In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.Please see later in the article for the Editors' Summary Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP ; other protocol-specified outcomes were also assessed.The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable n = 10,295; control, n = 10,201), per-protocol VE was 22.0%  against B-CAP (conclusive for primary objective) and 25.7%  against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2%  against B-CAP and 23.4%  against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD)  and AOM . Per-protocol VE was 16.1%  against clinically confirmed AOM, 67.1%  against vaccine serotype clinically confirmed AOM, 100%  against vaccine serotype IPD, and 65.0%  against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5%  and 22.6%  of PHiD-CV and control recipients, respectively. There were 19 deaths  in the PHiD-CV group and 26 deaths  in the control group. A significant study limitation was the lower than expected number of captured AOM cases.This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine  at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo  that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia  and acute otitis media . It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis . Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.Pneumococcal diseases are illnesses caused by Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial , the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.The researchers enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces  in the lungs filled with liquid instead of gas  or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort  was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis  was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event ; 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.http://dx.doi.org/10.1371/journal.pmed.1001657.Please access these websites via the online version of this summary at pneumococcal vaccination, including personal storiesThe US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and Public Health England provides information on pneumococcal disease and on pneumococcal vaccines pneumococcal disease, including personal storiesThe not-for-profit Immunization Action Coalition has information onpneumococcal disease and the importance of vaccination The GAVI Alliance provides information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish) MedlinePlus has links to further information about COMPAS is availableMore information about information about PHiD-CV (Synflorix)The European Medicines Agency provides  Streptococcus pneumoniae is a major cause of various diseases, ranging from septicemia and meningitis to pneumonia and acute otitis media (AOM). As community-acquired pneumonia (CAP) is a leading cause of childhood mortality Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) represent 70%–80% of those that cause invasive pneumococcal disease (IPD) and AOM in young children in Latin America In Latin America, pneumococcal disease rates among young children are intermediate in comparison with other global areas In contrast, for mucosal diseases–e.g., pneumonia and AOM–no such licensing criteria are defined. Furthermore, antibody levels for most of the pneumococcal serotypes contained in both vaccines, when expressed as geometric mean concentrations, tended to be higher with 7vCRM than with PHiD-CV The trial was sponsored by GlaxoSmithKline Biologicals. An independent data monitoring committee (IDMC), composed of seven independent experts in infectious diseases and/or statistics, provided oversight by reviewing serious adverse events (SAEs) and assessing potential treatment harm. The IDMC also made recommendations to the sponsor regarding safety measures, study design, and analysis and reporting plans. Written informed consent was obtained from children's parents/guardians, and the study was conducted in accordance with good clinical practice, all applicable regulatory requirements, and the Declaration of Helsinki. When deviations from these guidelines/regulatory requirements were detected , correctThis study was conducted at five sites: three in Argentina , one in Colombia , and one in Panama (Panama City). The study locations were chosen partly because local investigators and public health authorities from the three countries were experienced in collaborative epidemiological surveillance research on pneumococcal diseases, including an international surveillance study of invasive bacterial isolates  The study areas were mainly urban, and local climates have either clear seasonality (Argentina) or are tropical or subtropical (Panama and Colombia). Populations in these countries generally have good access to health care and drug treatments, including antibiotics . Immunization coverage for routine childhood vaccines is high in each country  All three countries are classified by the World Bank, based on gross national income per capita, as upper middle income economies, a classification shared by many other countries in Latin America, Eastern Europe, Asia, the Middle East, and North Africa This was a phase III double-blind randomized controlled study. The primary confirmatory objective of the study was to demonstrate the VE of PHiD-CV  against first episodes of likely bacterial CAP (B-CAP) occurring at least 2 wk after administration of the third dose of study vaccine in the per-protocol cohort for efficacy. Efficacy against clinically confirmed AOM (C-AOM) was evaluated as the first secondary confirmatory objective; efficacy against IPD and other CAP and AOM end points were assessed as secondary objectives .Haemophilus influenzae type b vaccine (Infanrix hexa) (PHiD-CV group) or hepatitis B vaccine (Engerix-B) and diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae type b vaccine  (control group) at approximately 2, 4, and 6 mo of age. This was followed by one dose of PHiD-CV or hepatitis A vaccine (Havrix), respectively, at 15–18 mo of age, both coadministered with DTPa-IPV/Hib , and treatment was concealed from all study personnel. Information on individual randomization could be obtained only through SBIR by the study safety physician if unblinding was needed, for example, because of an individual safety issue. Twenty-three participants were unblinded by the study safety physician as part of the emergency unblinding process or because the study participant was at risk for pneumococcal disease because of a medical condition diagnosed during the study. As a consequence they were censored at the time of unblinding, as defined in the statistical analysis plan. Three additional participants were unblinded by the study safety physician because of a suspected unexpected serious adverse reaction but remained in the per-protocol cohort for efficacy analysis. The randomization list was generated by the sponsor using a standard SAS (SAS Institute) program and was used to number the vaccines. A randomization blocking scheme was used to ensure that balance between treatment groups was maintained.Since there were minor differences in vaccine appearance, an observer-blind methodology was used to maintain double-blinding and avoid possible observer bias. This means that all vaccines were prepared and administered by dedicated personnel who took no further part in the study. The parents/guardians of children enrolled in the study and personnel involved in data gathering, processing, and analysis and safety assessment were blind to vaccine allocation.Exclusion/elimination criteria for further study participation were checked for all children at each scheduled and unscheduled visit after the first visit, including high-risk conditions for pneumococcal infections as defined by the American Academy of Pediatrics and the Argentinean Pediatric Society . The diaH. influenzae); 3 µg of serotype 18C capsular polysaccharide conjugated to tetanus toxoid; and 3 µg of serotype 19F capsular polysaccharide conjugated to diphtheria toxoid All study vaccines were manufactured by GlaxoSmithKline Vaccines. PHiD-CV contained 1 µg of each capsular polysaccharide for pneumococcal serotypes 1, 5, 6B, 7F, 9V, 14, and 23F and 3 µg for serotype 4 conjugated individually to protein D . Inclusion of a 7vCRM control group in our study was therefore deemed not mandatory Disease surveillance involved the major local pediatric hospitals and primary health care centers. Parents were advised to (1) seek medical attention if their child had any health problem, including fever or respiratory symptoms, (2) highlight their child's participation in COMPAS when seeking medical care, and (3) inform study personnel as soon as possible. Parents were asked at each study visit about symptoms of illness experienced by their child since the previous visit. Disease episodes were also captured by study personnel blinded to vaccine allocation via screenings of emergency room, hospital admissions, radiology, and outpatient records, and mortuary lists.Suspected pneumonia cases were identified by pediatricians based on medical history and clinical symptoms. Chest X-ray and laboratory tests to guide diagnosis and treatment were performed according to local routine clinical practice and the judgment of the treating physician. A child with an acute respiratory tract infection, referred by the treating pediatrician for a chest X-ray as part of the clinical assessment, was considered for suspected CAP study end points. Children with only symptoms of wheezing diseases  were not considered for suspected CAP end points. Serum samples for C-reactive protein (CRP) measurement were obtained from suspected CAP cases and stored at −20 °C until analyzed at the central laboratory.A group composed of representatives of participating radiology departments was established to install a quality assurance system in all centers where chest X-rays were performed. Analog X-ray films were digitalized using a Sierra Euro scanner (Vidar Systems Corporation), while digital X-ray images were used as such. Interpretation and classification of the digital images for study end point assessment was performed by an independent panel of external readers trained in WHO definitions before the start of image evaluation and regularly thereafter The CAP case definitions used in COMPAS overlap, and as they become more specific for CAP with bacterial origin, they also tend to detect fewer cases . The suspected CAP case definition, being the broadest, encompassed all other CAP case definitions and was selected because it reflects the first step in the clinical assessment of a sick child by the treating physician: to identify potential pneumonia cases that require further evaluation. The radiologically confirmed CAP case definition represents the next step in the clinical reasoning process, where the chest X-ray is examined in an attempt to confirm the presence or absence of pneumonia. However, for study purposes and end point evaluation, as described above, assessment of X-rays was performed by external readers, independently of disease management procedures. The consolidated CAP case definition was proposed by the WHO to facilitate comparisons between pneumonia efficacy trials In COMPAS, B-CAP was therefore defined as radiologically confirmed CAP with either alveolar consolidation/pleural effusion or non-alveolar infiltrates and CRP ≥ 40 µg/ml . The B-CThe AOM outcome was studied in Panama only. Training in order to standardize assessment of AOM cases was provided before the start of the study and regularly thereafter to the physicians involved with the study, which followed recommendations provided by an external consultant with expertise in AOM. Initially, cases of AOM were captured only when parents sought medical attention for children with symptoms of AOM. However, approximately 2 y into the study (July 2009), because of a lower than expected AOM rate, the surveillance was enhanced through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had symptoms suggestive of AOM. If AOM was suspected by the physician, the child was referred to one of the ear, nose, and throat (ENT) specialists involved in the trial. Study pediatricians and physicians on duty in emergency departments were asked not to initiate antibiotic treatment before referral to the ENT specialist.A C-AOM diagnosis required either altered visual appearance of the tympanic membrane  or the presence of middle-ear effusion (as demonstrated by simple or pneumatic otoscopy or by otomicroscopy). At least two of the following clinical symptoms, which started within the previous 5 d, were also required: ear pain, ear discharge, hearing loss, fever, lethargy, irritability, anorexia, vomiting, or diarrhea.The severity of each suspected AOM case was assessed, combining objective elements of the Friedman scale  S. pneumoniae or H. influenzae was identified in normally sterile body fluids such as blood, cerebrospinal fluid (CSF), pleural effusion, synovial fluid, or peritoneal fluid.Invasive disease was defined as any disease where 3, >100 leukocytes/mm3, or 10–99 leukocytes/mm3 and either glucose <30 mg/dl or protein >100 mg/dl), confirmed meningitis due to S. pneumoniae or H. influenzae (presence of S. pneumoniae or H. influenzae in CSF culture or purulent meningitis with blood culture positive for S. pneumoniae or H. influenzae), and probable bacterial meningitis due to S. pneumoniae or H. influenzae . Other clinical syndromes of focal invasive disease that were recorded included the following: bacteremic pneumonia , empyema , peritonitis , osteomyelitis , soft tissue infection , septic arthritis , pericarditis .Various clinical syndromes of focal invasive disease were recorded. These syndromes included purulent meningitis (CSF with >10 polymorphonuclear cells/mmS. pneumoniae or H. influenzae indicating viable bacteria in blood without an obvious focus of infection), was also reported. In addition, generalized infections were reported as sepsis  without overt focus of infection or with suspicion of meningitis, pneumonia, empyema, septic arthritis, peritonitis, osteomyelitis, pericarditis, or bacterial infection of soft tissue. In addition, a blood culture was to be seriously considered in children with a recent (within 24 h) history of febrile illness, especially if antipyretic treatment could have interfered with the temperature measurement at the time of physical examination of the child. In Panama, where dengue was endemic, it was recommended to perform dengue testing, according to local practices.S. pneumoniae or H. influenzae was isolated from blood cultures or other normally sterile body fluids and/or CSF, and in which testing for S. pneumoniae or H. influenzae antigens (BinaxNOW or Latex) was positive.In addition, study personnel at each site reviewed the records of the microbiology laboratories to identify study participants for whom H. influenzae protein D were measured by ELISA with an assay cutoff of 100 ELISA units (ELU)/ml.Immune responses against PHiD-CV antigens were planned to be assessed in approximately 1,000 infants (first 500 enrolled in selected centers in Argentina and Panama) and are reported from blood samples taken 1 mo after dose 3, just before booster, and 1 mo after booster vaccination. Serum anti-pneumococcal, serotype-specific IgG antibodies were measured using GlaxoSmithKline's 22F-inhibition ELISA with a cutoff value of 0.05 µg/ml, as described before SAEs are reported in this paper. Investigators were requested to report any SAE, defined as any medical event that resulted in death, was life-threatening, caused disability, or required hospitalization or prolongation of hospitalization, within 24 h of identification.Laboratory procedures are described in The study was sponsored by GlaxoSmithKline Biologicals, the vaccine developer and manufacturer. The data generated in the trial are subject to a confidentiality agreement between the investigators and sponsor that allowed the investigators full access to the study data at the end of the study and included an obligation for GlaxoSmithKline Biologicals to permit publication without excessive delay.The contract research organizations I3 and Progenitor (currently Encorium) were contracted to perform monitoring, Eurofins Medinet to perform biological sample processing, and S-Clinica to perform blinded statistical analyses. At each study center, data were remotely entered on electronic case report forms and transferred to GlaxoSmithKline for data management. All data cleaning processes were blinded to study group, and analyses before the end of the study were conducted by an external statistician  who performed the analyses using SAS and the StatXact 8.0 procedure in SAS based on cleaned datasets and quality control programs provided by GlaxoSmithKline.The per-protocol cohort for efficacy comprised participants who had complied with vaccination and did not fulfill elimination criteria. In the per-protocol analysis, follow-up was censored at whatever came first: data lock point, time of last contact , time of unblinding, time of booster vaccination (if the booster dose was not given correctly), or 18 mo of age (if the booster dose was not given by this age). The intent-to-treat analysis assessed efficacy against disease episodes from administration of the first vaccine dose.n, multiplied by 100. VE was estimated as one minus the hazard ratio and obtained, with its 95% CI, from a Cox regression model based on time to first disease episode. The Cox model was applied for VE and associated 95% CI and p-value computations when at least one event was observed in each group. Where zero cases were observed in one or more groups, the Poisson model, conditional to the number of cases, was applied without specific correction.The incidence (percentage) of first disease episodes was calculated as the number of first episodes during the respective follow-up period divided by The primary confirmatory objective was to demonstrate VE of PHiD-CV vaccination (three doses in children aged ≤18 mo or four doses if aged >18 mo) against first episodes of B-CAP occurring at least 2 wk after administration of the third dose of PHiD-CV in the per-protocol cohort for efficacy. The study was designed to detect a VE of 20% at study end, but allowed an earlier efficacy conclusion if a higher VE was achieved at the time of the interim analysis. As defined in the study protocol, the interim analysis was planned to occur at least 18 mo after study start, once 535 first B-CAP episodes were identified.A sample size of 24,000 healthy infants was planned to allow 21,600 evaluable children for the per-protocol CAP efficacy analysis. Power for B-CAP efficacy at the interim analysis and at the final analysis was calculated according to various VE assumptions and numbers of first B-CAP cases. With 535 first B-CAP cases and assuming a true VE of at least 25%, the study had 87.6% power to be conclusive at the interim analysis considering an adjusted one-sided alpha level of 1.75%.p-value for the null hypothesis (B-CAP VE ≤ 0%) was lower than the adjusted (Pocock adjustment) one-sided significance level of 1.75% (p<0.0175), a value accounting for the possibility of a second analysis of the primary end point if the first was inconclusive . The interim analysis was performed by an independent statistician to maintain blinding for the sponsor. The results were first shared with the IDMC, which, following agreement on the conclusions, sent them to the study sponsor.At the interim analysis, the primary objective was considered to be conclusive and final if the one-sided nominal n = 31) were also excluded from this sensitivity analysis, which was performed by an independent statistician on the database used for the interim analysis.After the interim analysis was performed, issues were discovered in Panama in relation to informed consent for some children , the number of first C-AOM episodes required to show VE>0% with 80% and 90% power  was calculated according to various true VE assumptions. If VE was 20%, 662 and 880 first C-AOM episodes were required to demonstrate positive VE with 80% and 90% power, respectively. If VE was 15%, 1,226 and 1,637 first C-AOM episodes were required for 80% and 90% power, respectively. Since the objective of the trial was to demonstrate VE in terms of a lower incidence of B-CAP or C-AOM in the vaccine group compared to the control group, only comparison in one direction was deemed necessary, hence the use of a one-sided statistical hypothesis linked to VE .p-value for VE against C-AOM was <0.025, allowing for control of the primary confirmatory B-CAP objective and the sequential secondary confirmatory C-AOM objective.The first secondary objective (to demonstrate VE of PHiD-CV against first C-AOM episodes) was considered significant if the primary objective was significant and the one-sided p-values. Interpretations of nonoverlapping 95% CI boundaries should therefore be made with caution, as no predefined criteria were fixed, with no formal control of the alpha level. A two-sided Schoenfeld residual test for the null hypothesis that the VE is homogeneous over the age/time range was performed in order to assess the proportionality assumption associated with the Cox model.Other analyses, including VE against first IPD episodes, were descriptive, and therefore there was no adjustment for multiplicity for the associated informative An analysis of VE against consolidated CAP was conducted among children who received the booster vaccine dose; VE was calculated for cases reported before the booster dose, given at 15–18 mo of age, and for cases reported after the booster dose. In another subanalysis, AOM severity was categorized according to the five symptoms on the Dagan scale. Cases were analyzed for which the presence or absence of each of the five symptoms had been recorded. In addition, a second complementary analysis of severity was conducted, considering cases that had at least one symptom score recorded, with the assumption that unrecorded symptoms were not observed.Immunogenicity analyses are reported for the per-protocol cohort for immunogenicity, defined as vaccinated children who met all eligibility criteria, complied with protocol-defined procedures, and had at least one antibody assay result available. An incorrect version of the informed consent form was used to obtain consent for children in the immunogenicity group in Panama see . When thThe numbers of children enrolled, randomized, and eligible for primary end point analysis are shown in The sum of the follow-up period, censored at the first occurrence of a respective end point event in each group, is provided in Pneumonia rates for the two groups are presented in p = 0.002). VE was also observed against the secondary CAP end points, with consistent results between the intent-to-treat and per-protocol analyses for the interim and end-of-study time points  and met prespecified criteria for conclusive results of the primary objective (e points . VE agaie points .p = 0.002), which was consistent with the final per-protocol CAP efficacy analysis result.In the sensitivity analysis of the primary objective (see Methods), 144 children were excluded out of 20,496 children. The results of this analysis showed 239 first B-CAP cases in the PHiD-CV group and 304 in the control group. VE against first B-CAP episodes was 22.3%  among children aged less than 12 mo, 26.7%  in children aged between 12 and 24 mo, and 21.3%  in children aged between 24 and 36 mo. In the per-protocol analysis these percentages were 15.1% , 31.8% , and 20.7% , respectively. VE against consolidated CAP was 21.7%  prior to the booster dose and 26.3%  after booster vaccination in the intent-to-treat analysis. In the per-protocol analysis, VE was 15.1%  and 26.3%  pre- and post-booster, respectively.p = 0.032) and 19.0%  in the intent-to-treat analysis (p = 0.007). VE against pneumococcal AOM and vaccine serotype AOM was 56.1%  and 67.1% , respectively, in the per-protocol analysis, with consistent results in the intent-to-treat analysis  of PHiD-CV recipients and 22.6%  of children in the control group  and S8. Nineteen deaths among 11,798 children  were reported in the PHiD-CV group, and 26 deaths among 11,799 children  were reported in the control group. This suggested that PHiD-CV vaccination reduced all-cause mortality by 27.0% , although this difference was not statistically significant. The majority of the reported fatal cases  involved children aged less than 1 y. None of the deaths were considered by the investigator to be causally related to vaccination.Efficacy of PHiD-CV was shown against a variety of CAP, AOM, and IPD end points, with consistent results between the per-protocol and intent-to-treat analyses. In the interim analysis, VE against first episodes of B-CAP was 22.0% and therefore (as predefined in the protocol) was considered conclusive for the primary objective. In this analysis, efficacy against WHO-defined consolidated CAP was 25.7%. In the end-of-study per-protocol analyses, VE was 16.1% against C-AOM, 67.1% against vaccine pneumococcal serotype C-AOM, 100% against vaccine serotype IPD, and 65.0% against IPD of any serotype.197-conjugated vaccines, and 11-valent vaccine containing tetanus toxoid and diphtheria toxoid carrier proteins), and took place in a variety of geographic and socioeconomic settings.This study thereby provides a comprehensive assessment of clinical protection of PHiD-CV against invasive and mucosal infections in Latin American children. In addition, despite the lower immunogenicity of PHiD-CV compared to 7vCRM, the antibody levels achieved were sufficient to provide a level of protection against WHO-defined CAP with alveolar consolidation (22–26%) that was consistent with the 20–37% efficacy reported in previous studies with other PCVs, including 7vCRM S. pneumoniae or by non-vaccine serotypes In our study, VE against WHO-defined consolidated CAP among children aged 12–24 mo and 24–36 mo remained above 20%, which was consistent with results obtained with 9vCRM in the Gambia The number of AOM cases identified in Panama was lower than expected, and various factors might have contributed to this outcome. Case detection was especially low during the first 2 y of the study, and by the time it was enhanced, the age period of expected peak in AOM incidence Regardless of the factors responsible, the relatively low incidence of AOM may help with interpretation of the C-AOM protection results since, in the prespecified primary outcome , the lower limit of the 95% CI around the 16.1% point estimate was slightly below zero . Analysis of the intent-to-treat cohort gave a similar point estimate (19.0%) but with a 95% CI lower limit above zero . This suggests that the lack of statistical significance in the per-protocol analysis was due to a lack of cases rather than to true lack of efficacy.Nevertheless, we consider these results as highly relevant to other settings, as the AOM cases had both pediatrician and ENT confirmation, and around half of the C-AOM episodes were mild, with the remainder being moderate or severe, thus representing the broad spectrum of clinical AOM. In any case, differences in case definitions contribute little to differences in PCV efficacy estimates against AOM H. influenzae in COMPAS suggested a beneficial effect, although the result was not significant (95% CI included zero). It should be noted that the COMPAS study was not powered to assess the nontypable H. influenzae end point. Also similar to the Pneumococcal Otitis Efficacy Trial, there was no evidence for replacement of vaccine serotypes with non-vaccine pneumococcal serotypes or other otopathogens during 31 mo of intent-to-treat follow-up for AOM analysis; in contrast, evidence of replacement disease was found early in the follow-up of the Finnish Otitis Media trial with 7vCRM, as of 2 mo of age Similar to the Pneumococcal Otitis Efficacy Trial and in contrast to the Finnish Otitis Media trial, VE against AOM caused by nontypable All invasive disease cases were first episodes and pneumococcal, and, as anticipated from the regional epidemiology of pneumococcal serotypes One limitation of this study, as noted earlier, lies in the low number of reported AOM cases, despite efforts to improve surveillance during the study. Another limitation was the study setting being in mostly urban areas, potentially affecting its generalizability to rural populations. This setting was chosen to aid recruitment and to improve the likelihood of capturing all pneumonia cases, as that might have been difficult in rural areas without easy access to health care centers and pediatric hospitals. An additional study limitation was that approximately 14% of participants were excluded from the per-protocol efficacy analyses, mainly because of early withdrawal and noncompliance with the primary vaccination schedule in both groups. This was predominantly as a result of adverse media coverage of the study in 2007/2008 linked to unfounded rumors of a causal relationship between PHiD-CV vaccination and infant mortality Nonetheless, these exclusions do not appear to have affected the robustness of the study, as VE results were consistent between the intent-to-treat and per-protocol analyses. Importantly, a 27% reduction  in overall mortality in PHiD-CV recipients was observed, which was most evident in children in the first year of life, when the risk of severe pneumococcal disease is highest In conclusion, COMPAS is, to our knowledge, the first double-blind randomized controlled trial to assess pneumococcal conjugate VE in Latin America, a region with an intermediate pneumococcal disease burden. The results of this study demonstrate the efficacy of PHiD-CV and document the magnitude of its impact against CAP and AOM, which are mucosal diseases of public health importance, commonly encountered in young children in clinical practice.Figure S1Number of children in the primary or booster vaccination intent-to-treat and per-protocol cohorts for immunogenicity.(DOCX)Click here for additional data file.Figure S2Trial profile for children included in the end-of-study analyses of community-acquired pneumonia and invasive pneumococcal disease.(DOCX)Click here for additional data file.Figure S3Clinical Otitis Media and Pneumonia Study timeline.(DOCX)Click here for additional data file.Table S1National public health authorities and ethical review committees.(DOCX)Click here for additional data file.Table S2Children at high risk of invasive pneumococcal infection.(DOCX)Click here for additional data file.Table S3Occurrence of first clinically confirmed acute otitis media episodes .(DOCX)Click here for additional data file.Table S4Occurrence of first clinically confirmed acute otitis media episodes .(DOCX)Click here for additional data file.Table S5Occurrence of invasive pneumococcal infection episodes .(DOCX)Click here for additional data file.Table S6Occurrence of invasive pneumococcal infection episodes .(DOCX)Click here for additional data file.Table S7Pneumococcal antibody concentration and opsonophagocytic activity in PHiD-CV group (per-protocol immunogenicity cohort for primary or booster vaccination).(DOCX)Click here for additional data file.Table S8Serious adverse events reported from study start and administration of the first vaccine dose up to study end .(DOCX)Click here for additional data file.Text S1Ethical considerations and informed consent.(DOCX)Click here for additional data file.Text S2Trial protocol.(PDF)Click here for additional data file.Text S3Major protocol changes.(DOCX)Click here for additional data file.Text S4Laboratory analyses.(DOCX)Click here for additional data file.Text S5CONSORT checklist.(DOCX)Click here for additional data file.


Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; however, little is known about prognosis of the first-ever COPD exacerbation and variables predicting its outcomes.A population-based cohort study among COPD patients with their first-ever exacerbations requiring hospitalizations was conducted. Main outcomes were in-hospital mortality and one-year mortality after discharge. Demographics, comorbidities, medications and in-hospital events were obtained to explore outcome predictors.The cohort comprised 4204 hospitalized COPD patients, of whom 175 (4%) died during the hospitalization. In-hospital mortality was related to higher age  and Charlson comorbidity index score ; angiotensin II receptor blockers  and β blockers  conferred a survival benefit. At one year after discharge, 22% (871/4029) of hospital survivors were dead. On multivariate Cox regression analysis, age and Charlson comorbidity index remained independent predictors of one-year mortality. Longer hospital stay  and ICU admission  during the hospitalization were associated with higher mortality risks. Prescription of β blockers  and statins  on hospital discharge were protective against one-year mortality.Even the first-ever severe COPD exacerbation signifies poor prognosis in COPD patients. Comorbidities play a crucial role in determining outcomes and should be carefully assessed. Angiotensin II receptor blockers, β blockers and statins may, in theory, have dual cardiopulmonary protective properties and probably alter prognosis of COPD patients. Nevertheless, the limitations inherent to a claims database study, such as the diagnostic accuracy of COPD and its exacerbation, should be born in mind. Chronic obstructive pulmonary disease (COPD), according to the definition by the Global initiative for chronic Obstructive Lung Disease (GOLD), is a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with chronic airway and lung inflammatory responses. Therefore, the aim of the present study is to describe the in-hospital and one-year outcomes and to investigate their predictors in patients with the first hospitalization for COPD exacerbations using a large population-based database.We conducted a retrospective population-based cohort study using the Longitudinal Health Insurance Database (LHID) from 2000 to 2008. Taiwan launched a mandatory National Health Insurance (NHI) program in 1995, which founded on the principle that every citizen should have equal access to healthcare. At the end of 2011, up to 99.9% of the 23 million people were enrolled in the NHI program. The study cohort consisted of all patients who had been hospitalized for COPD exacerbations between January 2005 and December 2007, and the patients were followed up till the end of 2008. Although only the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 491.21 denotes pure COPD exacerbations, we defined hospitalizations for COPD exacerbations as patients admitted with a primary diagnosis of COPD  or those with a primary diagnosis of pneumonia (ICD-9-CM codes of 480–486) and a secondary diagnosis of COPD in this study.2 agonists, anticholinergics, inhaled corticosteroids and theophyllines, were measured in the 6 months before the index hospitalization. Comorbidities as detailed in The outcomes of interest were in-hospital mortality and one-year mortality after discharge. The study cohort was followed from the date of the index hospitalization to one year after discharge or until death, whichever came first. The demographics, comorbid diseases, concomitant medications and COPD medications were also identified from the LHID. The COPD-related medications, including short-acting and long-acting βQualitative variables were expressed in percentages, and quantitative variables were summarized as mean ± standard deviation or as median and interquartile range as appropriate. To compare continuous variables, the Student’s t-test or Mann-Whitney U test were used. Categorical data were analyzed by the chi-square test. Independent predictors of in-hospital mortality were identified by use of multivariate logistic regression analysis. The multivariate relationship between survival time and covariates was determined with the Cox regression analysis model. Survival time was defined as the interval between hospital discharge and the date of death, or censored at one year if they remained alive at that time. Potential covariates were entered into the multivariate models if they were statistically significant in the univariate analysis. The survival curve was plotted using the Kaplan-Meier method. Data analyses were performed using SPSS software . A 2-sided P value of <0.05 was considered statistically significant.During 2005–2007, a total of 4204 study patients, 155 (3.7%), 2570 (61.1%), 36 (0.9%) and 1443 (34.3%) with ICD-9-CM codes of 490, 491, 492 and 496, respectively, were included in the study . The basDuring the index hospitalization, 175 (4%) of patients died . The nonA total of 3158 (78%) patients were alive at one year after discharge, as shown in In this population-based cohort study, we provide information about the first-ever hospitalizations for a COPD exacerbation. The main findings are summarized as follows: (i) During the index hospital stay, 10% of the patients required ICU admission, 8.3% had been placed on mechanical ventilation and the in-hospital mortality rate was 4.2%. (ii) The age and comorbidity index were independent in-hospital mortality predictors; the use of angiotensin II receptor blockers and β blockers was found to be associated with a reduction in the risk of in-hospital mortality. (iii) Among patients surviving the index hospitalization, 22% of them died within one year of discharge. (iv) Increased age, a higher comorbidity index, the presence of chronic comorbid conditions, such as liver cirrhosis and malignancy, and a longer hospital stay and ICU admission during the index hospitalization were associated with a higher mortality risk at one year. Statin or β blocker use may be beneficial in COPD patients with respect to the one-year outcome following discharge.Although COPD exacerbations have been widely studied, the exacerbation under study is seldom the first in the patient’s disease course. Recently, a study on first-ever hospitalizations for COPD demonstrated the risk of subsequent severe exacerbations and long-term mortality of these patients. Our study shows the high prevalence of comorbidities in patients hospitalized for COPD exacerbations and their importance in relation to in-hospital and one-year prognosis in this population. In stable COPD patients, the comorbidity severity, measured by the Charlson comorbidity index, is a well-established mortality predictor. 2 adrenoceptors. COPD is commonly associated with cardiovascular diseases, such as coronary artery disease, heart failure, hypertension and stroke, because of shared risk factors or a causal relationship. In line with prior studies, We found mortality in the first year after hospital discharge for COPD exacerbations to be 22%, a rate similar to that reported by another study. There were some limitations to this study. First, the accuracy of COPD diagnosis depends on proper ICD-9-CM coding. Although the lack of unique patient identifiers in the LHID prevented a validation study, the database has been widely used to study COPD. In conclusion, an exacerbation requiring hospitalization denotes a poor long-term outcome in COPD patients; even it is the first-ever one. The burden of comorbidities has a significant role in determining mortality risks, and should be carefully evaluated and managed. Angiotensin II receptor blockers, β blockers and statins may theoretically have dual cardiopulmonary protective effects and probably improve outcomes of a severe exacerbation in patients with COPD. Nevertheless, the limitations inherent to a claims database study, such as the diagnostic accuracy of COPD and its exacerbation, should be born in mind.S1 TableDefinitions of comorbidities.(DOC)Click here for additional data file.S2 TableCompliance categories for discharge medications.(DOC)Click here for additional data file.S3 TableCox regression analysis of factors associated with one-year mortality in patients surviving exacerbations of chronic obstructive pulmonary disease while only patients with good or moderate medication compliance were regarded as drug users.(DOC)Click here for additional data file.


Emax model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an  Plasmodium falciparum malaria and high levels of antimalarial drug resistance. Malaria has been an important cause of maternal mortality and a major factor contributing to low birth weight. As a result of providing ready access to effective treatment and weekly antenatal visits to clinics, malaria-related maternal mortality rates in a stable population of displaced persons have fallen from an estimated 1,000 per 100,000  in 1985 to zero from 2005 onwards  is the most commonly used ACT, providing excellent cure rates in nonpregnant patients (3–Artemisinin-based combination therapy (ACT) is the treatment of choice for uncomplicated atients 38. Artemeatients 3–11. Hightients 3–, 10. A stients 3–, 10 belotients 3–. Thus, ttients 3–.50s) of desbutyl-lumefantrine against clinical isolates of Plasmodium falciparum in three studies from northwest Thailand in 1997 and 1998 were 4.38, 6.54, and 8.94 nM, respectively  and 9.5 nM for chloroquine-resistant (W2mef) cultures  twice daily for 3 days with 200 ml to 250 ml of chocolate milk . Frequent venous blood samples (2 ml) were drawn from 13 pregnant women before the last dose and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 h after the last dose . Blood sm/z of lumefantrine (528.2 to 276.1) and desbutyl-lumefantrine (472.1 to 346.1) was monitored using multiple-reaction monitoring. The method did not show any signs of severe ion suppression/enhancement for lumefantrine or desbutyl-lumefantrine. The within-day and between-day accuracy and precision at all quality control levels were below 7%. The coefficients of variation were lower than 8.2% and 7.9% for all quality control samples during clinical sample analysis using UV detection and mass spectrometric detection, respectively.Venous plasma concentrations of both lumefantrine and desbutyl-lumefantrine were quantified by using liquid chromatography with UV detection (HPLC-UV) . CapillaMolar units of lumefantrine and desbutyl-lumefantrine plasma concentrations were transformed into their natural logarithms and modeled simultaneously using a linear drug-metabolite model. Estimations and simulations were performed using NONMEM v.7.2  with a G-Fortran compiler  on a Windows 7 operating system . Subroutine ADVAN6 was used for pharmacokinetic and pharmacodynamic model building, and the first-order conditional estimation method with interaction and the Laplacian estimation method with interaction were used to model the pharmacokinetic and pharmacodynamic data, respectively . PostproP = 0.05) improvement between two hierarchical models after inclusion of one additional parameter (one degree of freedom). Goodness-of-fit diagnostics and physiological/pharmacological plausibility were also considered during the model building process.The objective function value  was used to evaluate competing models during the model building process. A drop in OFV of 3.84 or more was considered a significant , distribution , variability (between-subject variability) and residual error  models were considered. Model parameters were assumed to be log-normally distributed , althougP values of 0.05 (ΔOFV = 3.84) and 0.001 (ΔOFV = 10.83) as cutoff criteria in the forward step and backward step, respectively.The differences in biological matrix  might be explained partly by different quantification methods . However, a correction factor embedded on a population level did not allow us to differentiate between differences resulting from the analytical quantification assay method and the biological matrix  . For desh(t), λ represents the (baseline) hazard estimate, t represents the time, α represents the shape parameter in the Weibull distribution, and t1/2 represents the elimination half-life of the hazard in the Gompertz model.The best pharmacokinetic drug-metabolite model was fixed and used to evaluate the pharmacodynamic properties with a time-to-event approach. Constant , WeibullPatients were screened weekly for malaria; and the start of the interval censoring time was therefore set to the time of the last parasite-negative visit, and the end of the interval was set to the time of the visit when recrudescent malaria was detected. This allows the event to take place at any time during the interval time and is not fixed to the time when the patients visited the clinic .(9)P were evaluated using individually predicted lumefantrine or desbutyl-lumefantrine plasma concentration (C), where E0 is the baseline effect (fixed to 1), Emax is the maximum effect (fixed to 1), and EC50 is the concentration realizing half of the maximum effect. Cumulative areas under the plasma concentration-time curves of lumefantrine or desbutyl-lumefantrine were also evaluated instead of predicted plasma concentrations. A stepwise covariate modeling procedure was performed on the pharmacodynamic parameters . Body weight, estimated gestational age, primary gravidity, age, parasitemia, and admission infection  were tested as categorical covariates or as continuous covariates using an exponential relationship. P values of 0.05 and 0.001 were used as significance cutoff criteria during the forward and backward steps, respectively.Drug effects (5 parasites released from the liver) and low  multiplication rates  by using fixed high . The predictive power of the model was assessed by using visual predictive checks  5th, 50th, and 95th percentiles with the 5th, 50th, and 95th percentiles of the observed data. The visual predictive check for the time-to-event analysis was visualized by overlaying the 95% confidence interval from the simulated  events with the observed data. The visual predictive check for the relative hazard (compared to the baseline hazard) was visualized by overlaying the simulated  90% confidence interval with the estimated relative hazard and observed lumefantrine or desbutyl-lumefantrine plasma concentrations. The reliability of individual parameter estimates and goodness-of-fit plots were assessed by the calculation of eta and epsilon shrinkage  were performed using the final population pharmacokinetic-pharmacodynamic model to assess the treatment outcome after a standard dose regimen (80 mg artemether/480 mg lumefantrine twice daily for 3 days), 80 mg artemether/480 mg lumefantrine twice daily for 5 days (Emax) model and would not be feasible in the clinic due to adherence issues. An increased and extended dose regimen  was also evaluated, and for this simulation scenario, bioavailability was assumed to be reduced by 7.5% because of dose-limited absorption  and sparse capillary (n = 103) samplings were embedded in a large drug efficacy trial , 18n = 1cy trial . The medcy trial .A two-compartment drug-metabolite model using first-order absorption with lag time was used to describe simultaneously the lumefantrine and desbutyl-lumefantrine pharmacokinetic data . The addP ≤ 0.05). However, only parasitemia on desbutyl-lumefantrine elimination clearance and estimated gestational age on the absorption rate constant and lumefantrine intercompartmental clearance could be retained in the backward step of the stepwise covariate modeling (P ≤ 0.001).Body weight in a power relation with all clearance (exponent fixed to 0.75) and distribution (exponent fixed to 1) parameters did not improve the model fit. The covariates parasitemia  and estimated gestational age  were selected during the forward step of the stepwise covariate modeling  indicated adequate predictive power for lumefantrine and desbutyl-lumefantrine plasma concentrations  and body weight  were all selected as significant covariates during the forward addition step of the stepwise covariate modeling (P ≤ 0.05). However, none of these covariates could be retained in the backward elimination of selected covariates (P ≤ 0.001). Admission malaria type  as a covariate on baseline hazard, hazard half-life, or lumefantrine IC50 did not significantly improve the model fit either. The median  individually predicted lumefantrine concentrations at day 7 and area under the concentration-time curve from zero to infinity (AUC0–∞) in patients with recrudescent malaria on admission  or novel malaria  tended to be only slightly lower than in patients with admission primary new malaria infections , but it did not reach statistical significance .Pharmacokinetic parameters were fixed to the final estimates, and pharmacokinetic-pharmacodynamic data were fitted simultaneously . IntervaThe 90% confidence interval of 2,000 simulated Kaplan-Meier plots described the observed recrudescent malaria accurately using either lumefantrine or desbutyl-lumefantrine as drug effects  and B. HEmax and sigmoidal Emax) on the constant hazard model did not improve the model fit significantly.Novel infections could be described using a constant hazard model with interval censoring, based on a back-calculated time interval representing the approximated start of the parasite blood stage. The implementation of a lumefantrine or desbutyl-lumefantrine drug effect  were performed using the final pharmacokinetic-pharmacodynamic model for a twice-daily artemether-lumefantrine treatment (with four tablets at each occasion) for 3 days, 5 days, and 10 days and a twice-daily dosing regimen with 5 tablets per dosing occasion for 4 days. Not surprisingly, simulated lumefantrine and desbutyl-lumefantrine concentrations at days 7 and 14 and day 42 cure rates increased with extended treatment duration . A possible explanation for the poor stability might be the small number of recrudescent malaria episodes (17 out of 116 observations) during the follow-up period. Lumefantrine and desbutyl-lumefantrine plasma concentrations could be used interchangeably as predictors for recrudescent malaria, which might be explained by the similarity in pharmacokinetic concentration-time profiles. However, desbutyl-lumefantrine concentrations were substantially lower, which explains the lower IC50 for desbutyl-lumefantrine than for lumefantrine. In this study, lumefantrine showed a better predictive power than desbutyl-lumefantrine, which might be a result of more accurate and precise predictions of lumefantrine than desbutyl-lumefantrine concentrations by the developed model  did not improve the model fit significantly in this analysis. However, a previously published clinical analysis  and so exerts considerably less posttreatment prophylactic activity than mefloquine or piperaquine .In silico dose optimizations displayed substantially increased lumefantrine exposures at day 7 and day 14 with the extended dose regimens. However, the relative improvement of the simulated cure rates at day 42 with extended treatments compared to the standard treatment was small. This could be explained by a failure to estimate a slope factor in the Emax model and/or the absence of the artemether/dihydroartemisinin drug effects in this model. Furthermore, relatively high eta shrinkage was observed, but it should not affect model mean predictions but only the simulated variability in the population. The model clearly underpredicted treatment success rates at day 42 after prolonged treatment, as the model does not adequately take into account the additional parasite killing provided by a longer course of artemether in this fixed combination. Prolonged artemether treatment will result in additional drug exposure in subsequent parasite life cycles, leaving a lower parasite density to be killed by lumefantrine. It is therefore important in future studies to dissect the artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine drug effects with respect to outcome to fully optimize the treatment. Indeed, a seven-day course of artemether alone provided 94% curative efficacy in earlier studies of recrudescent malaria in nonpregnant patients in this region, substantiating an increased killing of parasites when parasites are exposed to artemisinins for a sustained number of life cycles (e cycles . A proloSimulations performed here of prolonged treatments using the developed model assumed a time-independent lumefantrine and desbutyl-lumefantrine pharmacokinetics. Previous studies have reported dose-limited lumefantrine absorption, where patients receiving a single daily lumefantrine dose for 3 days displayed 30% lower exposure than patients receiving the same total dosage split into two lumefantrine doses per day for 3 days . TherefoOther factors rather than solely pharmacokinetic exposures might have an impact on the treatment outcome. For example, host immune responses are reduced during pregnancy, and this potentially means that a different lumefantrine day 7 concentration threshold is required in this special population. However, this is difficult to dissect and quantify, since ethnicity and geographical region might play a major role in the immune response. Furthermore, resistance to artemisinin derivatives in Southeast Asia increasingly compromises treatment efficacy, as this increases the number of residual parasites which have to be cleared by lumefantrine.The most important issues at this point are to understand the underlying source of the reduced efficacy of artemether/lumefantrine during pregnancy on the Thailand-Myanmar border and to determine whether adequate dose optimization can decrease the risk of treatment failures and resistance development. This could be of great importance in anticipating a future scenario of reduced efficacy in Africa. Indeed, lower drug exposures and cure rates in pregnant women than in nonpregnant women have been shown in Tanzania, but cure rates remained high in Uganda even though drug exposures were also substantially lower during pregnancy , 11, 13.Plasmodium falciparum malaria during the second and third trimesters of pregnancy and that increased treatment duration may facilitate improved cure rates.In conclusion, a simultaneous drug-metabolite model was developed which adequately described the pharmacokinetic properties of lumefantrine and desbutyl-lumefantrine. The pharmacodynamic data were modeled using a time-to-event model linked to the pharmacokinetic model. Lumefantrine and desbutyl-lumefantrine could be used interchangeably as predictors of treatment failure, but lumefantrine realized a better predictive power in this model. An additive drug effect of desbutyl-lumefantrine did not further improve the model fit. The simulations based on the current lumefantrine/desbutyl-lumefantrine drug effect model, which contains substantial limitations, indicated that the drug combination of artemether and lumefantrine with the standard dosing regimen has suboptimal efficacy on the Thailand-Myanmar border in the treatment of uncomplicated


There is no consensus regarding the relationship between body image and brace wear adherence in adolescents with adolescent idiopathic scoliosis (AIS).The aim of this study is to explore body image and brace wear adherence.This study used data from 171 BrAIST subjects that were in the randomized and preference brace treatment groups at baseline and did not switch to observation at any time during the study. Brace wear adherence categories were based on dose-response range efficacy findings in the BrAIST study. The three groups were: least adherent (0-6), middle adherent (6.1-12.8) and most adherent (≥ 12.9), using brace monitor data measuring hours/day in brace. The Spinal Appearance Questionnaire (SAQ)(1) was used to measure body image scores and scores were compared with largest Cobb angle, BMI, and quality-of-life measures. Wilcoxon ranked sum tests were conducted to test body image differences between the least adherent and the most adherent brace wear groups at baseline and at the 6, 12, 18, and 24 month follow-up visits.There were no differences between subjects in the least adherent group and the most adherent group at baseline  or at any follow-up visits regarding BMI, largest Cobb angle, quality-of-life, and body image.Findings from this study do not support previous research indicating that wearing a brace may have a negative impact on body image, which could ultimately lead to poor brace wear adherence. In fact, this study found no difference in body image between the least adherent and the most adherent brace wear groups at any follow-up visit up to 2 years. Further analysis is being conducted to assess relationships between body image, quality-of-life, and demographic and clinical variables within brace wear adherence groups.


Asians have high prevalence of central obesity despite the low prevalence of general obesity. We evaluated associations between the central obesity measure, waist-hip ratio (WHR) with total and cause-specific mortality in middle-aged and elderly Chinese participants. Data arise from two prospective population-based cohort studies: the Shanghai Men’s Health Study involves 53,425 men (participation rate = 74.0%), age 40–74 at baseline, and the Shanghai Women’s Health Study involves 63,017 women (participation rate = 92.7%), age 40–70 at baseline. Information on lifestyle factors and anthropometric measurements were taken at baseline interview. Vital status and causes of death were obtained via surveys and annual linkages to relevant Shanghai registries through December 31, 2011. After median follow-up time of 7.5 years for the Shanghai Men’s Health Study and 13.2 years for the Shanghai Women’s Health Study, there were 2,058 and 3,167 deaths, respectively. In models adjusted for BMI and other potential confounders, WHR was associated with all-cause mortality; hazard ratios (HRs)  across the first to fifth quintile increased from 1 (Reference), 1.10 , 1.21 , 1.11 , to 1.42  in men and from 1 (Reference), 1.10 , 1.11 , 1.20 , to 1.48  in women. WHR had a stronger association with cardiovascular disease, with multivariate-adjusted HRs of 1.5 to 1.7 observed for the highest versus lowest quintile of WHR. Dose-response associations were also seen for cancer and other-cause deaths. Stratified analyses suggested a stronger association with mortality among normal weight (BMI <25) than over-weight (BMI ≥25) individuals. Positive associations with mortality were observed in subgroups defined by follow-up duration, comorbidity, age, smoking, and physical activity. Greater central adiposity is associated with increased mortality in Chinese adults, even among individuals with low BMI. Physicians and the public should be aware of central adiposity’s independent effects on health. Greater adiposity is associated with multiple adverse health conditions including diabetes, coronary heart disease, and several cancer types . Most epConsidering measures of central fat distribution in addition to BMI may better quantify disease and mortality risk. Most studies conducted in North American and European samples report an approximately 50% increased mortality risk in individuals with the largest compared to the smallest central adiposity measures ,12–17. FThe designs and methods of the population-based prospective Shanghai Women’s Health Study and Shanghai Men’s Health Study have been previously described in detail –20. In bStructured questionnaires were used by trained interviewers at baseline to obtain information on demographics, lifestyle, and medical history. Anthropometric measurements were taken by interviewers according to standard protocol. Participants were asked to wear light indoor clothing when measured for weight, height, and circumferences of the waist and hips. Weight was measured to the nearest 0.1 kg using a digital scale that was calibrated every six months. Waist circumference was measured at 2.5 cm above the umbilicus and hip circumference at the level of maximum width of the buttocks with the subject in a standing position. All measurements were taken twice. A third measurement was taken if the difference of the first two measurements was greater than 1 kg for weight or 1 cm for height and circumference measurements. Waist-hip ratio and BMI were calculated using the average of the two closest measurements.International Classification of Diseases, Ninth Revision. The primary endpoints for analyses were deaths due to all-causes, cardiovascular disease (CVD) (codes 390–459), cancer (codes 140–208), and all other-causes.Information on vital status and cause of death was obtained by annual record linkages to the Shanghai Cancer Registry and the Shanghai Vital Statistics Registry and by in-person follow-up surveys conducted every two to three years. The present analysis includes outcome data through December 31, 2011. Mortality follow-up for these cohorts is virtually complete (>99%). For each death, the underlying cause of death was determined on the basis of death certificates and coded according to the Participants excluded from analysis were: missing waist or hip measurements , missing covariate data , lost to follow-up , had baseline diagnosis of cancer, stroke, or coronary heart disease , or pregnant at baseline interview (10 women). Very few women had ever smoked cigarettes , and were excluded to avoid confounding by cigarette use. To reduce possible influence of reverse causation on our study results, we excluded participants with less than two years of follow-up after the baseline survey  or BMI<18.5 . After these exclusions  data from 53425 Shanghai Men’s Health Study participants and 63017 Shanghai Women’s Health Study participants were available for analysis.a priori: education , occupation , BMI , regular exercise  hours/day, ≥1.2 MET-hours/day; men: <2.0 MET-hours/day, ≥2.0 MET-hours/day)), fruit and vegetable intake , saturated fat intake , alcohol consumption  who ever drank; men: never, former, current), height , menopausal status (women only) and smoking status . Postmenopausal status was defined as not having a menstrual period for ≥ 12 months before baseline. Statistical models to test for trends in risk of death included an ordinal term to represent central adiposity groupings. We used restricted cubic spline regression to evaluate the shape of the association of waist-hip ratio and BMI with all-cause mortality [th, 35th, 65th, and 95th percentiles of the anthropometric measurement sex-specific distributions.Sex-specific analyses were conducted in consideration of major differences between men and women in the distribution of anthropometric measurements, smoking, and drinking habits. Frequencies and distributions of the participant characteristics were tabulated for the total sample and by waist-hip ratio quintiles. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazard models for the association between central adiposity measures and mortality using age as the time scale with entry time defined as age at baseline interview and exit time as age at death or December 31, 2011 . Waist-hTo further elucidate the relationship between waist-hip ratio and mortality, we stratified analyses by factors hypothesized to modify the association such as age at baseline, BMI, physical activity, smoking status, comorbidity, and duration of follow-up. We evaluated potential effect modification on the association between central adiposity and mortality by using likelihood ratio tests to compare main effects models with and without the addition of a cross-product interaction term. Statistical analyses were performed using SAS statistical software .There were 2058 deaths in the Shanghai Men’s Health Study after a median follow-up time of 7.5 years (range: 2 to 10 years) and 3167 deaths in the Shanghai Women’s Health Study with a median follow-up time of 13.2 years (range: 2 to 15 years). The most common causes of death over the study period were CVD  and cancer . The majority of the cohort was of normal BMI (median baseline BMI of 23.8 for men and 23.7 for women) and did not participate in regular exercise (66.0% of men and 66.4% of women). Many men in the cohort were current smokers (60.5%). On average, male participants with smaller waist-hip ratios were more likely to have lower BMI and an occupation in manufacturing or agricultural work than males with larger waist-hip ratios . Female P-trends < 0.001). Similarly, increasing waist circumference was associated with increasing all-cause mortality risk (data not shown).In age-adjusted models waist-hip ratio was modestly associated with all-cause mortality . AdjustmIn men and women, positive associations were observed between waist-hip ratio and the cause-specific mortality outcomes examined: cardiovascular diseases, cancer, and other-causes; although the association observed between waist-hip ratio and cancer mortality was relatively weak . ChronicP-interaction > 0.05, perhaps due to a small sample size among those with a high BMI but a low waist-hip ratio. No apparent effect modification of baseline age or physical activity were observed on the associations between central adiposity and all-cause mortality in either sex (P-interaction = 0.84).We evaluated effect modification of the association between central adiposity and mortality by baseline BMI, age, physical activity, and smoking status. In BMI stratified analyses, robust associations were observed between waist-hip ratio and all-cause death, CVD death and other-cause death in normal weight participants Figs  and 3. Wther sex . Among mSensitivity analyses were conducted to evaluate the strength of the association between waist-hip ratio and all-cause mortality in subgroups defined by chronic disease status. The associations between waist-hip ratio and all-cause mortality were consistent regardless of baseline existing diabetic or hypertensive conditions . In womeIn this prospective study of Chinese adults, greater central adiposity is associated with increased risk of cardiovascular disease mortality, cancer mortality, and all-cause mortality in a dose-response manner. In both men and women a 1.5-fold elevated risk of all-cause death is found in comparisons between the largest and the smallest waist-hip ratio quintiles underscoring the detrimental association between large waist-hip ratio and death. This positive association is observed regardless of baseline age, comorbidity, or smoking status in men. There are several biologic mechanisms that may explain the association between excess central adiposity and higher mortality, including chronic inflammation and insulin resistance .Compared with the results obtained from an early analysis of Shanghai Women’s Health Study data , the assWe present central adiposity and mortality associations both with and without adjustment for BMI. Our models suggest that when BMI is held constant participants with larger waist-hip ratio are at increased mortality risk. Mortality risk associated with high waist-hip ratio for a given BMI may reflect the consequences of increased abdominal/visceral fat. Alternatively, the increased risk may indicate low muscle tone and peripheral fat for a given BMI in those with a high waist-hip ratio. We are unable to distinguish between these two possibilities without further study and a more comprehensive measurement of body fat and composition. We also investigated potential interaction between BMI and waist-hip ratio. Although tests for interactions between waist-hip ratio and BMI were mostly non-significant, the association between central adiposity and all-cause mortality is most apparent in normal weight BMI participants. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study found a slightly stronger association between central adiposity measures and mortality in participants with lower BMI values . Both thP-interaction = 0.02), however, smoking did not modify the positive association between waist-hip ratio and all-cause mortality in EPIC men or women (P-interaction = 0.79 in men and 0.57 in women) [Similar to previous studies, we did not observe effect modification of the association between waist-hip ratio and mortality by physical activity , or smokEpidemiologic studies of adiposity and mortality are susceptible to reverse causation. Study participants with the lowest BMI are usually a heterogeneous group of individuals including smokers and chronically ill participants . To addrResults from our large prospective population-based studies find a linear association between central adiposity and CVD and all-cause mortality. The association is more evident for participants with a normal weight BMI than those with an overweight BMI at baseline. Central adiposity is a major public health concern and an important predictor of mortality risk in Chinese adults, as it is in North American and European adults. Our data emphasize the need to go beyond BMI and to incorporate measures of central fat distribution in assessing the heath impact of the rising obesity epidemic.


To examine the value of surveillance urethro-cystoscopy in patients with neurogenic lower urinary tract dysfunction (NLUTD) in regard to the conflicting literature as it is generally agreed that patients with NLUTD are at increased risk for bladder cancer.In a cross-sectional study, a consecutive series of 129 patients  suffering from NLUTD for at least 5 years was prospectively investigated using urethro-cystoscopy and bladder washing cytology at a single university spinal cord injury (SCI) center.Due to suspicious urethro-cystoscopy and/or bladder washing cytology findings, 13 (10%) of 129 patients underwent transurethral resection of the bladder lesion and/or random bladder biopsies. Overall, 9 relevant histological findings were found in 5% (7/129) of our patients: bladder melanosis (n = 1), nephrogenic adenoma (n = 3), keratinizing squamous metaplasia (n = 1), intestinal metaplasia (n = 3), and muscle-invasive adenocarcinoma of the bladder (n = 1).Using surveillance urethro-cystoscopy, we found relevant histological findings in 5% of our patients suffering from NLUTD for at least 5 years. Thus, surveillance urethro-cystoscopy might be warranted, although the ideal starting point and frequency remain to be determined in further prospective studies. Bladder cancer, as defined by the 10th revision of the International Classification of Diseases (ICD-10) . Men areFrom January 2011 to November 2013, a consecutive series of 129 patients suffering from NLUTD for at least 5 years was prospectively investigated in a cross-sectional study using urethro-cystoscopy and bladder washing cytology at the SCI Center, University of Zürich, Balgrist University Hospital, Zürich, Switzerland. Study exclusion criteria was current urinary tract infection (UTI), gross hematuria and age <18 years. This study was approved by the local ethics committee, i.e. Kantonale Ethikkommision (KEK) Zürich, Switzerland; study identification number: KEK-ZH-NR: 2010-0207/0 and all patients provided written informed consent according to the Helsinki II declaration.According to the EAU guidelines, urethro-cystoscopy and bladder washing cytology are both established routine follow-up investigations for patients with NLUTD . At our ® 2x 10 mL, Farco-Pharma GmbH, Germany) was instilled into the urethra and exposed for 10 minutes. Urethro-cystoscopy was performed in a lithotomy or supine position using a rigid or flexible cystoscope in women and men, respectively. After urethro-cystoscopy, we routinely performed a bladder washing cytology. In the case of suspicious urethro-cystoscopy and/or bladder washing cytology findings, the patient was scheduled for transurethral resection of the bladder (TUR-B) and/or random cold biopsies in spinal or general anesthesia. Histological and cytological findings were reported by board certified pathologists and cytologists, respectively, according to findings on routinely processed and stained specimen.Patients with a UTI were excluded and adequately treated according to the antibiotic sensitivity pattern before urethro-cystoscopy. For local anesthesia, lidocaine gel . Descriptive statistical analyses were performed using IBMMean age of the 129 patients was 51 ± 16 years (range 18 to 88). 50 (39%) and 79 (61%) were women and men, respectively. The cause of NLUTD was SCI in 89 patients (69%), multiple sclerosis in 20 (16%), myelomeningocele in 8 (6%), cerebral palsy in 4 (3%) and other neurological disorders in 8 (6%). Patients’ characteristics are shown in Overall, 58 (45%) of the 129 patients were exposed to at least one risk factor for bladder cancer . Due to Using surveillance urethro-cystoscopy, we detected relevant histological findings in 5% of our patients suffering from NLUTD for at least 5 years. Considering this important percentage of clinically relevant findings, surveillance urethro-cystoscopy might be warranted, although the ideal patient population, starting point and frequency remain to be determined in further prospective studies.In comparison to the general population, an up to 25 times higher risk of developing bladder cancer has been reported in patients with SCI relying on chronic indwelling catheters . This meGross hematuria, a well-known phenomenon in SCI patients with indwelling catheters, has a significantly higher incidence the longer the duration of catheterization is . The iniWith no consensus on how to manage patients with NLUTD to detect urological malignancies at an early stage, the need for establishing suitable diagnostic methods is substantial. Ultrasound of the bladder, a non-invasive diagnostic tool, is reported to be inferior to urethro-cystoscopy in identifying bladder cancer in patients with hematuria  and therAccording to the consortium for spinal cord medicine , SCI patIn an attempt to minimize morbidity caused by urethro-cystoscopy, antibiotic prophylaxis might be considered in high-risk patients suffering from NLUTD in order to prevent symptomatic UTI. In patients with SCI being at risk of the development of autonomic dysreflexia due to bladder distension during urethro-cystoscopy might profit from using a less traumatic flexible instead of a rigid cystoscope while being on continuous cardiovascular monitoring at the same time, that is, blood pressure and heart rate . To imprIn the present study using surveillance urethro-cystoscopy, relevant histological findings varied widely and included bladder melanosis, nephrogenic adenoma, keratinizing squamous metaplasia, intestinal metaplasia, and mucus-producing adenocarcinoma. Considering the fact that relevant histological findings were present even in 15% (2/13) of the patients with NLUTD who voided spontaneously, NLUTD itself might be a risk factor for the development of bladder cancer as suggested by Kalisvaart et al. .Although a relevant high percentage (45%) of patients was exposed to at least one risk factor for bladder cancer, we did not find any dysplastic lesions. Bladder melanosis , a rare Intestinal metaplasia  of the bIn patients with muscle-invasive bladder cancer, bilateral pelvic lymphadenectomy and radical cystectomy combined with urinary diversion is mandatory as in our SCI patient with co-existing intestinal metaplasia and mucus-producing adenocarcinoma of the bladder .Patients with NLUTD require an extensive and specific work-up before embarking on an individualized therapy taking into account the patients’ medical and physical condition as well as their expectations . ConsideMetaplastic lesions such as nephrogenic adenoma, keratinizing squamous metaplasia and intestinal metaplasia may progress to a malignant condition but the underlying mechanisms involved are unclear and remain to be elucidated. Given the heterogeneous nature and management of neurogenic LUTD, it would be of great interest to know which sub-group of patients is at highest risk to develop relevant histological lesions. In addition, further studies are needed to determine the ideal starting point and frequency of surveillance urethro-cystoscopy. Thus, prospective large-scale multicenter studies are highly warranted to investigate these still unanswered questions and to further improve the management of patients with NLUTD.The present study has some limitations. Although we evaluated a well-defined patient population with NLUTD, there are limitations that should be addressed. Most of our patients suffered from SCI, that is, patients with other neurological disorders were under-represented. Our unit is part of a highly specialized university SCI center so that a negative selection bias, that is, inclusion of more severe cases, cannot to be completely ruled out. Considering that we only studied patients suffering from NLUTD for at least 5 years, it is unclear whether the results could be extrapolated to patients with a shorter exposure time to the neurological disease. Due to the cross-sectional study design, randomization was not possible and patients with versus without surveillance urethro-cystoscopy could not be compared. Moreover, because of the limited patient number in some groups, we did not perform sub-group analysis. Nevertheless, the present study was prospective and representative of daily clinical practice.In patients suffering from NLUTD for at least 5 years, we detected suspicious urethro-cystoscopy and/or bladder washing cytology findings in 10% and relevant histological findings in 5%. The relevant histological findings varied widely, that is, from bladder melanosis to muscle-invasive mucus-producing adenocarcinoma of the bladder. Considering the important percentage of clinically relevant findings, surveillance urethro-cystoscopy might be warranted. However, we cannot conclude from our data which sub-group of patients with NLUTD would profit most from surveillance urethro-cystoscopy. In addition, starting point and frequency of surveillance urethro-cystoscopy remain unclear. Thus, further well-designed, adequately powered and sampled prospective studies are needed to investigate these highly relevant issues.S1 Dataset(XLSX)Click here for additional data file.S1 Fig(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.