***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: Because the clinics in a multiclinic r and omized clinical trial represent neither fixed stratification effects nor r and om classificatory effects , the appropriate analysis of data from such a trial has been the subject of controversy and debate . The following are some of the elements of controversy that are discussed and for which some bases for resolution are proposed . Is it ever valid to ignore the effects of clinics in the analysis ? Is it ever valid to drop clinics from the analysis ? Is a multiclinic clinical trial similar in structure or not to a single-clinic clinical trial in which patients have been stratified on a classificatory factor ? Assuming that clinics will be taken account of in the analysis , should it be the weighted or the unweighted average of within-clinic treatment differences that is to be taken as the best estimate of the overall difference between the treatments ? How should the data be analyzed if there is evidence of treatment-by-clinic interaction The efficacy and safety of prophylactic low dose amantadine hydrochloride was assessed in two double-blind , placebo-controlled , r and omized studies . In a study of 476 subjects aged 18 to 55 years , adverse reactions were not significantly different between the group receiving 100 mg/day amantadine and the placebo group but significantly greater in the group given 200 mg/day ( P less than 0.009 ) . The influenza attack rate in this study was too low to assess efficacy . In an experimental challenge study of influenza A/Beth/1/85 in 78 subjects of similar age the prophylactic administration of 50 mg , 100 mg or 200 mg/day doses of amantadine were more effective than placebo in preventing influenza illness ( P less than 0.02 , 66 , 74 and 82 % protection , respectively ) , and in suppressing viral replication ( P = 0.02 ) . There was no significant difference between amantadine groups in influenza illness or viral shedding . Compared with the placebo group the 100 and 200 mg amantadine groups showed a significant decrease in infection rate ( 100 mg : 40 % protection : P = 0.012 ; 200 mg : 32 % protection : P = 0.045 ) whereas the 50 mg group did not ( 20 % protection : P = 0.187 ) . These results suggest that 100 mg/day of amantadine will reduce toxicity but maintain the prophylactic efficacy seen with 200 mg/day The relative toxicities of amantadine and rimantadine were compared in a double-blind , placebo-controlled study involving healthy adults . In separate studies , drugs were administered at a dosage of 200 mg/day ( 52 volunteers ) or 300 mg/day ( 196 volunteers ) for 4.5 days . Both drugs were well tolerated at the lower dosage . At 300 mg/day amantadine recipients had a greater frequency and severity of central nervous system ( nervousness , lightheadedness , difficulty concentrating ) and sleep ( insomnia , fatigue ) complaints compared with rimantadine or placebo recipients . Amantadine recipients also performed less well on an objective test measuring sustained attention and problem-solving ability . Both amantadine and rimantadine recipients reported adverse gastrointestinal symptoms more often than placebo recipients . Because of better tolerance at higher dosage , rimantadine offers more promise than amantadine for treatment of influenza A virus infections In a double-blind , placebo-controlled study , the comparative toxicities and blood concentrations of amantadine hydrochloride and rimantadine hydrochloride were determined . Healthy , working adults ingested either 200 ( n = 52 ) or 300 mg ( n = 196 ) per day in divided doses for 4.5 days . Mean plasma drug concentrations at 4 h after the first dose were lower in rimantadine recipients given 100- ( 140 versus 300 ng/ml for rimantadine and amantadine , respectively ; P less than 10(-5 ) ) or 200-mg doses ( 310 versus 633 ng/ml ; P less than 10(-5 ) ) . The plasma drug concentrations after the first dose correlated significantly with total symptom sources for both amantadine and rimantadine , but the plasma levels of toxic and nontoxic subjects overlapped extensively . At 300-mg/day dosage amantadine was associated more often with adverse central nervous system symptoms ( 33 % of amantadine versus 9 % of rimantadine recipients ; P less than 0.001 ) and sleep disturbance ( 39 versus 13 % ; P less than 0.001 ) , but not gastrointestinal symptoms ( 19.5 versus 16.0 % ) . However , no differences between the drugs were noted in symptom frequency or scores in volunteers with similar plasma concentrations . Amantadine and rimantadine differ in their pharmacokinetics but not in their potential for side effects at comparable plasma concentrations In a boarding school for boys , where routine influenza vaccination is carried out annually , 267 boys were given amantadine ( 100 mg daily ) and 269 received no specific treatment during an influenza A ( H1N1 ) outbreak . 3 boys receiving amantadine and 29 boys receiving no medication had laboratory-proven influenza A. There are circumstances when the prophylactic use of amantadine may be justified for the control of influenza A outbreaks in boarding schools and other institutions where high attack-rates are experienced Prophylactic administration of amantadine in doses of 100 mg . twice a day offered statistically significant protection against influenza A2 infection in a double-blind field trial involving 391 medical student volunteers during the influenza A2 Hong Kong epidemic in Helsinki in the winter of 1969 . Serologically verified influenza , as measured by complement fixation and /or haemagglutination inhibition , occurred in 27 out of 192 students in the  amantadine  group against 57 out of 199 in the placebo group , giving a protection rate of 52 % The usefulness of amantadine in the protection of humans against influenza A ( H1N1 ) virus was evaluated in a double-blind field trial with 555 volunteers in Finl and in the winter of 1978 . Three population s-- patients in a general hospital , adults in a home for the aged , and two groups of military conscripts -- were chosen . Epidemic influenza occurred only in the two groups of conscripts : the incidence of serologically verified influenza was 66 % and 83 % in the groups that received placebo and 43 % and 51 % in the groups that received amantadine , giving protection rates of 36 % ( P = 0.05 ) and 39 % ( P = 0.001 ) . The evaluation of the effect of amantadine on the occurrence of illness was obscured by concomitant adenoviral infections that caused influenza-like symptoms . No clear difference in the occurrences of side effects was observed between the placebo and amantadine-treated groups ; however , a significantly greater number of participants who took 200 mg of amantadine/day ( 16.9 % ) stopped medication during the trial as compared with the placebo groups ( 7.6 % ) ( P < 0.02 ) Abstract Early prophylactic treatment with 1-adamantanamine hydrochloride ( aminoadamantane , amantadine ) of household contacts of index cases of serologically confirmed influenza reduced the incidence of clinical influenza from 14.1 % to 3.6 % . Such treatment also produced a statistically significant reduction in the serological evidence of infection from 39.1 % in the  placebo group to 14.6 % in the aminoadamantane-treated  group . The incidence of sub clinical ( asymptomatic ) infections in the contacts of serologically confirmed index cases was reduced from 24.6 % in the placebo  group to 14.6 % in the aminoadamantane-treated group Amantadine hydrochloride , a chemotherapeutic anti‐influenza compound , was tested for prophylactic and curative effects in double‐blind trials on 794 and 55 prisoner volunteers during an Asian influenza epidemic .  Oral 200 mg . doses were given for 10 to 14 days . In the prophylactic trial , 5 of 439 ( 1.1 per cent ) drug‐treated subjects became ill in contrast to 15 of 355 ( 4.2 per cent ) placebo subjects , indicating significant protection . Among unselected drug‐treated subjects , fourfold or greater titer rises occurred in 30 per cent fewer subjects than in the placebo group ( p < 0.05 ) . Subjects with initial titers of 40 or less showed a 43 per cent titer rise difference ( p < 0.02 ) . Measured by the rises of mean titers , amantadine exerted a 52 per cent protection ( p < 0.05 ) . Reduced antibody titer rises accompanying therapeutic drug administration were not significant Abstract Objectives : To determine the extent to which publication is influenced by study outcome . Design : A cohort of studies su bmi tted to a hospital ethics committee over 10 years were examined retrospectively by review ing the protocol s and by question naire . The primary method of analysis was Cox 's proportional hazards model . Setting : University hospital , Sydney , Australia . Studies : 748 eligible studies su bmi tted to Royal Prince Alfred Hospital Ethics Committee between 1979 and 1988 . Main outcome measures : Time to publication . Results : Response to the question naire was received for 520 ( 70 % ) of the eligible studies . Of the 218 studies analysed with tests of significance , those with positive results ( P<0.05 ) were much more likely to be published than those with negative results ( P0.10 ) ( hazard ratio 2.32 ( 95 % confidence interval 1.47 to 3.66 ) , P=0.0003 ) , with a significantly shorter time to publication ( median 4.8 v 8.0 years ) . This finding was even stronger for the group of 130 clinical trials ( hazard ratio 3.13 ( 1.76 to 5.58 ) , P=0.0001 ) , with median times to publication of 4.7 and 8.0 years respectively . These results were not material ly changed after adjusting for other significant predictors of publication . Studies with indefinite conclusions ( 0.05 P<0.10 ) tended to have an even lower publication rate and longer time to publication than studies with negative results ( hazard ratio 0.39 ( 0.13 to 1.12 ) , P=0.08 ) . For the 103 studies in which outcome was rated qualitatively , there was no clear cut evidence of publication bias , although the number of studies in this group was not large . Conclusions : This study confirms the evidence of publication bias found in other studies and identifies delay in publication as an additional important factor . The study results support the need for prospect i ve registration of trials to avoid publication bias and also support restricting the selection of trials to those started before a common date in undertaking systematic review s. Key messages This retrospective cohort study of clinical research projects confirms the findings of publication bias found in previous studies Delay in the publication of studies with negative results has been identified as an additional important factor in publication bias With the recognised importance of evidence based medicine , these results have important implication s for the selection of studies included in systematic review s Prospect i ve registration of clinical research projects will avoid many of the problems associated with publication bias However , it is also important to restrict inclusion in systematic review s to studies started before a certain date to allow for the delay in completing studies with negative A placebo-controlled , double-blind study to evaluate the safety and prophylactic efficacy of a low dose ( 100 mg ) of rimantadine hydrochloride against naturally occurring influenza in adults was conducted at two sites . After the onset of the influenza season , volunteers ( ages , 18 to 55 years ) were assigned r and omly to receive rimantadine or placebo daily . Subjects were monitored for adverse effects and evidence of influenza virus infection weekly for six weeks . Only 10 ( 8.7 % ) of 114 rimantadine recipients and 5 ( 4.4 % ) of 114 placebo control recipients reported one or more mild to moderate adverse symptoms , most of which were related to the gastrointestinal or central nervous system . Compared with placebo , low-dose rimantadine was highly effective in the prevention of influenza A virus infection ( 20 of 110 versus 7 of 112 participants ; P less than 0.01 ) and influenza illness ( 7 of 110 versus 1 of 112 participants ; P = 0.04 ) . Influenza A/Leningrad/87-like ( H3N2 ) virus was recovered from the nasopharynxes of only five placebo recipients . These findings indicate that low-dose rimantadine is well tolerated and highly effective for the prevention of influenza A illness in healthy adults Prospect i ve virologic surveillance has defined two influenza epidemics representing the fifth and sixth outbreaks attributed to H3N2 viruses since the prototype , A/Hong Kong/68 ( ( H3N2 ) , emerged in 1968 . The 1975 epidemic was caused by influenza A/Port Chalmers and yielded an estimated attack rate of 9 per cent ; the second , attributed to influenza A/Victoria , produced an explosive outbreak , with an estimated attack rate of 18 per cent in 1976 
    Output:
    
This meta- analysis demonstrates that amantadine and rimantadine are superior to placebo in the prevention of influenza A illness .
Both antiviral agents have an increased number of adverse events compared with placebo ; however , the use of amantadine is associated with significantly higher numbers of central nervous system events and treatment withdrawals compared with rimantadine .