost and perhaps undermined by an “epistemological obstacle.”62 In regard to its application to psychiatry, social cognitive neuroscience may even represent an involution relative to relevant conceptual framework Carfilzomib and tools already available for clinicians.63 A narrow view of social cognition applied to psychiatry understands the person to be studied as an object whose properties are measured in order to uncover purported elementary social cognitive processes (eg, perception of facial Crenolanib mw expression, instrumental learning, etc) and their mechanisms to predict social functioning, adaptation, and outcome. These putative elementary processes are often studied with the goal of (re)defining nosology, identifying potential endophenotypes (or heritable biomarkers present not just during the active phase of the illness) for specific psychiatric disorders, and targets for novel pharmacological treatments.

(Or to be more precise, quercetin supplementation showed no greater beneficial effects than placebo.) All three groups improved their test scores,

showing, perhaps, the effects of training and expectation. Nothing in this appropriately powered, well conducted study suggests any role for quercetin as a cognitive enhancer. Cortisol plays a major part in the development of depression, to the extent that it is probable that Inhibitors,research,lifescience,medical all depression results from some degree altered cortisol responsiveness. The best and most cited example of the potency of cortisol in this respect is that where cortisol levels are pathologically high in Cushing Syndrome, depression affects almost everyone. When cortisol Inhibitors,research,lifescience,medical levels are normalised, the depression abates (Kelly et al., 1996). Extrapolating from these observations, psychiatrists wondered whether reducing cortisol levels in non-Cushing’s subjects might treat depression. Paul David Singalas and co-workers review the role of metyrapone in this issue. Metyrapone inhibits cortisol synthesis and so reduces cortisol plasma levels. Most of the studies of metyrapone have been limited in size, scope and scientific rigour but all have been broadly positive. The best conducted study showed an effect size of 0.6 when metyrapone was added to standard antidepressants. Clearly more studies are required but metyrapone

shows considerable promise – only its Inhibitors,research,lifescience,medical lack of patent protection Inhibitors,research,lifescience,medical militates against its more widespread testing and use. In the second review article in this issue, Praharaj and Sharma report on the use of amantadine for olanzapine-induced Ganetespib mechanism weight gain. Amantadine is a dopamine releaser and re-uptake inhibitor that started out as an antiviral agent used Inhibitors,research,lifescience,medical for influenza. It also reduces appetite and is associated with weight loss. As such it seemed an excellent candidate to prevent or reverse the often profound weight gain seen with olanzapine. Praharaj and

Sharma uncovered six studies examining the use of amantadine with olanzapine but only two met their inclusion criteria. These two studies combined showed a statistically significant and clinically worthwhile advantage over placebo in terms of weight reduction and frequency of weight loss. Drug_discovery Amantadine thus is a suitable treatment for olanzapine-associated weight gain but is perhaps a second-line treatment after the better established metformin which has additional antidiabetic properties. Two further letters-to-the-editor Afatinib structure demonstrate the need to expect the unexpected even when prescribing commonly used drugs. Hayward and Luft describe a peculiar presentation of delirium caused by a combination of lithium clomipramine and Channing and colleagues demonstrate the dangers of using successive doses of long- acting drugs (clonazepam in this case) in acute situations – the danger of accumulation should not be underestimated.

In PD patients, we expected to find the opposite pattern of results, that is high cardioceptive accuracy to impair intuitive decision making due to PD patients’ catastrophic interpretation of such cues. Methods Sample The patient sample consisted of 17 inpatients (eight female patients; M = 41.59 years, SD = 13.30), admitted to a www.selleckchem.com/products/BI6727-Volasertib.html psychosomatic hospital (Schön Klinik Roseneck, Hospital of Behavioral Medicine, Prien, Germany). All patients Inhibitors,research,lifescience,medical had a principal diagnosis of PD as assessed by trained clinical psychologists. Diagnoses were based on DSM-IV-TR criteria (American Psychiatric Association 2000), and verified by J. W., based on the PD-related parts of the SKID-I (Wittchen et

al. 1997). The control group comprised Inhibitors,research,lifescience,medical of 17 volunteers (eight female volunteers; M = 36.53 years; SD = 12.10) without mental disorders, matched for gender

and age. As indicated by self-disclosure, none of the control participants had a psychiatric diagnosis or any cardiac and/or neurological disorder and, therefore, no related medication. Moreover, none of the participants had taken benzodiazepines within 2 weeks prior to the experimental assessment. Patients with an additional Inhibitors,research,lifescience,medical diagnosis of somatoform disorder were excluded, due to the suggested role of abnormal perception of physical symptoms in this diagnostic category. Nevertheless, those meeting criteria for secondary Inhibitors,research,lifescience,medical anxiety disorders (social phobia n = 1, 11.76%), generalized anxiety disorder (n = 1, 5.88%), or major selleck chem inhibitor depression (n = 16, 94.10%) were included, thus representing

a typical sample of PD patients in clinical practice (Kaufmann and Charney 2000; Brown et al. 2001). Materials Equipment ECG was recorded with the NeXus-10® system (Mind Media BV/Roermond-Herten, Netherlands) using Einthoven lead I configuration with Ambu® Blue Sensor VL (Ambu GmbH/Bad Nauheim/Germany) electrodes. Data were sampled at 512 Hz. A freeware IGT application was run on a personal computer (ASUS®, Taipeh, Taiwan) Inhibitors,research,lifescience,medical with Windows XP operating system and presented on a 15-inch LCD-monitor at 1024 × 768 pixel screen resolution with ˜40 cm head-to-screen distance. Iowa Gambling Task The IGT consists of four decks of cards (A, B, C, D). Drawing cards from deck A or B results in large gains but high Carfilzomib losses, leading to an overall loss. In comparison, drawing cards from decks C and D results in small gains but similarly small losses and an overall net profit (see Table ​Table11 for details). Participants are instructed to draw 100 cards from these decks, with the aim to maximize their profit. Typically, control participants begin by selecting cards more or less randomly, followed by a period of implicit learning with a preference for the net gain option and finally explicit knowledge resulting in a clear preference for decks C and D. Table 1 Characteristics of the Iowa Gambling Task. Mental-tracking task Following Herbert et al.