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: In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients From the pooled plasma of 54 adult donors immunized with Haemophilus influenzae type b capsular polysaccharide ( CP )  , a human hyperimmune globulin termed bacterial polysaccharide immune globulin ( BPIG ) was prepared . The pharmacokinetics of antibody to H. influenzae type b CP in high-risk children was compared after BPIG and conventional immune serum globulin ( ISG ) were administered intramuscularly at a dose of 0.5 - 0.6 ml/kg . The increase in antibody level four to seven days after injection was ninefold higher with BPIG than with ISG and remained higher throughout the three-month follow-up period . The mean half-life of antibody to H. influenzae type b CP was similar after BPIG ( 27 days ) and ISG ( 29 days ) . Antibody levels returned to baseline one to two months after ISG but remained significantly above baseline three months after BPIG ( mean concentration , 385 ng/ml ) . Based on the assumption that 150 ng of IgG antibody to H. influenzae type b CP/ml is the minimal protective level , it is concluded that a single intramuscular dose of 0.5 ml of BPIG/kg will protect children for four months BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the  9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo .  All children received Haemophilus influenzae type b conjugate vaccine .  Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection Haemophilus influenzae type B vaccine is recommended for children 1.5 to 6 years of age with sickle cell anemia , but the adequacy of their response is unknown . A total of 69 children with sickle cell syndromes , 1.5 to 5.6 years of age , were immunized with two vaccines alternatively , single blind . PRP vaccine was given to 36 children and a diphtheria toxoid conjugated vaccine , PRP-D , was given to 36 . Coded pre- and postvaccine sera were tested by radioimmunoassay for anti-PRP antibody . The groups did not differ in age distribution or type of sickle hemoglobinopathy .  Preexisting antibody levels were low in both vaccine groups ; 65 % were less than 0.15 microgram/mL. The vaccines were safe but associated with frequent minor reactions .  PRP-D gave higher geometric mean titers and mean fold titer increase than PRP in all children ( 15.58 micrograms/mL [ 234-fold ] v 2.63 micrograms/mL [ 29-fold ] ) and in the subgroups 1.5 to 2.5 years of age or with pretiter values less than 0.15 microgram/mL. Titers for 64 % of children receiving PRP and 94 % receiving PRP-D were greater than or equal to 1.0 microgram/mL. Thus , both vaccines were useful in this population , but PRP-D was more immunogenic . Duration of antibody levels postvaccination , booster responses , and PRP-D immunogenicity in younger children with sickle cell syndromes all require further study BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule OBJECTIVES ( 1 ) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and ( 2 ) to determine whether continued penicillin prophylaxis had any adverse effects on these responses . STUDY DESIGN Children with sickle cell anemia , who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday , were r and omly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment .  These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of r and omization . RESULTS Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor ; the poorest response was to serotype 6B . The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment , and in subjects who received one or two pneumococcal vaccinations before reimmunization . The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype . CONCLUSIONS Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies , regardless of previous pneumococcal vaccine history . Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization Repeat ( booster ) pneumococcal vaccination was administered to 32 patients with sickle cell disease in a double blind , placebo-controlled crossover study as early as 2.3 years after initial immunization . A significantly greater proportion of patients reported local pain , swelling or redness after booster , as compared to that after placebo ( P < 0.001 ) , and pneumococcal antibody titer before vaccination was the predominant predictive variable for the development of fever , local pain and swelling after booster . A comparison of reaction rates following primary or booster immunization showed no significant differences in the frequency of reported symptoms except for muscle pain which occurred less frequently after booster ( P < 0.005 ) . The concern for adverse reactions after repeat pneumococcal vaccination should not be an obstacle to the pursuit of further studies on the efficacy of pneumococcal vaccine and booster responses BACKGROUND Ear infections are a common cause of illness during the first two years of life . New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae . METHODS We enrolled 1662 infants in a r and omized , double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197 . The children received either the study vaccine or a hepatitis B vaccine as a control at 2 , 4 , 6 , and 12 months of age . The clinical diagnosis of acute otitis media was based on predefined criteria , and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy . RESULTS Of the children who were enrolled , 95.1 percent completed the trial . With the pneumococcal vaccine , there were more local reactions 
    Output:
    
agent
***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: In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients From the pooled plasma of 54 adult donors immunized with Haemophilus influenzae type b capsular polysaccharide ( CP )  , a human hyperimmune globulin termed bacterial polysaccharide immune globulin ( BPIG ) was prepared . The pharmacokinetics of antibody to H. influenzae type b CP in high-risk children was compared after BPIG and conventional immune serum globulin ( ISG ) were administered intramuscularly at a dose of 0.5 - 0.6 ml/kg . The increase in antibody level four to seven days after injection was ninefold higher with BPIG than with ISG and remained higher throughout the three-month follow-up period . The mean half-life of antibody to H. influenzae type b CP was similar after BPIG ( 27 days ) and ISG ( 29 days ) . Antibody levels returned to baseline one to two months after ISG but remained significantly above baseline three months after BPIG ( mean concentration , 385 ng/ml ) . Based on the assumption that 150 ng of IgG antibody to H. influenzae type b CP/ml is the minimal protective level , it is concluded that a single intramuscular dose of 0.5 ml of BPIG/kg will protect children for four months BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the  9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo .  All children received Haemophilus influenzae type b conjugate vaccine .  Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection Haemophilus influenzae type B vaccine is recommended for children 1.5 to 6 years of age with sickle cell anemia , but the adequacy of their response is unknown . A total of 69 children with sickle cell syndromes , 1.5 to 5.6 years of age , were immunized with two vaccines alternatively , single blind . PRP vaccine was given to 36 children and a diphtheria toxoid conjugated vaccine , PRP-D , was given to 36 . Coded pre- and postvaccine sera were tested by radioimmunoassay for anti-PRP antibody . The groups did not differ in age distribution or type of sickle hemoglobinopathy .  Preexisting antibody levels were low in both vaccine groups ; 65 % were less than 0.15 microgram/mL. The vaccines were safe but associated with frequent minor reactions .  PRP-D gave higher geometric mean titers and mean fold titer increase than PRP in all children ( 15.58 micrograms/mL [ 234-fold ] v 2.63 micrograms/mL [ 29-fold ] ) and in the subgroups 1.5 to 2.5 years of age or with pretiter values less than 0.15 microgram/mL. Titers for 64 % of children receiving PRP and 94 % receiving PRP-D were greater than or equal to 1.0 microgram/mL. Thus , both vaccines were useful in this population , but PRP-D was more immunogenic . Duration of antibody levels postvaccination , booster responses , and PRP-D immunogenicity in younger children with sickle cell syndromes all require further study BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule OBJECTIVES ( 1 ) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and ( 2 ) to determine whether continued penicillin prophylaxis had any adverse effects on these responses . STUDY DESIGN Children with sickle cell anemia , who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday , were r and omly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment .  These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of r and omization . RESULTS Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor ; the poorest response was to serotype 6B . The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment , and in subjects who received one or two pneumococcal vaccinations before reimmunization . The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype . CONCLUSIONS Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies , regardless of previous pneumococcal vaccine history . Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization Repeat ( booster ) pneumococcal vaccination was administered to 32 patients with sickle cell disease in a double blind , placebo-controlled crossover study as early as 2.3 years after initial immunization . A significantly greater proportion of patients reported local pain , swelling or redness after booster , as compared to that after placebo ( P < 0.001 ) , and pneumococcal antibody titer before vaccination was the predominant predictive variable for the development of fever , local pain and swelling after booster . A comparison of reaction rates following primary or booster immunization showed no significant differences in the frequency of reported symptoms except for muscle pain which occurred less frequently after booster ( P < 0.005 ) . The concern for adverse reactions after repeat pneumococcal vaccination should not be an obstacle to the pursuit of further studies on the efficacy of pneumococcal vaccine and booster responses BACKGROUND Ear infections are a common cause of illness during the first two years of life . New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae . METHODS We enrolled 1662 infants in a r and omized , double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197 . The children received either the study vaccine or a hepatitis B vaccine as a control at 2 , 4 , 6 , and 12 months of age . The clinical diagnosis of acute otitis media was based on predefined criteria , and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy . RESULTS Of the children who were enrolled , 95.1 percent completed the trial . With the pneumococcal vaccine , there were more local reactions 
    Output:
    