Evaluating the FRIENDS program: a cognitive-behavioral group treatment for anxious children and their parents.

Conducted the 1st randomized clinical trial evaluating the efficacy of the FRIENDS program, a family-based group cognitive-behavioral treatment (FGCBT) for anxious children. Children (n = 71) ranging from 6 to 10 years of age who fulfilled diagnostic criteria for separation anxiety (SAD), generalized anxiety disorder (GAD), or social phobia (SOP) were randomly allocated to FRIENDS or to a 10-week wait-list control group. The effectiveness of the intervention was evaluated at posttreatment and 12-month follow-up. Results indicated that 69% of children who completed FGCBT were diagnosis-free, compared to 6% of children completing the wait-list condition. At 12-month follow-up, 68% of children were diagnosis-free. Beneficial treatment effects were also evident on the self-report measures completed by the children and their mothers. Parents and children reported high treatment satisfaction. Results suggest that FRIENDS is an effective treatment for clinically anxious children. Limitations of this study and directions for future research are discussed.

Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial.

BACKGROUND: Superficial basal cell carcinoma (sBCC) is an increasingly common tumor in fair-skinned populations throughout the world. Imiquimod, an immune response modifier that induces cytokines including interferons, has been shown in preliminary studies to have an effect when applied topically to BCC. OBJECTIVE: We conducted a multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC assessing efficacy and safety of different dose regimens. METHODS: Ninety-nine patients were randomized to 6 weeks' application of imiquimod in 1 of 4 treatment regimens: twice every day, once every day, twice daily 3 times/week, once daily 3 times/week. The treatment site was excised and examined histologically 6 weeks after cessation of imiquimod. RESULTS: Intention-to-treat analysis revealed 100% (3/3) histologic clearance in the twice-daily regimen, 87.9% (29/33) clearance in the once every day regimen, 73.3% (22/30) clearance in the twice-daily 3 times/week regimen, and 69.7% (23/33) clearance in the once-daily 3 times/week regimen. Dose-related inflammatory skin reactions at the site of application were common. The majority were well tolerated and only 1 patient withdrew from the trial as a result of a medication-related skin reaction. CONCLUSION: Imiquimod 5% cream appears to have potential as a patient-administered treatment option in sBCC.

The influence of family and experimental context on cognition in anxious children.

Examined the influence of family on anxious children's cognition. Research by Barrett, Rapee, Dadds, and Ryan (1996) found anxious children reported increased avoidance after interacting with their parents. They labelled this finding the FEAR effect-Family Enhancement of Avoidant Responses. Whilst some subsequent studies have found similar results, others have not. These contradictory findings question whether the direction of parental influence on anxious children is determined by the perceived demands of the experimental context. Anxious children (N = 101) and their parents were asked to interpret seven ambiguous situations and to discuss what their child would do if the scenario actually occurred. Study 1 found that children in the anxious group and an externalizing control group were more likely to interpret ambiguous situations as threatening than nonclinic children were. Study 2 sought to examine changes in the children's responses from pre- to postfamily discussion, and to identify variables associated with the FEAR effect in anxious families. Interestingly, anxious children whose families completed the discussion task after they (children) had been offered treatment were more likely to show a FEAR effect than anxious families who completed the task as part of assessment. Study 3 examined predictors of enhanced avoidance in anxious families. Treatment context and maternal distress were correlated with the child's increased avoidance following family discussion. Limitations of these studies and directions for future research are discussed.

Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream.

BACKGROUND: Basal cell carcinoma (BCC) responds to interferon therapy. Imiquimod is a cytokine and interferon inducer. OBJECTIVE: This randomized, double-blind pilot trial evaluated the safety and efficacy of imiquimod 5% cream versus vehicle in the treatment of BCC. METHODS: In this population of 35 patients with BCC, 24 received imiquimod 5% cream and 11 received vehicle cream in 1 of 5 dosing regimens for up to 16 weeks. Six weeks after treatment, an excisional biopsy of the target site was performed. RESULTS: BCC cleared (on the basis of histologic examination) in all 15 patients (100%) dosed twice daily, once daily, and 3 times weekly; in 3 of 5 (60%) patients dosed twice weekly; 2 of 4 (50%) dosed once weekly; and in 1 of 11 (9%) treated with vehicle. Adverse events were predominantly local reactions at the target tumor site, with the incidence and severity of local skin reactions declining in groups dosed less frequently. CONCLUSION: Imiquimod 5% cream shows clinical efficacy in the treatment of BCC.

Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts.

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.

Treatment of genital warts with an immune-response modifier (imiquimod).

BACKGROUND: Genital warts are a common sexually transmitted disease caused by human papillomavirus. Imiquimod is a novel immune-response modifier capable of inducing a variety of cytokines, including interferon alfa, tumor necrosis factor-alpha, as well as interleukins 1, 6, and 8. In animal models imiquimod has demonstrated antiviral, antitumor, and adjuvant activity. In vitro, imiquimod has no antiviral or antitumor activity. OBJECTIVE: Our purpose was to determine the safety and efficacy of topical imiquimod for the treatment of external genital warts. METHODS: This prospective double-blind, placebo-controlled, parallel design clinical trial was performed in three outpatient centers, a public health clinic, a university-based clinic, and a private practice. One hundred eight patients with external genital warts (predominantly white men) were entered into the trial. Fifty-one patients were randomly selected to receive 5% imiquimod cream; 57 patients were randomly chosen to receive placebo cream. Study medication was applied three times weekly for up to 8 weeks. Patients whose warts cleared completely were observed for up to 10 weeks to determine recurrence rates. RESULTS: In the intent-to-treat analysis, the warts of 37% (19 of 51) of the imiquimod-treated patients and 0% (0 of 57) of the placebo group cleared completely (p < 0.001). In addition, many patients experienced a partial response. A reduction in baseline wart area of 80% or more was observed in 62% of imiquimod-treated patients (28 of 45) and 4% of the placebo group (2 of 50) (p < 0.001); a 50% reduction or more in wart area was noted in 76% of imiquimod-treated patients (34 of 45) and 8% of placebo recipients (4 of 50) (p < 0.001). Of imiquimod-treated patients whose warts cleared completely and who finished the 10-week follow-up period, 19% (3 of 16) experienced recurrences of warts. Imiquimod-treated patients experienced a significantly greater number of local inflammatory reactions than the placebo group. Symptoms and signs associated with the local inflammatory reactions included itching (54.2%), erythema (33.3%), burning (31.3%), irritation (16.7%), tenderness (12.5%), ulceration (10.4%), erosion (10.4%), and pain (8.3%). There were no differences in systemic reactions or laboratory abnormalities between treatment groups. CONCLUSION: Topical 5% imiquimod cream appears to have a significant therapeutic effect in the treatment of external genital warts.

Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus.

OBJECTIVE: To compare the safety and effectiveness of 5% and 1% imiquimod cream with vehicle cream in the treatment of external anogenital warts. DESIGN: Randomized, double-blind, placebo-controlled comparison that evaluated patients for total clearance of their warts. Patients who experienced total clearance were evaluated for recurrence in a 12-week follow-up. SETTING: Eleven ambulatory offices, including both private physician offices and referral medical centers. PATIENTS: Three hundred eleven healthy men and women aged 18 years or older with 2 to 50 external anogenital warts were recruited from the practices of investigators, referring physicians, and advertisements. Eighty-two additional patients were screened but did not qualify. Four patients discontinued use of the medication because of adverse effects. INTERVENTIONS: Five percent imiquimod (Aldara) cream, 1% imiquimod cream, or vehicle cream was applied to all external warts overnight 3 times each week for 16 weeks, or until all treated warts disappeared, whichever occurred first. MAIN OUTCOME MEASUREMENTS: The number of patients experiencing the elimination of all baseline warts and the recurrence rate of these warts. In addition, the reduction in baseline wart area the duration of therapy required to eliminate warts, and the frequency and severity of adverse reactions were principal measurements. RESULTS: In the intent-to-treat analysis, 54 (50%) of 109 patients who received 5% imiquimod cream, 21 (21%) of 102 of those who received 1% imiquimod cream, and 11 (11%) of 100 patients treated with vehicle cream experienced eradication of all treated baseline warts. The difference between the effectiveness of 5% imiquimod cream and the vehicle cream was statistically significant (P < .001). Of those patients whose warts cleared during therapy, 13% of patients who received 5% imiquimod experienced a recurrence of at least 1 wart. Recurrences occurred in none of the patients who used 1% imiquimod cream and in 10% of patients who used the vehicle cream. Local erythema was the most common adverse reaction, but the majority of patients in each group experienced no or only mild local inflammatory reactions. There were no differences in incidences of flulike symptoms among treatment groups. CONCLUSIONS: Five percent imiquimod cream is an effective and safe self-administered therapy for external anogenital warts when applied 3 times a week overnight for up to 16 weeks. The recurrence rate is low.

Flecainide acetate for paroxysmal supraventricular tachyarrhythmias. The Flecainide Supraventricular Tachycardia Study Group.

Flecainide has been shown to be effective in short-term, controlled studies for prevention of paroxysmal supraventricular tachycardia (SVT) and paroxysmal atrial fibrillation (AF). However, it is unknown whether this beneficial response is maintained during long-term chronic therapy. Forty-nine patients were studied who enrolled in double-blind, placebo-controlled, short-term studies of safety and efficacy and subsequently received long-term, open-label therapy for > or = 6 months (mean duration of therapy, 17 months). To evaluate chronic efficacy, events during long-term therapy were documented by a transtelephonic monitor for either 4 or 8 weeks, comparable to the corresponding 4- or 8-week placebo-baseline periods in the same patients. Results during chronic therapy were compared with those at baseline and after the initial (short-term) treatment period. Compared with placebo-baseline results, the number of patients free of arrhythmic attacks increased significantly for both patients with SVT (from 24% to 82%, p = 0.013, n = 17) and patients with AF (from 12% to 68%, p < 0.001, n = 25). Mean time to first attack and mean number of days between attacks also showed significant and parallel increases during the chronic efficacy period. In patients with paired short- and long-term efficacy evaluations with the same dose of flecainide, end points were maintained at equivalent levels or showed further improvement (i.e., mean rate of AF attacks decreased further with chronic therapy, p = 0.036). No proarrhythmic events, death, or myocardial infarction occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Dry rehydratable film for enumeration of total coliforms and Escherichia coli in foods: collaborative study.

Rehydratable dry-film plating methods for total coliforms and Escherichia coli in foods have been compared to the AOAC most probable number methods. Fourteen laboratories participated in the collaborative study. Three coliform and E. coli levels in 6 samples of 4 product types (flour, nuts, cheese, and beef with gravy) and in 3 samples of 2 product types (mushrooms and raw turkey) were tested in duplicate by the participants. The mean log counts for the 3 methods were comparable. In general, the repeatability and reproducibility variances of the plating methods were as good as or better than that of the MPN method. The method has been adopted official first action by AOAC.

Comparison of the Petrifilm™ Yeast and Mold Culture Film Method to Conventional Methods for Enumerating Yeasts and Molds in Foods.

Petrifilm™ Yeast and Mold (YM) plates were compared to acidified potato dextrose agar (APDA) and chloramphenicol-supplemented plate count agar (CPCA) for its suitability to enumerate yeasts and molds in 13 groups of food products. These products consisted of beans (dry and frozen, green), corn meal, flour (wheat), fruit (apple), a meat/vegetable entree (chicken pot pie), a precooked meat (beef), milk (dehydrated, nonfat), nuts (pecans), pasta, potatoes (dehydrated), precooked sausage, and a spice (black pepper). Correlation coefficients of Petrifilm™ YM plates versus APDA and CPCA pour plates for recovering total yeasts and molds from a composite of the thirteen test foods were, respectively, 0.961 and 0.974. Individually, Petrifilm™ YM plate counts were equivalent or higher than APDA and CPCA for some food groups and lower for other food groups. Because food particle interference can make enumeration of yeast and mold colonies on Petrifilm™ YM plates difficult for some food groups, potential food interference will need to be evaluated for each food group tested.

Dry rehydratable film for enumeration of total aerobic bacteria in foods: collaborative study.

A rehydratable dry-film plating procedure for aerobic plate counts has been compared to the standard agar plate method (966.23B and C, 15th ed.; 46.014-46.015, 14th ed.) in a collaborative study by 12 laboratories. Each laboratory analyzed the normal microflora of 3 samples in duplicate for 6 products. The aerobic plate counts ranged from 1.0 x 10(3) to 1.0 x 10(8) cfu/g. The products were flour, nuts, frozen raw shrimp, spice, frozen raw ground turkey, and frozen and refrigerated vegetables. Repeatability standard deviations of the 2 methods did not differ significantly for 13 of 18 test samples. For 1 shrimp and 2 turkey samples, the dry-film method had lower repeatability variances (P less than 0.05) and for 1 spice sample the agar method had lower repeatability variances (P less than 0.05). Relative standard deviations of repeatability were between 1.7 and 15.5% for the dry-film method and 1.2 and 16.0% for the agar method. Relative standard deviations of reproducibility ranged from 2.4 to 23.4% for the dry-film method and 2.3 to 18.8% for the agar method. The dry rehydratable film method has been adopted official first action for determination of the aerobic plate count.

Evaluation of a Culture Film (Petrifilm™ YM) Method for Enumerating Yeasts and Molds in Selected Dairy and High-Acid Foods.

The Petrifilm™ Yeast and Mold (YM) plate was compared to acidified potato dextrose agar (APDA) and chloramphenicol-supplemented plate count agar (CPCA) using pour- and surface-plating techniques for its ability to recover yeasts and molds from hard and soft cheeses, cottage cheese, yogurt, sour cream, fruit juice, salad dressing, relishes, and tomato-based sauces. Correlation coefficients of Petrifilm™ YM plates versus pour-APDA, surface-APDA, pour-CPCA, and surface-CPCA for recovering total yeasts and molds from a composite of the eight test foods were, respectively, 0.993, 0.993, 0.994, and 0.995. Slope and intercept values for populations detected using Petrifilm™ YM plates versus traditional systems ranged, respectively, from 0.984 to 1.008 and -0.051 to 0.149. The coefficient of variation for total yeast and mold populations recovered on Petrifilm™ YM plates was 1.0% compared to 1.2 to 1.7% for traditional enumeration systems. Regardless of the enumeration system employed or the type of fungal cell, i.e., yeast or mold, being enumerated, significantly (P ≤ 0.05) higher populations were generally detected after 5 d compared to 3 d of incubation. After 5 d of incubation, in no case were yeast or total yeast and mold populations detected in the eight food products using Petrifilm™ YM plates significantly lower than respective populations detected using traditional pour- and surface-plating techniques and media. When Petrifilm™ YM plates were used, significantly higher total yeast and mold populations were detected in 3, 1, and 1 out of eight food products compared to using, respectively, pour-APDA, surface-APDA, and surface-CPCA enumeration systems. The Petrifilm™ YM plate offers an acceptable alternative to traditional methods for enumerating yeasts and molds in the dairy and high-acid products evaluated in this study.

Dry rehydratable films for enumeration of coliforms and aerobic bacteria in dairy products: collaborative study.

A collaborative study was conducted to compare proposed dry-film plating methods, using aerobic count plates and coliform count plates, to standard agar plating methods for quantifying aerobic bacteria and coliforms in dairy products. In this study, 5 food products (chocolate milk, pasteurized cheese, nonfat dry milk, evaporated milk, and vanilla ice cream), selected as representative dairy products, were analyzed by 11 collaborating laboratories. The results indicate that the dry-film plating methods are equivalent to or better than the agar plating methods. The aerobic count and coliform count dry-film plating methods have been adopted official first action.

Use of Petrifilm™ to Evaluate the Microflora of Frozen Dessert Mixes 1.

Ninety vanilla frozen dessert mix samples were analyzed to determine total microbial populations and coliforms present in samples inoculated with a coliform isolated from raw milk. Standard methods agar (SMA, PCA, Difco) and violet red bile agar (VRBA, Difco) as well as Petrifilm™ (PSM, PVRB) were used for plating of samples. Standard VRBA 1:10 method produced significantly higher counts of colony-forming units (CFU) than PVRB 2:3 and VRBA 2:3 methods. VRBA 2:3 colony-forming unit counts were also significantly higher than those on PVRB 2:3, but both methods showed a moderately strong linear relationship. Repeatabilities of all three coliform plating methods (VRBA 1:10, VRBA 2:3, and PVRB 2:3) were acceptably low. Less than 10% of samples plated on SMA and PSM resulted in total aerobic colony-forming units in the countable range, making evaluation of data difficult and resulting in a lack of strong linear relationship between PSM and SMA. An additional 70 local retail store samples containing naturally occurring coliforms were evaluated using PVRB 2:3 and VRBA 1:10 methodology, confirmed in brilliant green lactose bile broth (BGLB, Difco) and compared to standard VRBA 1:10 previously analyzed. All methods were equivalent for mean log coliforms, i.e., 1.38,1.33, and 1.31 for PVRB 2:3, VRBA 2:3, and VRBA 1:10, respectively. Petrifilm™ methods were comparable to standard methods for enumerating coliforms in frozen dairy products, and would be a valid alternative to standard coliform and total plate count methods.

Evaluation of the 3M Petrifilm™ Culture Plate Method for Enumerating Aerobic Flora and Coliforms in Poultry Processing Facilities.

Petrifilm™ methods were compared to traditional plating methods for monitoring microbial contamination in poultry processing facilities. No differences were seen between the Petrifilm methods and conventional method for enumeration of total bacterial populations, and no trends were seen in the ability of either method to detect coliforms in naturally contaminated samples. When processed poultry products were artificially inoculated with a variety of microorganisms, no difference in efficiency of recovery of the bacteria was noted. The Petrifilm methods were shown to be a practical and accurate alternative for monitoring microbial levels in poultry processing facilities.

Nuclear Overhauser effect studies of the conformations of MgATP bound to the active and secondary sites of muscle pyruvate kinase.

MgATP binds both at the active site (site 1) and at a secondary site (site 2) on each monomer of muscle pyruvate kinase as previously found by binding studies and by X-ray analysis. Interproton distances on MgATP bound at each site have been measured by the time-dependent nuclear Overhauser effect in the absence and presence of phosphoenolpyruvate (P-enolpyruvate), which blocks ATP binding at site 1. Interproton distances at site 2 are consistent with a single conformation of bound ATP with a high antiglycosidic torsional angle (chi = 68 +/- 10 degrees) and a C3'-endo ribose pucker (delta = 90 +/- 10 degrees). Interproton distances at site 1, determined in the absence of P-enolpyruvate by assuming the averaging of distances at both sites, cannot be fit by a single adenine-ribose conformation but require the contribution of at least three low-energy structures: 62 +/- 10% low anti (chi = 30 degrees), C3'-endo; 20 +/- 8% high anti (chi = 55 degrees), O1'-endo; and 18 +/- 8% syn (chi = 217 degrees), C2'-endo. Although a different set of ATP conformations might also have fit the interproton distances, the mixture of conformations used also fits previously determined distances from Mn2+ to the protons of ATP bound at site 1 [Sloan, D. L., & Mildvan, A. S. (1976) J. Biol. Chem. 251, 2412] and is similar to the adenine-ribose portion of free Co(NH3)4ATP, which consists of 35% low anti, 51% high anti, and 14% syn [Rosevear, P. R., Bramson, H. N., O'Brian, C., Kaiser, E. T., & Mildvan, A. S. (1983) Biochemistry 22, 3439].(ABSTRACT TRUNCATED AT 250 WORDS)

Enumeration of total bacteria and coliforms in milk by dry rehydratable film methods: collaborative study.

Eleven laboratories participated in a collaborative study to compare the dry rehydratable film (Petrifilm SM and Petrifilm VRB) methods, respectively, to the standard plate count (SPC) and violet red bile agar (VRBA) standard methods for estimation of total bacteria and coliform counts in raw and homogenized pasteurized milk. Each laboratory analyzed 16 samples (8 different samples in blind duplicate) for total count by both the SPC and Petrifilm SM methods. A second set of 16 samples was analyzed by the VRBA and Petrifilm VRB methods. The repeatability standard deviations (the square root of the between-replicates variance) of the SPC, Petrifilm SM, VRBA, and Petrifilm VRB methods were 0.05104, 0.0444, 0.14606, and 0.13806, respectively; the reproducibility standard deviations were 0.7197, 0.06380, 0.15326, and 0.13806, respectively. The difference between the mean log10 SPC and the mean log10 Petrifilm SM results was 0.027. For the VRBA and Petrifilm VRB methods, the mean log10 difference was 0.013. These results generally indicate the suitability of the dry rehydratable film methods as alternatives to the SPC and VRBA methods for milk samples. The methods have been adopted official first action.

Assessing differential drug effect.

The regression effect gives a misleading impression of the relationship between drug or treatment effect and baseline measurement. We propose a method of adjusting for the regression effect; we also suggest a corresponding test for the differential drug effect. The likelihood ratio test for no differential drug effect is equivalent to a test for equality of variances, suggested by Pitman (1939, Biometrika 31, 9-12) and Morgan (1939, Biometrika 31, 13-19). The proposed adjustment and test are applied to an example of blood pressure data.

Evaluation of the 3M Dry Medium Culture Plate (Petrifilm™ SM) Method for Determining Numbers of Bacteria in Raw Milk 1.

The 3M Company has developed a sample-ready system (Petrifilm ™ SM) for enumerating bacteria in milk and other food products. The testing unit consists of Standard Methods culture medium coated onto a base film and overlaid with a second film coated with a cold-water-soluble gelling agent and tetrazolium indicator dye. As such, the system is ready to accept samples of product. A pipette or 0.001-ml plate loop continuous pipetting syringe can be used for applying samples. In this study, both methods of sample addition were used and results compared with those of the Standard Plate Count (SPC) and standard Plate Loop (PL) methods for determining bacteria numbers in raw milk. In total, 108 samples were analyzed in duplicate by each of the four methods. The correlation coefficients (r) between the 3M-SPC and SPC, 3M-PL and PL, 3M-PL and SPC and PL and SPC were 0.946, 0.935, 0.941, and 0.974, respectively. Repeatability, as measured by mean log10 variance for duplicate determinations, was essentially the same for the four methods, and in all instances less than 0.005. The mean log10 differences between the SPC and 3M-SPC, and SPC and 3M-PL were, respectively, -0.177 and -0.168. The preceding statistical criteria suggest the Petrifilm™ SM method to be a suitable alternative to the SPC or the PL procedure.

Regression analysis applied to PVC histories: a statistical procedure for evaluating antiarrhythmic drug efficacy.

Suppression of premature ventricular contractions (PVCs) is one of the goals of antiarrhythmic therapy. In a clinical trial, however, it may be difficult to distinguish antiarrhythmic drug effect from spontaneous variation in PVCs. We propose the application of linear regression to PVC histories to ascertain drug effect in individual patients. The model determines which variables are important in explaining a patient's PVCs. One such variable indicates the presence or absence of the drug; the model determines whether the drug has an effect on the patient's PVCs, while compensating for the other explanatory variables. In addition to determining the statistical significance of any drug effect, the model estimates the strength of the effect for each patient. We demonstrate the method with data from a three-day clinical trial which used 24-hour Holter monitoring. The method is flexible and can be modified to apply to any clinical study design. It allows for inferences concerning populations and subpopulations of patients.