Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors.

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer's disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 µM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 µM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Benzophenone Derivatives with Histamine H3 Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease.

The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10-6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.

Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aß oligomerisation.

Alzheimers disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where ß-amyloid structures (Aß) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aß-monomers. The structure-activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.

Cyanobiphenyls: Novel H3 receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of Ki values) for human histamine H3 receptors (hH3R) and good nonselective inhibitory potency (micromolar range of IC50 values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH3R/eeAChE/eqBuChE/hMAO B ligand (5: hH3R Ki = 9.2 nM; eeAChE IC50 = 2.63 µM; eqBuChE IC50 = 1.30 µM; hMAO B IC50 = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

Discovery of Potential, Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties.

In an attempt to find new dual acting histamine H3 receptor (H3R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H3 receptor (hH3R) ligand KSK63. As a result, 15 obtained compounds show moderate hH3R affinity, the best being the compound 17 (hH3R Ki = 518 nM). Docking to the histamine H3R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH3R Ki = 592 nM) showed the strongest antioxidant properties at the concentration of 10-4 mol/L. It significantly reduced the amount of free radicals presenting 50-60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH3R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H3R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.

Biphenylalkoxyamine Derivatives-Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity.

Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.

Differential G protein activation by the long and short isoforms of the dopamine D2 receptor.

BACKGROUND AND PURPOSE: The dopamine D2 receptor is expressed as a short (D2S) and a long (D2L) isoform with 29 additional amino acids in the third intracellular loop. The D2S isoform shows higher presynaptic expression than the D2L isoform, and decreased D2S expression has recently been linked to an increased risk for schizophrenia. Here, we present the first investigation, at receptor isoform level, of kinetic differences in the G protein activation profiles of the D2S, compared with the D2L isoform. EXPERIMENTAL APPROACH: We employed a NanoBRET-based approach to G protein dissociation to interrogate the time-resolved coupling profile of 3×HA-tagged D2L and D2S to Gαi/o/z proteins in vitro. KEY RESULTS: Using dopamine as a D2 receptor agonist, we observed a more pronounced activation of Gαo and Gαz than Gαi proteins by D2L compared with D2S. This differentiation was not observed for D2S, which activated Gαo and Gαz with lower efficacy than D2L. These signalling differences were preserved on second messenger level and were not due to differences in receptor expression. Expanding to a set of seven full and partial D2 receptor agonists showed these effects were not restricted to dopamine but rather a mutual, receptor-associated property. Contrasting this trend, we found that D2S activated G proteins faster than D2L upon full receptor activation. CONCLUSION AND IMPLICATIONS: The findings highlight that both D2L and D2S are mechanistically able to activate all non-visual Gαi/o proteins. Thereby, they add to previous reports about isoform-specificity to certain Gαi/o proteins observed in specific cell types.

Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.

OLHA (Nα-oleoylhistamine) modulates activity of mouse brain histaminergic neurons.

Histaminergic (HA) neurons are located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus, from where they project throughout the whole brain to control wakefulness. We examined the effects of Nα-oleoylhistamine (OLHA), a non-enzymatic condensation product of oleic acid (OLA) and histamine, on activity of mouse HA neurons in brain slices. OLHA bidirectionally modulated the firing of HA neurons. At 10 nM OLHA inhibited or had no action, whereas at 1 µM it evoked excitatory and inhibitory responses. Inhibition was not seen in presence of the histamine receptor H3 (H3R) antagonist clobenpropit and in calcium-free medium. Pre-incubation with a histamine-reuptake blocker prevented the decrease in firing by OLHA. OLHA-evoked increase in firing (EC50 ∼44 nM) was insensitive to blockers of cannabinoid 1 and 2 receptors and of the capsaicin receptor, but was significantly impaired by the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) antagonist MK886, which suppressed also the rise in intracellular calcium level caused by OLHA. The OLHA-evoked excitation was mimicked by synthetic PPAR-alpha agonists (gemfibrozil and GW7647) and was abolished by the PKA inhibitor H-89. The H3R affinity (Ki) for histamine, measured in HEK293 cells with stable expression of human H3R, was higher than for OLHA (Ki: 42 vs 310 nM, respectively). Expression of PPAR-alpha was not different between TMN regions of males and females, responses to OLHA did not differ. Molecular modelling of PPAR-alpha bound to either OLHA or OEA showed similar binding energies. These findings shed light on a novel biotransformation product of histamine which may play a role in health and disease.

Dual Targeting Ligands-Histamine H3 Receptor Ligands with Monoamine Oxidase B Inhibitory Activity-In Vitro and In Vivo Evaluation.

The clinical symptoms of Parkinson's disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H3 receptor (H3R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H3R (hH3R) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for hH3R (Ki > 500 nM), but very good inhibitory potency for hMAO B (IC50 < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine (13: hH3R: Ki = 25 nM; hMAO B IC50 = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H3R (decline in food and a water consumption), decline in MAO B activity (>90%) in rat cerebral cortex (CTX), and an increase in DA content in CTX and striatum. Moreover, compound 13 caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound 13 is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.

Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 - Triazine and 1H-indole like derivatives against the human histamine H4 receptor.

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.

A planned care approach and patient registry to improve adherence to clinical guidelines for the diagnosis and management of attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) affects almost 2.4 million US children. Because American Academy of Pediatrics guidelines for ADHD recommend use of standardized diagnostic instruments, regular follow-up and the chronic care model, this pilot project sought to implement and assess an electronic registry of patients with ADHD combined with care coordination by a planned care team. METHODS: This quality improvement project was structured with 2 intervention and 2 control clinics to facilitate evaluation of the use of a planned care system for management of ADHD. Care teams included a pediatrician, nurse, medical assistant, and care coordinator and tracked patients using an electronic registry with data drawn from the EMR. Clinical work flows were pilot tested to facilitate use of the Vanderbilt scales and their incorporation into the EMR at intervention sites. Outcome measures included 2 recommended clinical follow-ups based on HEDIS measures as well as use of the Vanderbilt rating scales. Initiation phase measure was for follow-up after initiating medication, while the continuation phase measure was for subsequent follow-up during the first year of treatment. Measures were monitored during the project year and then also in the ensuing period of spread of the intervention to other sites. RESULTS: Although the modified HEDIS initiation phase measure for patients newly on medication remained static at approximately 50% throughout the project period, the continuation phase measure showed improvement from 35% at baseline to 45% at the end of the project assessment year, a 29% increase. Follow-up for patients stable on medications also remained unchanged during the project period, but during subsequent spreading of the intervention to nonproject sites, follow-up of these patients improved to over 90%. In adjusted analyses, patients with ADHD at intervention sites were over 2 times more likely than patients at control sites to have had a Vanderbilt score documented in their records. CONCLUSIONS: The project achieved modest improvements in the diagnostic and treatment process for patients with ADHD. The use of a planned care system and electronic patient registry shows promise for improving the diagnosis and treatment process for patients with ADHD.

Pediatric provider processes for behavioral health screening, decision making, and referral in sites with colocated mental health services.

OBJECTIVE: Validated behavioral health (BH) screens are recommended for use at well-child visits. This study aimed to explore how pediatricians experience and use these screens for subsequent care decisions in primary care. METHODS: The study took place at 4 safety net health centers. Fourteen interviews were conducted with pediatricians who were mandated to use validated BH screens at well-child visits. Interview questions focused on key domains, including clinic BH context, screening processes, assessment of screening scores, and decision making about referral to mental health services. Qualitative analysis used the Framework Approach. RESULTS: A variety of themes emerged: BH screens were well accepted and valued for the way they facilitated discussion of mental health issues. However, screening results were not always used in the way that instrument designers intended. Providers' beliefs about the face validity of the instruments, and their observations about performance of instruments, led to discounting scored results. As a result, clinical decisions were made based on a variety of evidence, including individual item responses, parent or patient concerns, and perceived readiness for treatment. Additionally, providers, although interested in expanding their mental health discussions, perceived a lack of time and of their own skills to be major obstacles in this pursuit. CONCLUSIONS: Screens act as important prompts to stimulate discussion of BH problems, but their actual scored results play a variable role in problem identification and treatment decisions. Modifications to scheduling policies, additional provider training, and enhanced collaboration with mental health professionals could support better BH integration in pediatric primary care.

Dental health indicators of hunter-gatherer adaptation and cultural change in Siberia's Cis-Baikal.

This investigation of the Cis-Baikal dental record focuses on health and lifestyle reconstruction of the region's mid-Holocene foragers, with particular interest in an apparent fifth millennium BC biocultural hiatus. The four cemetery populations considered represent two distinct biological and cultural groups separated by an apparent 700-year hiatus: the late Mesolithic-early Neolithic Kitoi culture (6800-4900 BC) and the middle Neolithic-early Bronze Age Serovo-Glaskovo cultural complex (4200-1000 BC). Research focuses on the frequency and severity of seven dental health indicators: enamel hypoplasia, caries, alveolar defects, periodontitis, antemortem tooth loss, dental calculus, and dental attrition. Together, these seven indicators provide a basis not only for better understanding mid-Holocene lifeways in the Cis-Baikal but also for independently assessing the relative effectiveness of the different adaptive strategies employed by pre- and posthiatus peoples. Results reveal some discrepancies between the Kitoi and Serovo-Glaskovo, specifically in their relative vulnerability to physiological stress, providing evidence to support previous interpretations of their distinct adaptive regimes (namely the narrower resource base and decreased mobility of the former). Results also suggest that some of the differences observed among the four sites may reflect geographical or environmental factors rather than simply cultural ones. However, despite these distinctions, the overriding trend appears to be one of general continuity, social equality, and good health among all mid-Holocene occupants of the Cis-Baikal, pre- and posthiatus alike.

Mental health screening in pediatric practice: factors related to positive screens and the contribution of parental/personal concern.

OBJECTIVES: The goals were to examine factors related to positive Pediatric Symptom Checklist scores in an urban practice and to examine the relative contribution of parental/personal concern about emotional and behavioral problems to mental health problem identification. METHODS: Annual screening using the Pediatric Symptom Checklist was implemented in Cambridge Pediatrics (Cambridge, MA). A social worker was colocated in the clinic to provide therapeutic interventions for patients. A sample of 1668 screened patients between 4 years 11 months and 19 years of age was used for analysis. Bivariate and multivariate analyses were conducted to determine factors predictive of positive Pediatric Symptom Checklist scores, including demographics, socioeconomic indicators, enrollment in counseling, and parental/personal concern. Parental/personal concern, counseling, and positive Pediatric Symptom Checklist scores were examined to determine their efficacy as screening methods. RESULTS: Six percent of the population had positive Pediatric Symptom Checklist scores. There were statistically significant relationships between a positive score and being in counseling, parental/personal concern, having public insurance, and living in an area with median household incomes of less than 50,000 dollars. Parental/personal concern was 40% sensitive for a positive score. A positive Pediatric Symptom Checklist score with or without parental/personal concern identified 3.8% of the population; parental/personal concern with or without a positive Pediatric Symptom Checklist score identified 4.5%. CONCLUSIONS: Mental health screening can be effectively implemented in a pediatric practice. Colocated mental health professionals provide additional support. The combination of a screening tool and questions about parental/personal concern and present counseling can provide critical information about a child's mental health.

Evaluation of the Clinical Assessment project: a computer-based multimedia tool to assess problem-solving ability in medical students.

OBJECTIVE: The purpose of this work was to describe Clinical Assessment, a computer-based multimedia patient simulation used to assess the problem-solving abilities of medical students and to evaluate its capacity to guide the assignment of course grade. METHODS: This was a multisite reviewer-blinded comparison of course grades, National Board of Medical Examiners pediatric examination score, and Clinical Assessment scores at 3 pediatric clerkship sites of the Harvard Medical School. Participants included 470 students completing their pediatric clerkships. Each student's performance on < or = 4 Clinical Assessment patient case simulations was compared with National Board of Medical Examiners pediatric examination scores and course grades assigned by clerkship directors based on overall ward performance. RESULTS: Data from both the National Board of Medical Examiners pediatric "shelf" examination and the course grade were available for 411 students who completed > or = 1 Clinical Assessment case. There was a strong correlation between Clinical Assessment score and course grade when comparing students receiving honors versus satisfactory category course grades. Students who ordered more expensive or greater numbers of laboratory tests did not achieve greater diagnostic accuracy on Clinical Assessment. Clinical Assessment had a high positive predictive value for course grade: 95% of students scoring > or = 90% on Clinical Assessment achieved an honors category course grade. CONCLUSIONS: Because nearly all of the students who scored very well on Clinical Assessment received honors category course grades, future high scorers on this examination merit consideration for assigning a high course grade. A computer-based multimedia patient simulation assessment tool provides objective information that can complement a student's National Board of Medical Examiners score and course grade and may assist in evaluating clinical problem-solving ability.