Lead For Studies Research Articles

Diabetes: A Risk or Protective Factor in ALS?

Patrice Wendling is with the Chicago Bureau of Elsevier Global Medical News. CHICAGO — Diabetes mellitus appears to delay the onset of motor symptoms in patients with amyotrophic lateral sclerosis, but it also may be associated with diminished cognitive functioning in patients with the neurodegenerative disease, according to the findings of a retrospective study. Although a cause and effect relationship could not be determined because of the design of the study, it is hoped the findings will stimulate research into whether increasing blood glucose level might benefit patients who have ALS, said the study's lead investigator, Paul E. Schulz, MD, of Baylor College of Medicine, Houston. Among 2,359 consecutive patients with ALS, mean patient age at the onset of motor symptoms was significantly greater in 174 patients with diabetes than in 2,185 patients without diabetes (60.3 years vs. 56.3 years). Patients in the study were diagnosed with ALS from 1977 to 2006, and were tested for diabetes at the time of their ALS diagnosis. Overall, the mean age at first ALS symptom was 56.6 years; 62% of the patients were male and 89% were white. Later age of onset for ALS is typically associated with a faster rate of progression of motor symptoms. However, the mean rate of progression on the Appel scale (3.1) and the mean duration of ALS (3.2 years) were similar between diabetics and nondiabetics at baseline, Dr. Schulz and his associates reported in a poster at the annual meeting of the American Academy of Neurology. “To my knowledge, diabetes mellitus is the first factor that has been associated with a later age of onset for ALS, and hence one that might be protective against ALS,” Dr. Schulz, director of the cognitive disorders clinics at Baylor, said in an interview. On neuropsychological testing that controlled for age, ALS patients with diabetes performed significantly worse than did nondiabetics on tasks measuring memory, confrontation naming, semantics, and processing speed. Some of these domains tend to be relatively preserved in ALS patients, Dr. Schulz said. ALS patients with diabetes also did significantly worse on tests measuring executive function including the Verbal Series Attention Test, both time to completion (VSAT-T) and errors (VSAT-E), and phonemic fluency (FAS test), Dr. Schulz said. Cognitive status by FAS scores was rated “intact” in 228 patients, of which 3% were diabetic; “mild” in 163 patients, of which 5.5% were diabetic; and “moderate” in 50 patients, of which 16% were diabetic. The difference between diabetics and nondiabetics was significant, indicating that the severity of cognitive function correlated with the presence of diabetes, he said. ALS patients with diabetes were also significantly more likely than those without diabetes to score positive for depression on the Beck Depression Inventory. There are several possible explanations for the poor cognitive findings, Dr. Schulz said. It could be that diabetes advances the loss of neurons in the cognitive areas of the brain or that diabetes protects against motor neuron loss, but not cognitive neuronal loss. Finally, “it could be that diabetes produces a different kind of dementia than we normally see in ALS patients, which is frontotemporal dementia.” Previous work by the same study group and others has shown some degree of cognitive impairment in about 50% of patients with ALS. Dr. Schulz disclosed that he has given talks on Alzheimer's disease that were sponsored by Pfizer Inc. and Forest Pharmaceuticals Inc., which market Aricept (donepezil) and Namenda (memantine), respectively.

A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.

PROBING TITAN'S SMOG

WITHIN THE ORANGE HAZE shrouding Saturn's moon Titan lies a complex chemical environment, originating with N 2 and methane and powered by solar ultraviolet radiation and charged particles from Saturn's magneto sphere. Spectroscopic data from NASA's Cassini spacecraft have now allowed scientists to penetrate the chemistry behind the smog, yielding surprising results. To begin with, chemical reactions are occurring much higher in Titan's atmosphere than previously believed, at an altitude around 1,000 km. There, CH 4 and N 2 react to form simple organic molecules such as acetylene, ethylene, and HCN. Then, reactions between ions and neutral molecules link those components into larger molecules, including benzene ( Science 2007,316,870). The study's lead investigator, J. Hunter Waite Jr. of Southwest Research Institute, notes that researchers previously believed that reactions would occur predominantly by radical processes lower in the atmosphere. Now, it appears that ion-neutral reactions occur in the upper...

Escitalopram in the Long-Term Treatment of Major Depressive Disorder in Elderly Patients

Aim: The primary aim was to investigate the long-term safety and tolerability of escitalopram (10 or 20 mg/day) treatment of elderly patients suffering from major depressive disorder. The secondary aim was to examine response to treatment, as measured by change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from study entry to each visit, using observed cases. Method: This extension trial included 225 patients who had completed an 8-week, double blind, placebo-controlled lead-in study, which was performed in outpatients in primary care and in specialist clinics. The intent-to-treat population comprised 223 patients. Results: The overall withdrawal rate was 24%. The most common reason for withdrawal was adverse events (9%). The 5 most common adverse events were accidental injury, rhinitis, weight increase, arthralgia and coughing, with an incidence ranging from 8 to 13%. No new types of adverse events were reported in this extension study compared to the 8-week lead-in study. The mean weight increased from 69.7 kg at study entry to 70.3 kg at endpoint. The percentage of patients in remission (MADRS total score ≤12) increased from 48% at study entry to 72% by week 52. Conclusion: Escitalopram demonstrated a favourable tolerability profile during 52 weeks of open-label treatment of elderly patients, with further improvement in depressive symptoms.

Efficacy Similar for SSRIs, TCAs In Postpartum Depression

Efficacy Similar for SSRIs, TCAs In Postpartum Depression

Escitalopram in the Long-term Treatment of Major Depressive Disorder

Escitalopram has been proven safe and efficacious in the treatment of major depressive disorder (MDD) in short-term studies. The long-term clinical tolerability and response to treatment are presented from a 12-month open-label study with a total exposure time to escitalopram of 486 patient years. Patients (n = 590) with MDD entered the study after completing one of two 8-week, double-blind, placebo-controlled, lead-in studies in primary care. Escitalopram was administered at doses of 10 or 20 mg/day (dose based on physician's clinical judgement) with an average exposure to escitalopram of 315 days. The primary efficacy parameter was the Montgomery Asberg Depression Rating Scale (MADRS) total score. The overall withdrawal rate was 26%; and the withdrawal rate due to adverse events was 9%. The most common adverse events were headache, back pain, upper respiratory tract infection, rhinitis and nausea, with an incidence ranging from 11% to 17%. No new types of adverse events were seen after the acute period of 8 weeks, and the incidence declined with time. At baseline (entry into the 12-month study), patients had a mean MADRS total score of 14.2, which decreased to 10.5 after 8 weeks and 7.2 after 52 weeks (LOCF). The percentage of patients in remission (MADRS total score </=12) increased from 46% at baseline to 65% by Week 8 and 86% by Week 52. Escitalopram (10 to 20 mg/day) demonstrated a favorable safety and tolerability profile over 12-months treatment, with further improvement in patient response.

Pregnant Women Should Discuss Antidepressant Risks

Pregnant Women Should Discuss Antidepressant Risks

Dementia Diagnosis Can Benefit Patients and Caregivers

Dementia Diagnosis Can Benefit Patients and Caregivers

Marital Strife May Keep Wounds From Healing

Marital Strife May Keep Wounds From Healing

Therapy by Phone Helpful When Office Visit Difficult

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessTherapy by Phone Helpful When Office Visit DifficultEve BenderEve BenderSearch for more papers by this authorPublished Online:7 Oct 2005https://doi.org/10.1176/pn.40.19.00400024For most, the telephone is a way to reach out to friends and family. Now, researchers at the University of California, San Francisco (UCSF), have discovered that the phone may also be an essential tool in depression treatment for some patients.In a study of 120 patients with multiple sclerosis who had been diagnosed with depression, depression symptoms lifted in those who received either telephone-administered cognitive-behavioral therapy (T-CBT) or telephone-administered supportive emotion-focused therapy (T-SEFT).However, a greater percentage of those who received T-CBT experienced a reduction in depressive symptoms when compared with those who received T-SEFT.The results appeared in the September Archives of General Psychiatry.David Mohr, Ph.D., the study's lead investigator and an associate professor of psychiatry at UCSF, recruited 120 patients who had been diagnosed with multiple sclerosis from the Kaiser Permanente Medical Care Group of Northern California and from regional chapters of the National Multiple Sclerosis Society.To be included in the study, patients had to have a score of 3 or higher (of a possible score of 6) on the Guy's Neurological Disability Scale, a score of 16 or higher on the Beck Depression Inventory, and 14 or higher on the Hamilton Depression Rating Scale (HDRS).Researchers used these and other instruments, including the Structured Clinical Interview for DSM-IV and the Positive and Negative Affect Scale, to assess patients for up to a year after the initial assessment.The patients were randomized to receive T-CBT or T-SEFT from a doctoral-level psychologist once a week for 16 weeks. About the same percentage of patients in both groups were taking an antidepressant during the study.According to Mohr, T-CBT is similar to standardized, face-to-face CBT, but is administered over the phone. Therapists taught patients skills to help them manage cognitions and behaviors that can contribute to depression.The goal of T-SEFT was to increase patients' awareness of emotions such as anger that, when unacknowledged, could contribute to depression, according to proponents of the therapy.The authors said that “patients showed significant improvements in depression and positive affect during the 16 weeks of telephone-administered treatment” but that T-CBT brought about greater improvement in depression than did T-SEFT.For instance, at week 16, patients in the T-CBT group had significantly improved scores compared with those of the T-SEFT group on the HDRS (p=.02) and the Positive and Negative Affect Scale (p=.008).In addition, at the week 16 assessment, just eight patients in the T-CBT group still met criteria for a diagnosis of depression, while 18 in the T-SEFT group did (p=.02).Despite recognizing that telephone-administered psychotherapy is not ideal in all circumstances, Mohr told Psychiatric News that he believes that “patients and therapists can form meaningful, therapeutic relationships over the phone” and that telephone-administered psychotherapy may be the only way to reach some patients who have no access to traditional psychotherapy provided in an office or clinic.Some patients, for example, may have problems getting to a therapist's office due to physical disabilities, as is the case with some people with multiple sclerosis. Others may face a range of treatment barriers including difficulties related to transportation, time, stigma, and child- or elder-care issues, Mohr noted.The study's very low attrition rate—5 percent as compared with 25 percent in trials of face-to-face psychotherapy, according to the report—may support the belief that telephone-administered psychotherapy reduces the barriers that keep some individuals from receiving psychotherapy in person, Mohr noted.However, the report pointed out that T-CBT may not be indicated for all patients and that “it will be important to examine if the outcomes of telephone-administered therapies are equivalent to face-to-face interventions....”Future research should also investigate whether telephone-administered psychotherapy may be helpful to people with depression who have little or no access to treatment in the wake of a disaster such as Hurricane Katrina, he said.“What has not been studied is the use of these treatments in disaster situations, where there may be a sudden need for counseling and intervention” for survivors.An abstract of “Telephone-Administered Psychotherapy for Depression” is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/62/9/1007>.▪ Arch Gen Psychiatry 2005 62 1007 ISSUES NewArchived

Talking about…

Talking about…

Sleep Experts Wake Up to Value Of CBT for Insomnia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSleep Experts Wake Up to Value Of CBT for InsomniaJim RosackJim RosackSearch for more papers by this authorPublished Online:3 Dec 2004https://doi.org/10.1176/pn.39.23.00390032aResearchers at Harvard Medical School have shown that patients with chronic sleep-onset insomnia see greater improvement from a course of cognitive-behavioral therapy (CBT) than they do from the market-leading hypnotic medication zolpidem (Ambien).The study, reported in the September 27 Archives of Internal Medicine, was a randomized controlled trial involving 63 adults with chronic sleep-onset insomnia. The research was funded by grants from the National Institutes of Health and National Institute on Drug Abuse.Patients were randomly assigned to CBT, pharmacotherapy (with zolpidem), a combination of CBT and zolpidem, or placebo. Those in the CBT group received five 30-minute sessions over six weeks. The patients were given daily exercises to teach them to “recognize, challenge, and change stress-inducing thoughts,” according to the study's lead author, Gregg Jacobs, Ph.D., an assistant professor of psychiatry at Harvard and a researcher at the Harvard-affiliated Sleep Disorders Center at Beth Israel Deaconess Medical Center.Patients were taught techniques such as delaying time of going to bed or getting up to read if they were unable to fall asleep within about 20 minutes of going to bed, Jacobs said in a press release.Those assigned to receive zolpidem started with 10 mg a night for the first 28 nights (four weeks) of the eight-week treatment period. For the following seven days (week 5), they received 5 mg a night, and then 5 mg every other night for an additional week (week 6). No medication was taken during the final two weeks.Patients randomly assigned to receive placebo followed the same protocol as the medication group without any CBT or “sham therapy.”Jacobs was surprised at what he and his team found.“Sleeping pills are the most frequent treatment for insomnia, yet CBT techniques clearly were more successful in helping the majority of study participants to become normal sleepers. The pills were found to be only moderately effective compared with CBT, and lost their effectiveness soon after they were discontinued.”All patients kept sleep diaries for 14 days before treatment began, for 14 days at mid-treatment (weeks 3 and 4), and for 14 days after treatment ceased (the end of the protocol). In addition, patients underwent three nights of home-based “nightcap” recordings before and after treatment. The“ nightcap monitor” is a two-channel sleep monitor that measures sleep-onset latency as well as other measures of sleep by using eyelid- and head-movement sensors attached to a small, battery-operated recorder placed under the bed pillow.The CBT and the combination groups showed the greatest changes in sleep-onset latency at mid-treatment, with both groups showing a 44 percent reduction in the amount of time it took to fall asleep at bed time. Those taking zolpidem showed only a 29 percent reduction, and those on placebo had only a 10 percent reduction in sleep latency. By the end of week 8, the CBT and combined treatment group each yielded a 52 percent reduction in sleep onset. These significant improvements were maintained for the follow-up period of 18 months, whereas improvements seen in the zolpidem group were not maintained over the long term. In fact, Jacob pointed out, “by the end of the eight-week treatment phase, insomnia returned to baseline levels and did not differ from [those of] the placebo group.”Intriguingly, no significant differences emerged among the groups in terms of total sleep time, though each group exhibited some increase.“Our results suggest CBT should now be considered the first-line treatment for insomnia, which is experienced on a nightly basis by one-third of the nation's adult population,” Jacobs concluded.An abstract of “Cognitive-Behavior Therapy and Pharmacotherapy for Insomnia” is posted online at<http://archinte.ama-assn.org/cgi/content/abstract/164/17/1888>.▪ Arch Intern Med 2004 164 1888 ISSUES NewArchived

Genetic Testing after Breast Cancer Diagnosis: Implications for Physician-Patient Communications

In November 2003, researchers at Cambridge University announced they had identified a gene associated with an elevated risk of breast and related ovarian cancers. The gene—christened EMSY in honor of a breast-cancer nurse who is the sister of the study's lead author—is particularly significant because it is linked to so-called sporadic cancers. Such cancers do not arise from hereditary mutations of the BRCA1 and BRCA2 genes, in which genes that ordinarily prevent breast and ovarian cancers are altered, often giving rise to multiple cases of cancer within a family as the mutation is passed along. The Cambridge researchers determined that the presence of extra copies of EMSY in an individual may instead switch off a healthy BRCA2 gene.

Chronic Health Problems Often Accompany PTSD in Women

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessChronic Health Problems Often Accompany PTSD in WomenEve BenderEve BenderSearch for more papers by this authorPublished Online:3 Sep 2004https://doi.org/10.1176/pn.39.17.0390036Women with posttraumatic stress disorder (PTSD) have a greater number of medical conditions such as arthritis, lower back pain, obesity, and hypertension, and worse health status overall than women with only depression or with neither disorder, according to a large new study of women veterans.“While it is well established that depression is associated with poor physical health, we found that women with PTSD in addition to their depression had even worse physical health than women with depression alone,” said Susan Frayne, M.D., M.P.H., who is the study's lead investigator and an advanced research career development fellow at the Center for Health Care Evaluation at the VA Palo Alto Health Care System and Stanford University. The finds are described in the June 28 Archives of Internal Medicine.Frayne and her colleagues from the Veterans Affairs hospitals in Menlo Park, Calif., and Bedford, Mass., examined survey data from about 30,800 women veterans who responded to the 1999 Health Survey of Veterans to determine whether a doctor had ever diagnosed them with PTSD, depression, or a number of nonpsychiatric health problems such as chronic lower back pain, high blood pressure, obesity, emphysema, or cancer.A total of 4,348 women reported they had been diagnosed with PTSD, 7,580 with depression, and 18,937 reported that they'd never been diagnosed with either condition.Nearly 90 percent of the women who reported ever having been diagnosed with PTSD indicated that they had at least one medical condition, with arthritis, chronic lower back pain, obesity, and hypertension topping the list.Frayne and colleagues found that regardless of age, the number of medical conditions was higher in women with PTSD than in women with depression alone or with neither disorder.For example, among women younger than age 45, the mean number of medical conditions was 1.8 for women with PTSD, 1.5 for women with depression, and 1.1 for women with neither disorder.Among women aged 65 and older, the mean number of medical conditions was 3.3 for women with PTSD, 3.1 for women with depression, and 2.6 for women with neither.Frayne also used information from the Veterans SF-36 instrument to obtain information about four domains of physical health: physical functioning, role limitations due to physical problems, bodily pain, and energy/vitality.Each of these four scales is scored from 0 to 100, with 100 being the best possible score in each area.When Frayne examined role limitations due to physical problems, she found that among women with PTSD under age 45, the mean score was 31. That score jumped to 47.2 for women with depression and 69.1 for women with neither condition.Women with PTSD in the same age range also reported experiencing more bodily pain and scored lower on the SF-36 instrument (39) in this domain than women with depression (47.6) or neither condition (58.9). On this scale, which ranges from 0 to 100, lower scores indicate greater bodily pain.Frayne told Psychiatric News that while the study was not designed to determine the nature of the link between PTSD and poor physical health, several mechanisms may underlie the association.“Other work has indicated that a history of trauma exposure can be associated with chronic neuroendocrine dysregulation and with risky health behaviors such as smoking or substance use, which can potentially contribute to ill health,” she said, adding that more research needs to be conducted to explore this key link.While recent research has pointed to the importance of access to mental health services for veterans with PTSD, Frayne said her study “indicates that attending to the physical health needs of women veterans with PTSD is also critical.”“Psychiatrists may be in an excellent position to connect women who have PTSD with needed services for their comorbid medical conditions,” she pointed out.An abstract of the article, “Burden of Medical Illness in Women With Depression and Posttraumatic Stress Disorder,” is posted online at<archinte.amaassn.org>.▪ ISSUES NewArchived

IRIS Trial

Although early release of data from this international randomized trial of interferon and imatinib at ASCO's 2002 Annual Meeting was hailed as a big advance for leukemia patients, one of the study's lead investigators initially had reservations about reporting 12-month follow-up data.

Exploratory pilot study with olanzapine in generalized anxiety disorder (GAD) showed anxiolytic treatment with low-dosages of the atypical antipsychotic

To investigate the effectiveness, safety, and tolerability of vortioxetine in patients treated at therapeutic doses (5–20 mg/day) for both acute and maintenance treatment, patient-level data were pooled from 5 long-term (52-week), open-label extension studies of major depressive disorder. The mean (±standard deviation) MADRS total score improved from 17.1±10.2 at the start of maintenance therapy to 7.6±8.2 (observed cases [OC]) or 10.3±9.9 (last observation carried forward [LOCF]) at week 52. The mean HAM-A total scores improved from 11.3±6.9 to 6.0±6.0 (OC) or 7.5±6.7 (LOCF) and the mean CGI-S score improved from 3.11±1.20 to 1.94±1.08 (OC) or 2.27±1.26 (LOCF) at week 52. Response and remission rates increased over time. At week 52, the total response rate was 75.4% (n=916/1215, LOCF) and the total remission rate was 60.7% (n=738/1215, LOCF). There were no differences in effectiveness as assessed by MADRS total scores at week 52 in subgroups based on gender, age (<55 vs ≥55 years), baseline HAM-A total score (<20 vs ≥20), baseline MADRS total score (<30 vs ≥30), previous major depressive episodes (MDEs) (<3 vs ≥3) or current MDE duration (<6 vs ≥6 months) at the start of the lead-in studies, or response status (≥50% decrease in MADRS total score during the lead-in study). The most commonly reported adverse event during the maintenance period was nausea.

The LEADIN study

The LEADIN project involves linking six large hypertension databases, each with a long period of follow up in terms of patient years and endpoints. The results of this pooled observational-type trial involving such a large group of patients outside the framework of the explanatory type of clinical trial will be of considerable interest.

Transportation modeling in a changing world: a Miami case study

Cities throughout the United States are placing increasing demands on the Urban Mass Transportation Administration for funding of improved transit systems. Approximately 40 of these communities are serious about developing rapid transit in one form or another. However, as a class, these proposals are extremely expensive and could utilize the entire Urban Mass Transportation Administration funding as established under the National Mass Transportation Administration Act of 1974 ($11 billion over six years). To assure fair, systematic evaluation of these requests, the Urban Mass Transportation Administration has developed a series of policy guidelines that emphasize local decision-makers in creating a sound approach to alternative systems evaluation so that the technical results of all lead-in studies to rapid transit funding requests can be factually supported. Traditional technical approaches to transportation models are not tailored to the needs of planners and decision-makers. Using the Miami setting as a basis, a modeling approach is discussed that is directed toward: providing local officials and planners with policy options that will allow them to achieve stated goals with regard to the role of the transportation system in the urban environment; and evaluating quantitatively and analytically the effects of various uncertainties on the capital-intensive system investments. This approach uses a mathematically based risk analysis model together with sensitivity analysis and policy modal split techniques. The first model evaluates the degree of uncertainty involved in patronage and revenue projections and thus provides measures of the risk involved in investment alternatives. The latter set of models is capable of developing system characteristics and policy combinations that will achieve modal split objectives for the region and for certain predefined trip and tripmaker strata. In addition to discussing these approaches and their application in Dade County, Miami, the role of calibration in the behavioral modeling package is described and illustrated.