human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective : Stimulant medications , such as methylpheni date ( MPH ) , improve the academic performance of children with attention-deficit hyperactivity disorder ( ADHD ) . However , the mechanism by which MPH exerts an effect on academic performance is unclear . We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task , inhibitory control , selective attention , and reaction time variability . Methods : Children with ADHD aged 7 to 11 years ( N = 93 ) completed a timed math worksheet ( with problems tailored to each individual 's level of proficiency ) and 2 neuropsychological tasks ( Go/No-Go and Child Attention Network Test ) at baseline , then participated in a 4-week , r and omized , controlled , titration trial of MPH . Children were then r and omly assigned to their optimal MPH dose or placebo for 1 week ( administered double-blind ) and repeated the math and neuropsychological tasks ( posttest ) . Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task . Results : Children taking MPH completed 23 more math problems at posttest compared to baseline , whereas the placebo group completed 24 fewer problems on posttest versus baseline , but the effects on math accuracy ( percent correct ) did not differ . Path analyses revealed that only change in time on-task was a significant mediator of MPH 's improvements in math productivity . Conclusions : MPH-derived  math productivity improvements may be explained in part by increased time spent on-task , rather than improvements in neurocognitive parameters , such as inhibitory control , selective attention , or reaction time variability OBJECTIVE Methylpheni date ( MPH ) , the most commonly prescribed drug for attention-deficit/hyperactivity disorder ( ADHD ) , has a short half-life , which necessitates multiple daily doses . The need for multiple doses produces problems with medication administration during school and after-school hours , and therefore with compliance . Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH . This study tests the efficacy and duration of action , in natural and laboratory setting s , of an extended-release MPH preparation design ed to last 12 hours and therefore be equivalent to 3-times-daily dosing . METHODS Sixty-eight children with ADHD , 6 to 12 years old , participated in a within-subject , double-blind comparison of placebo , immediate-release ( IR ) MPH 3 times a day ( tid ) , and Concerta , a once-daily MPH formulation . Three dosing levels of medication were used : 5 mg IR MPH tid/18 mg Concerta once a day ( qd ) ; 10 mg IR MPH tid/36 mg Concerta qd ; and 15 mg IR MPH tid/54 mg Concerta qd . All children were currently medicated with MPH at enrollment , and each child 's dose level was based on that child 's  MPH dosing before the study . The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received . To achieve the ascending rate of  MPH delivery determined by initial investigations to provide the necessary continuous coverage , Concerta doses were 20 % higher on a daily basis than a comparable tid regimen of IR MPH . Children received each medication condition for 7 days . The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting . Parents received behavioral parent training and teachers were taught to establish a school-home daily report card ( DRC ) . A DRC is a list of individual target behaviors that represent a child 's most salient areas of impairment . Teachers set daily goals for each child 's impairment targets , and parents provided rewards at home for goal attainment . Each weekday , teachers completed the DRC , and it was used as a dependent measure of individualized medication response . Teachers and parents also completed weekly st and ardized ratings of behavior and treatment effectiveness . To evaluate the time course of medication effects , children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program . Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets . Measures of social behavior were taken in structured , small-group board game setting s and unstructured recess setting s. Measures included behavior frequency counts , academic problems completed and accuracy , independent observations , teacher and counselor ratings , and individualized behavioral target goals . Reports of adverse events , sleep quality , and appetite were collected . RESULTS On virtually all measures in all setting s , both drug conditions were significantly different from placebo , and the 2 drugs were not different from each other . In children 's regular school setting s , both medications improved behavior as measured by teacher ratings and individualized target behaviors ( the DRC ) ; these effects were seen into the evening as measured by parent ratings . In the laboratory setting , effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing . Concerta was significantly superior to tid MPH on 2 parent rating scores , and when asked , more parents preferred Concerta than preferred tid IR MPH or placebo . Side effects on children 's sleep and appetite were similar for the 2 preparations . In the lab setting , both medications improved productivity and accuracy on arithmetic seatwork assignments , disruptive and on-task behavior , and classroom rule following . Both medications improved children 's rule following and negative behavior in small group board games , as well as in unstructured recess setting s. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting . Children 's behavior across setting s deteriorated across the laboratory day , and the primary effect of medication was to prevent this deterioration as the day wore on . Results support the use of background behavioral treatment in clinical trials of stimulant medication , and illustrate the utility of a measure of individualized daily target goals ( ie , the DRC ) as an objective measure of medication response in both the laboratory and natural school setting s. CONCLUSION This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening . ( ABSTRACT TRUNCATED Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind , placebo-controlled , crossover evaluation of the efficacy of st and ard methylpheni date twice a day and comparable doses every morning of a sustained-release preparation of methylpheni date ( SR-20 Ritalin ) , a sustained-release form of dextroamphetamine ( Dexedrine Spansule ) , and pemoline . The children were participating in a summer treatment program in which they engaged in recreational and classroom activities . Dependent measures include evaluations of social behavior during group recreational activities , classroom performance , and performance on a continuous performance task . Results revealed generally equivalent and beneficial effects of all four medications . Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication . The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion , and the effects lasted for 9 hours . The implication s of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed OBJECTIVE The objective of this study was to evaluate differences in the pharmacodynamic ( PD ) profile of 2 second-generation extended-release ( ER ) formulations of methylpheni date ( MPH ) : Meta date CD ( MCD ; methylpheni date HCl , US Pharmacopeia ) extended-release capsules , CII , and Concerta ( CON ; methylpheni date HCl ) extended-release tablets , CII . Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior . Previous studies have shown that the near-equal doses of MCD and CON provide equivalent , total exposure to MPH as measured by area under the plasma concentration time curve , yet their pharmacokinetic ( PK ) plasma concentration versus time profiles are different . We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes : 1 ) an initial bolus dose of immediate-release ( IR ) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing , which for the MCD capsule is delivered by 30 % of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22 % of the total daily dose ; and 2 ) an extended , controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus , which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system . According to this PK/PD model , clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration . METHODS This was a multisite , double-blind , double-dummy , 3-way crossover study of 2 active treatments ( MCD and CON ) and placebo ( PLA ) . Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low ( 20 mg of MCD and 18 mg of CON ) , medium ( 40 mg of MCD and 36 mg of CON ) , or high ( 60 mg of MCD and 54 mg of CON ) , and in a r and omized order each of the study treatments was administered once daily in the morning for 1 week . On the seventh day of each treatment week , children attended a laboratory school , where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals . Safety was assessed by patient reports of adverse events , parent ratings on a stimulant side-effects scale , and measurement of vital signs . RESULTS The analyses of variance revealed large , statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures ( deportment , attention , and permanent product ) . The interactions of treatment x session were also highly significant for all 3 outcome measures . Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day : 1 ) PLA > MCD approximately CON ( PLA superiority ) immediately after dosing ; 2 ) MCD > CON > PLA during the morning ( MCD superiority ) ; 3 ) MCD approximately CON > PLA during the afternoon ( PD equivalence of MCD and CON ) ; and 4 ) CON > MCD approximately PLA in the early evening ( CON superiority ) . The effect of site was significant , because some study centers had low and some high scores for behavior in the lab classroom , but both the low- and high-scoring sites showed similar PD patterns across the day . The interaction of dose x treatment was not significant , indicating that the pattern of treatment effects was consistent across each dose level . There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events , ratings of side effects , or vital signs . Two additional PK/PD questions were addressed : 1 . The a priori hypothesis called for a comparison of the average of sessions ( removing session as a factor ) during a time period that corresponds to the length of a typical school day ( from 1.5 through 7.5 hours after dosing ) . For the planned contrast of the 2 treatment conditions ( MCD versus CON ) , the difference was significant , confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period . 2 . In the design of the study , the dose factor represented the total daily dose , consisting of 2 components : the initial bolus doses of IR MPH , which differ for the near-equal total daily doses of MCD and CON , and the reservoir doses of ER MPH , which were the same for the 2 formulations . To evaluate the moderating effects of the bolus component of dose on outcome , average effect size ( ES ) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels . The correlation ( r ) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures ( r approximately .9 ) , indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation . For the 2 dose conditions with equal 12-mg IR MPH boluses ( MCD 40 and CON 54 ) , the ESs were large and indistinguishable ( eg , deportment ES approximately 0.75 for both ) . CONCLUSIONS Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting . As predicted by the PK/PD model , superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration Objective . To assess effects of OROS methylpheni date on cognitive and academic tasks in 9 to 12 year olds with attention-deficit/hyperactivity disorder ( ADHD ) . Methods . A double-blind , within-subject , crossover design was used to compare OROS methylpheni date with placebo in a laboratory classroom setting on several cognitive and academic tasks for 68 children who met r and omization criteria . Results . Performance on the following measures was significantly better when children received individually optimized OROS methylpheni date than placebo :  math fluency and accuracy measured by the Permanent Product Math Test , ADHD symptoms observed in the laboratory setting , computerized indices of attention and impulsivity as measured by the Test of Variables of Attention ( TOVA ) , and visual — spatial working memory ( Finger Windows Backwards ) . 
    Output:
    
agent
None of the mediators or moderators tested affected methylpheni date efficacy .
Academic improvements were small compared to symptom improvements ; qualitative changes limited to math .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective : Stimulant medications , such as methylpheni date ( MPH ) , improve the academic performance of children with attention-deficit hyperactivity disorder ( ADHD ) . However , the mechanism by which MPH exerts an effect on academic performance is unclear . We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task , inhibitory control , selective attention , and reaction time variability . Methods : Children with ADHD aged 7 to 11 years ( N = 93 ) completed a timed math worksheet ( with problems tailored to each individual 's level of proficiency ) and 2 neuropsychological tasks ( Go/No-Go and Child Attention Network Test ) at baseline , then participated in a 4-week , r and omized , controlled , titration trial of MPH . Children were then r and omly assigned to their optimal MPH dose or placebo for 1 week ( administered double-blind ) and repeated the math and neuropsychological tasks ( posttest ) . Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task . Results : Children taking MPH completed 23 more math problems at posttest compared to baseline , whereas the placebo group completed 24 fewer problems on posttest versus baseline , but the effects on math accuracy ( percent correct ) did not differ . Path analyses revealed that only change in time on-task was a significant mediator of MPH 's improvements in math productivity . Conclusions : MPH-derived  math productivity improvements may be explained in part by increased time spent on-task , rather than improvements in neurocognitive parameters , such as inhibitory control , selective attention , or reaction time variability OBJECTIVE Methylpheni date ( MPH ) , the most commonly prescribed drug for attention-deficit/hyperactivity disorder ( ADHD ) , has a short half-life , which necessitates multiple daily doses . The need for multiple doses produces problems with medication administration during school and after-school hours , and therefore with compliance . Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH . This study tests the efficacy and duration of action , in natural and laboratory setting s , of an extended-release MPH preparation design ed to last 12 hours and therefore be equivalent to 3-times-daily dosing . METHODS Sixty-eight children with ADHD , 6 to 12 years old , participated in a within-subject , double-blind comparison of placebo , immediate-release ( IR ) MPH 3 times a day ( tid ) , and Concerta , a once-daily MPH formulation . Three dosing levels of medication were used : 5 mg IR MPH tid/18 mg Concerta once a day ( qd ) ; 10 mg IR MPH tid/36 mg Concerta qd ; and 15 mg IR MPH tid/54 mg Concerta qd . All children were currently medicated with MPH at enrollment , and each child 's dose level was based on that child 's  MPH dosing before the study . The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received . To achieve the ascending rate of  MPH delivery determined by initial investigations to provide the necessary continuous coverage , Concerta doses were 20 % higher on a daily basis than a comparable tid regimen of IR MPH . Children received each medication condition for 7 days . The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting . Parents received behavioral parent training and teachers were taught to establish a school-home daily report card ( DRC ) . A DRC is a list of individual target behaviors that represent a child 's most salient areas of impairment . Teachers set daily goals for each child 's impairment targets , and parents provided rewards at home for goal attainment . Each weekday , teachers completed the DRC , and it was used as a dependent measure of individualized medication response . Teachers and parents also completed weekly st and ardized ratings of behavior and treatment effectiveness . To evaluate the time course of medication effects , children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program . Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets . Measures of social behavior were taken in structured , small-group board game setting s and unstructured recess setting s. Measures included behavior frequency counts , academic problems completed and accuracy , independent observations , teacher and counselor ratings , and individualized behavioral target goals . Reports of adverse events , sleep quality , and appetite were collected . RESULTS On virtually all measures in all setting s , both drug conditions were significantly different from placebo , and the 2 drugs were not different from each other . In children 's regular school setting s , both medications improved behavior as measured by teacher ratings and individualized target behaviors ( the DRC ) ; these effects were seen into the evening as measured by parent ratings . In the laboratory setting , effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing . Concerta was significantly superior to tid MPH on 2 parent rating scores , and when asked , more parents preferred Concerta than preferred tid IR MPH or placebo . Side effects on children 's sleep and appetite were similar for the 2 preparations . In the lab setting , both medications improved productivity and accuracy on arithmetic seatwork assignments , disruptive and on-task behavior , and classroom rule following . Both medications improved children 's rule following and negative behavior in small group board games , as well as in unstructured recess setting s. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting . Children 's behavior across setting s deteriorated across the laboratory day , and the primary effect of medication was to prevent this deterioration as the day wore on . Results support the use of background behavioral treatment in clinical trials of stimulant medication , and illustrate the utility of a measure of individualized daily target goals ( ie , the DRC ) as an objective measure of medication response in both the laboratory and natural school setting s. CONCLUSION This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening . ( ABSTRACT TRUNCATED Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind , placebo-controlled , crossover evaluation of the efficacy of st and ard methylpheni date twice a day and comparable doses every morning of a sustained-release preparation of methylpheni date ( SR-20 Ritalin ) , a sustained-release form of dextroamphetamine ( Dexedrine Spansule ) , and pemoline . The children were participating in a summer treatment program in which they engaged in recreational and classroom activities . Dependent measures include evaluations of social behavior during group recreational activities , classroom performance , and performance on a continuous performance task . Results revealed generally equivalent and beneficial effects of all four medications . Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication . The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion , and the effects lasted for 9 hours . The implication s of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed OBJECTIVE The objective of this study was to evaluate differences in the pharmacodynamic ( PD ) profile of 2 second-generation extended-release ( ER ) formulations of methylpheni date ( MPH ) : Meta date CD ( MCD ; methylpheni date HCl , US Pharmacopeia ) extended-release capsules , CII , and Concerta ( CON ; methylpheni date HCl ) extended-release tablets , CII . Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior . Previous studies have shown that the near-equal doses of MCD and CON provide equivalent , total exposure to MPH as measured by area under the plasma concentration time curve , yet their pharmacokinetic ( PK ) plasma concentration versus time profiles are different . We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes : 1 ) an initial bolus dose of immediate-release ( IR ) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing , which for the MCD capsule is delivered by 30 % of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22 % of the total daily dose ; and 2 ) an extended , controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus , which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system . According to this PK/PD model , clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration . METHODS This was a multisite , double-blind , double-dummy , 3-way crossover study of 2 active treatments ( MCD and CON ) and placebo ( PLA ) . Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low ( 20 mg of MCD and 18 mg of CON ) , medium ( 40 mg of MCD and 36 mg of CON ) , or high ( 60 mg of MCD and 54 mg of CON ) , and in a r and omized order each of the study treatments was administered once daily in the morning for 1 week . On the seventh day of each treatment week , children attended a laboratory school , where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals . Safety was assessed by patient reports of adverse events , parent ratings on a stimulant side-effects scale , and measurement of vital signs . RESULTS The analyses of variance revealed large , statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures ( deportment , attention , and permanent product ) . The interactions of treatment x session were also highly significant for all 3 outcome measures . Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day : 1 ) PLA > MCD approximately CON ( PLA superiority ) immediately after dosing ; 2 ) MCD > CON > PLA during the morning ( MCD superiority ) ; 3 ) MCD approximately CON > PLA during the afternoon ( PD equivalence of MCD and CON ) ; and 4 ) CON > MCD approximately PLA in the early evening ( CON superiority ) . The effect of site was significant , because some study centers had low and some high scores for behavior in the lab classroom , but both the low- and high-scoring sites showed similar PD patterns across the day . The interaction of dose x treatment was not significant , indicating that the pattern of treatment effects was consistent across each dose level . There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events , ratings of side effects , or vital signs . Two additional PK/PD questions were addressed : 1 . The a priori hypothesis called for a comparison of the average of sessions ( removing session as a factor ) during a time period that corresponds to the length of a typical school day ( from 1.5 through 7.5 hours after dosing ) . For the planned contrast of the 2 treatment conditions ( MCD versus CON ) , the difference was significant , confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period . 2 . In the design of the study , the dose factor represented the total daily dose , consisting of 2 components : the initial bolus doses of IR MPH , which differ for the near-equal total daily doses of MCD and CON , and the reservoir doses of ER MPH , which were the same for the 2 formulations . To evaluate the moderating effects of the bolus component of dose on outcome , average effect size ( ES ) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels . The correlation ( r ) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures ( r approximately .9 ) , indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation . For the 2 dose conditions with equal 12-mg IR MPH boluses ( MCD 40 and CON 54 ) , the ESs were large and indistinguishable ( eg , deportment ES approximately 0.75 for both ) . CONCLUSIONS Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting . As predicted by the PK/PD model , superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration Objective . To assess effects of OROS methylpheni date on cognitive and academic tasks in 9 to 12 year olds with attention-deficit/hyperactivity disorder ( ADHD ) . Methods . A double-blind , within-subject , crossover design was used to compare OROS methylpheni date with placebo in a laboratory classroom setting on several cognitive and academic tasks for 68 children who met r and omization criteria . Results . Performance on the following measures was significantly better when children received individually optimized OROS methylpheni date than placebo :  math fluency and accuracy measured by the Permanent Product Math Test , ADHD symptoms observed in the laboratory setting , computerized indices of attention and impulsivity as measured by the Test of Variables of Attention ( TOVA ) , and visual — spatial working memory ( Finger Windows Backwards ) . 
    Output:
    