Low-grade inflammation from prenatal period to age 6-8 years in a Vitamin D trial.

BACKGROUND: Low-grade systemic inflammation measured as high sensitivity C-reactive protein (hs-CRP) has been associated with non-communicable disease risk. We assessed whether prenatal inflammation and early-childhood vitamin D are associated with inflammation until age 6-8. METHODS: We analyzed blood hs-CRP and 25-hydroxy vitamin D [25(OH)D] in pregnancy, at birth from umbilical cord blood (UCB), from offspring at ages 1, 2, and 6-8 years in the Vitamin D Intervention in Infants (VIDI) study. VIDI was a randomized-controlled trial of vitamin D supplementation of 10 µg/day or 30 µg/day from age 2 weeks until 2 years in 975 infants recruited in 2013-14, with follow-up at age 6-8 in 2019-21 (n = 283). RESULTS: Pregnancy hs-CRP was associated with UCB hs-CRP (r = 0.18, p < 0.001) but not independently with childhood hs-CRP (Estimate [95% CI] 0.04 [<-0.00, 0.09]). Higher UCB hs-CRP was associated independently with higher hs-CRP until 6-8 years (0.20 [0.12, 0.29]). Infant vitamin D dose had no effect on longitudinal hs-CRP (6-8 years, 0.11 [-0.04, 0.25]). Childhood 25(OH)D were associated positively with hs-CRP until age 6-8 (0.01 [>0.00, 0.01]). CONCLUSION: Our results indicate that in children, inflammation, assessed by hs-CRP, persists from birth until 6-8 years. We observed positive associations between 25(OH)D and hs-CRP in vitamin D-sufficient children. IMPACT: High sensitivity C-reactive protein (hs-CRP) concentrations tract from birth to age 8 years Our novel finding suggests a long-lasting pro-inflammatory phenotype in the child Higher vitamin D concentration - but not dose - is associated with higher childhood hs-CRP Chronic disease risk related to inflammation may in part originate from the prenatal period or early childhood Further studies are needed to investigate the effects of inflammation on long-term clinical health outcomes.

Serum ceramides in early pregnancy as predictors of gestational diabetes.

Ceramides contribute to the development of type 2 diabetes but it is uncertain whether they predict gestational diabetes (GDM). In this multicentre case-control study including 1040 women with GDM and 958 non-diabetic controls, early pregnancy (mean 10.7 gestational weeks) concentrations of four ceramides-Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)-were determined by a validated mass-spectrometric method from biobanked serum samples. Traditional lipids including total cholesterol, LDL, HDL and triglycerides were measured. Logistic and linear regression and the LASSO logistic regression were used to analyse lipids and clinical risk factors in the prediction of GDM. The concentrations of four targeted ceramides and total cholesterol, LDL and triglycerides were higher and HDL was lower among women with subsequent GDM than among controls. After adjustments, Cer(d18:1/24:0), triglycerides and LDL were independent predictors of GDM, women in their highest quartile had 1.44-fold (95% CI 1.07-1.95), 2.17-fold (95% CI 1.57-3.00) and 1.63-fold (95% CI 1.19-2.24) odds for GDM when compared to their lowest quartiles, respectively. In the LASSO regression modelling ceramides did not appear to markedly improve the predictive performance for GDM alongside with clinical risk factors and triglycerides. However, their adverse alterations highlight the extent of metabolic disturbances involved in GDM.

Body composition among Malawian young adolescents: Cross-validating predictive equations for bioelectric impedance analysis using deuterium dilution method.

BACKGROUND: Body composition can be measured by several methods, each with specific benefits and disadvantages. Bioelectric impedance offers a favorable balance between accuracy, cost and ease of measurement in a range of settings. In this method, bioelectric measurements are converted to body composition measurements by prediction equations specific to age, population and bioimpedance device. Few prediction equations exist for populations in low-resource settings. We formed a prediction equation for total body water in Malawian adolescents using deuterium dilution as reference. METHODS: We studied 86 boys and 92 girls participating in the 11-14-year follow-up of the Lungwena Antenatal Intervention Study, a randomized trial of presumptive infection treatment among pregnant women. We measured body composition by Seca m515 bioimpedance analyser. Participants ingested a weight-standardized dose of deuterium oxide, after which we collected saliva at baseline, at 3 and 4 h post-ingestion, measured deuterium concentration using Fourier-transform infrared spectroscopy and calculated total body water. We formed predictive equations for total body water using anthropometrics plus resistance and reactance at a range of frequencies, applying multiple regression and repeated cross-validation in model building and in prediction error estimation. RESULTS: The best predictive model for percentage total body water (TBW %) was 100*(1.11373 + 0.0037049*height (cm)2/resistance(Ω) at 50 kHz- 0.25778*height(m)- 0.01812*BMI(kg/m2)- 0.02614*female sex). Calculation of absolute TBW (kg) by multiplying TBW (%) with body weight had better predictive power than a model directly constructed to predict absolute total body water (kg). This model explained 96.4% of variance in TBW (kg) and had a mean prediction error of 0.691 kg. Mean bias was 0.01 kg (95% limits of agreement -1.34, 1.36) for boys and -0.01 kg (1.41, 1.38) for girls. CONCLUSIONS: Our equation provides an accurate, cost-effective and participant-friendly body composition prediction method among adolescents in clinic-based field studies in rural Africa, where electricity is available.

School grades and educational attainments of adolescents and young adults born preterm.

Attendance in special education (SE) is more common among individuals born preterm than among those born at term. Less is known about school grades of those born preterm in mainstream education (ME), and how these grades predict later educational attainment. This population-based register-linkage study assessed (1) attendance in SE, and then focused on those in ME by assessing (2) school grades at 16 year, (3) completed educational level at 25 year, and (4) school grades as predictors for completed education by gestational age (GA) with full-term birth (39-41 completed weeks) as reference. The sample comprised 223,744 individuals (10,521 preterm, 4.7%) born in Finland (1/1987-9/1990). Of the sample, 4.9% attended SE. Those born preterm had up to 5.5-fold rates for SE. In ME, those born extremely preterm (EPT) had marginally lower mathematics grades compared with full-term counterparts, whilst those born late preterm or early term had slightly higher grades. Those born EPT or very preterm had lower physical education grades in ME. However, the minor differences in school grades according to GA appear not to translate into educational differences in young adulthood. The associations between school grades at 16 year and completed education at 25 year did not vary by GA.

Risk-Taking Behavior of Adolescents and Young Adults Born Preterm.

OBJECTIVES: To study sexually transmitted Chlamydia trachomatis infections (STCTs), teenage pregnancies, and payment defaults in individuals born preterm as proxies for engaging in risk-taking behavior. STUDY DESIGN: Our population-based register-linkage study included all 191 705 children alive at 10 years (8492 preterm [4.4%]) born without malformations in Finland between January 1987 and September 1990 as each mother's first child within the cohort. They were followed until young adulthood. We used Cox regression to assess the hazards of STCTs, teenage pregnancies, payment defaults, criminal offending, and substance abuse by gestational age. Gestational age was considered both as a continuous and categorical (extremely, very, moderately, late preterm, early term, post term, and full term as reference) exposure. RESULTS: A linear dose-response relationship existed between gestational age and STCT and teenage pregnancy; adjusted hazard for STCT decreased by 1.6% (95% CI, 0.7%-2.6%), and for teenage pregnancy by 3.3% (95% CI, 1.9%-4.8%) per each week decrease in gestational age. Those born extremely preterm (23-27 completed weeks) had a 51% (95% CI, 31%-83%) lower risk for criminal offending than their full-term born counterparts, and those born very preterm (range, 28-31 weeks) had a 28% (95% CI, 7%-53%) higher hazard for payment defaults than those born at full term. Gestational age was not associated with substance abuse. CONCLUSIONS: The lower risk-taking that characterizes people born preterm seems to generalize to sexual and to some extent criminal behavior. Those born very preterm are, however, more likely to experience payment defaults.

Health care costs related to hepatitis B in Finland are mostly due to chronic infections: a register-based study.

BACKGROUND: Finland is among the countries with low hepatitis B endemicity. We evaluate the hepatitis B-related disease and economic burden needed for evidence-based immunisation policy decision-making. METHODS: Hepatitis B-related cases in 2004-2012 were retrieved from population-based nationwide registers. We evaluated the incidence, health care resource use, health care costs, and life years lost due to hepatitis B-related outcomes. An episode of care was constructed from each individual's hepatitis B-related events retrieved from individually linkable registers. RESULTS: The mean health care costs per an acute hepatitis B case were €450 (SD 240), €2030 (SD 350), and €5400 (SD 3370) in those aged 0-14, 15-64, and ≥65 years, respectively. For chronic infection, the mean cost per case among Finnish-born individuals was €990 and among foreign-born €1360. The costs per case of liver cirrhosis were €15,350 and liver cancer €19,080. In addition, the annual antiviral medication costs per case receiving antiviral medication were €4710 to €5530. Annually <10% of the chronic and approximately 20% of liver cirrhosis cases received antiviral medication. We identified annually 21 acute, 264 chronic, three liver cirrhosis, and four liver cancer cases and 63.7 life years lost due to hepatitis B per 5.3 million inhabitants. The total annual health care costs were €1.2 million of which 60% were antiviral medication costs and 86% accounted for chronic hepatitis B. CONCLUSIONS: When planning prevention of hepatitis B infection, it is pivotal to notice that the overall disease and economic burden due to hepatitis B is mostly due to chronic infection.

Preterm birth and subsequent timing of pubertal growth, menarche, and voice break.

BACKGROUND: We evaluated pubertal growth and pubertal timing of participants born preterm compared to those born at term. METHODS: In the ESTER Preterm Birth Study, we collected growth data and measured final height of men/women born very or moderately preterm (<34 gestational weeks, n = 52/55), late preterm (34-<37 weeks, 94/106), and term (≥37 weeks, 131/151), resulting in median 9 measurements at ≥6 years. Timing of menarche or voice break was self-reported. Peak height velocity (PHV, cm/year) and age at PHV (years) were compared with SuperImposition by Translation And Rotation (SITAR) model (sexes separately). RESULTS: Age at PHV (years) and PHV (cm/year) were similar in all gestational age groups. Compared to term controls, insignificant differences in age at PHV were 0.1 (95% CI: -0.2 to 0.4) years/0.2 (-0.1 to 0.4) for very or moderately/late preterm born men and -0.0 (-0.3 to 0.3)/-0.0 (-0.3 to 0.2) for women, respectively. Being born small for gestational age was not associated with pubertal growth. Age at menarche or voice break was similar in all the gestational age groups. CONCLUSIONS: Timing of pubertal growth and age at menarche or voice break were similar in participants born preterm and at term. IMPACT: Pubertal growth and pubertal timing were similar in preterm and term participants in a relatively large cohort with a wide range of gestational ages. Previous literature indicates that small for gestational age is a risk for early puberty in term born children. This was not shown in preterm children. While our study had limited power for children born very preterm, all children born preterm were not at increased risk for early puberty.

Gestational Age, Parent Education, and Education in Adulthood.

BACKGROUND: Adults born preterm (<37 weeks) have lower educational attainment than those born term. Whether this relationship is modified by family factors such as socioeconomic background is, however, less well known. We investigated whether the relationship between gestational age and educational attainment in adulthood differed according to parents' educational level in 4 Nordic countries. METHODS: This register-based cohort study included singletons born alive from 1987 up to 1992 in Denmark, Finland, Norway, and Sweden. In each study population, we investigated effect modification by parents' educational level (low, intermediate, high) on the association between gestational age at birth (25-44 completed weeks) and low educational attainment at 25 years (not having completed upper secondary education) using general estimation equations logistic regressions. RESULTS: A total of 4.3%, 4.0%, 4.8%, and 5.0% singletons were born preterm in the Danish (n = 331 448), Finnish (n = 220 095), Norwegian (n = 292 840), and Swedish (n = 513 975) populations, respectively. In all countries, both lower gestational age and lower parental educational level contributed additively to low educational attainment. For example, in Denmark, the relative risk of low educational attainment was 1.84 (95% confidence interval 1.44 to 2.26) in adults born at 28 to 31 weeks whose parents had high educational level and 5.25 (95% confidence interval 4.53 to 6.02) in adults born at 28 to 31 weeks whose parents had low educational level, compared with a reference group born at 39 to 41 weeks with high parental educational level. CONCLUSIONS: Although higher parental education level was associated with higher educational attainment for all gestational ages, parental education did not mitigate the educational disadvantages of shorter gestational age.

Social Distancing and SARS-CoV-2 Transmission Potential Early in the Epidemic in Finland.

BACKGROUND: Information about social mixing patterns under heavy social distancing is needed to model the impact of nonpharmaceutical interventions on SARS-CoV-2 transmission. METHODS: We conducted a survey on daily person-to-person contacts during the early phase of the SARS-CoV-2 epidemic in Finland, one month after strong social distancing measures had been introduced nationwide. We defined a contact as exchange of at least a few words in proximity of another person. We also considered physical ("skin-to-skin") contacts separately. Based on 3,171 reported contacts by 1,320 participants of 1-79 years of age, we estimated age-stratified contact matrices essential in modeling virus transmission. RESULTS: Compared with contacts during prepandemic conditions, as learned from the Finnish part of the Polymod study, there was a 72% (95% credible interval, CI = 71, 74) reduction in the daily number of all contacts and a 69% (95% CI = 66, 73) reduction in the daily number of physical contacts in April 2020. The largest reduction, of almost 90%, occurred in physical contacts by individuals more than 70 years of age. The estimated reduction in the transmission potential of the virus attributable solely to reduced contact frequencies varied between 59% (whole population; physical contacts; 95% CI = 52, 68) and 77% (over 20-year olds; physical contacts; 95% CI = 70, 89). CONCLUSIONS: We surmise that the large reduction in the daily numbers of social contacts in the early part of the SARS-CoV-2 epidemic in Finland was likely a major contributor to the steady decline of the epidemic in the country since early April.

Migraine in children and adults born preterm: A nationwide register linkage study.

OBJECTIVE: Being born preterm is related to adverse health effects later in life. We studied whether preterm birth predicts the risk of migraine. METHODS: In this nationwide register study, we linked data from six administrative registers for all 235,624 children live-born in Finland (January 1987 to September 1990) and recorded in the Finnish Medical Birth Register. n = 228,610 (97.0%) had adequate data and were included. Migraine served as primary outcome variable and was stringently defined as a diagnosis from specialised health care and/or ≥2 reimbursed purchases of triptans. We applied sex- and birth year-stratified Cox proportional hazard regression models to compute hazard ratios and confidence intervals (95% confidence intervals) for the association between preterm categories and migraine. The cohort was followed up until an average age of 25.1 years (range: 23.3-27.0). RESULTS: Among individuals born extremely preterm (23-27 completed weeks of gestation), the adjusted hazard ratios for migraine was 0.55 (0.25-1.24) when compared with the full-term reference group (39-41 weeks). The corresponding adjusted hazard ratios and 95% confidence intervals for the other preterm categories were: Very preterm (28-31 weeks); 0.95 (0.68-1.31), moderately preterm (32-33 weeks); 0.96 (0.73-1.27), late preterm (34-36 weeks); 1.01 (0.91-1.11), early term (37-38 weeks); 0.98 (0.93-1.03), and post term (42 weeks); 0.98 (0.89-1.08). Migraine was predicted by parental migraine, lower socioeconomic position, maternal hypertensive disorder and maternal smoking during pregnancy. CONCLUSION: We found no evidence for a higher risk of migraine among individuals born preterm.

Impact and effectiveness of a conjugate vaccine against invasive pneumococcal disease in Finland - a modelling approach.

The evaluation of the public health impact of a vaccination program is essential in monitoring its policy relevance. Vaccine impact (VI) is usually assessed in a before-after design, in which data on disease burden without vaccination program is required from a historical reference period. It takes into account the indirect effects and therefore aims to describe the public health performance of the vaccination program in the population. Vaccine effectiveness (VE), measured in parallel settings, quantifies the benefit for an individual of being vaccinated but does not address the indirect effects of a vaccination program. The motivation of this paper is to gain insight into patterns of how VI and VE have manifested under large-scale use of a ten-valent pneumococcal conjugate vaccine in Finnish children. We construct a simple pseudo-dynamic model that mimics typical post-vaccination trends in the incidences of pneumococcal carriage and invasive disease in children when the proportion of vaccine-type carriage decreases. In the context of the model, we define the parameters of interest for VI and VE and explore how their expected values evolve over time. For comparison, we demonstrate the application of VI and VE estimation by using register data.

Chronotype in very low birth weight adults - a sibling study.

Chronotype is the temporal preference for activity and sleep during the 24 h day and is linked to mental and physical health, quality of life, and mortality. Later chronotypes, so-called "night owls", consistently display poorer health outcomes than "larks". Previous studies have suggested that preterm birth (<37 weeks of gestation) is associated with an earlier chronotype in children, adolescents, and young adults, but studies beyond this age are absent. Our aim was to determine if adults born preterm at very low birth weight (VLBW, ≤1500 g) display different chronotypes than their siblings. We studied VLBW adults, aged 29.9 years (SD 2.8), matched with same-sex term-born siblings as controls. A total of 123 participants, consisting of 53 sibling pairs and 17 unmatched participants, provided actigraphy-derived data on the timing, duration, and quality of sleep from 1640 nights (mean 13.3 per participant, SD 2.7). Mixed effects models provided estimates and significance tests. Compared to their siblings, VLBW adults displayed 27 min earlier sleep midpoint during free days (95% CI: 3 to 51 min, p =.029). This was also reflected in the timing of falling asleep, waking up, and sleep-debt corrected sleep midpoint. The findings were emphasized in VLBW participants born small for gestational age. VLBW adults displayed an earlier chronotype than their siblings still at age 30, which suggests that the earlier chronotype is an enduring individual trait not explained by shared family factors. This preference could provide protection from risks associated with preterm birth. ABBREVIATIONS: AGA: Appropriate for gestational age; ELBW: Extremely low birth weight, ≤ 1000 grams; FMBR: Finnish Medical Birth Registry; HeSVA: Helsinki Study of Very low birth weight Adults; MSFsc: Midsleep on free days, corrected for sleep debt; SGA: Small for gestational age, ≤ -2 SD; VLBW: Very low birth weight, ≤ 1500 grams; WASO: Wake after sleep onset.

Out-of-home care placements of children and adolescents born preterm: A register-based cohort study.

BACKGROUND: Preterm birth predisposes to child protection action in the form out-of-home care. The impact of the degree of preterm birth on the likelihood for OHC placement(s) and their timing is unknown. METHODS: This population-based register-linkage study assessed the likelihood of OHC placement in different gestational age groups using multivariable Cox regression models. All 193 033 traceable singleton (8324 preterm, 4.3%) liveborn in Finland (January 1987-September 1990), as the first index child of each mother within the cohort period, were followed up until their 18th birthday. RESULTS: A total of 6562 children (3.4%) experienced OHC. In comparison with full-term children (39-41 weeks), those born at 23-33 completed weeks were predisposed to OHC (hazard ratio [HR] 2.11, 95% confidence interval [CI] 1.74, 2.56). For those born late preterm (34-36 weeks) and early term (37-38 weeks), the HR were 1.54 (95% CI 1.37, 1.73) and 1.19 (95% CI 1.12, 1.26), respectively. Adjustment for parental and child characteristics attenuated the HRs: 23-33 weeks: 1.31 (95% CI 1.07, 1.59), 34-36 weeks: 1.17 (95% CI 1.04, 1.31), and 37-38 weeks: 1.08 (95% CI 1.02, 1.16). However, the adjusted HRs for first OHC entries at 0-5 years of age were higher: 23-33 weeks 2.29 (95% CI 1.72, 3.05), 34-36 weeks 1.76 (95% CI 1.46, 2.13), and 37-38 weeks 1.40 (95% CI 1.25, 1.56). Among those born preterm or early term, in comparison with their term born peers, no excess risk for OHC was seen after 5 years. CONCLUSIONS: A dose-response relationship exists between the level of preterm birth and OHC placement risk. OHC placements are more common among early and late preterm, and early term children, compared with those born full term, and occur at younger age. Perinatal and postnatal adverse circumstances appear to explain the phenomenon only partly.

Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data.

BACKGROUND: In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged <5years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine-serotype disease may re-emerge once the effects of the catch-up campaign wear off. METHODS: We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10-valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. RESULTS: The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1-5year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. CONCLUSION: We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign.

Optimal serotype compositions for Pneumococcal conjugate vaccination under serotype replacement.

Pneumococcal conjugate vaccination has proved highly effective in eliminating vaccine-type pneumococcal carriage and disease. However, the potential adverse effects of serotype replacement remain a major concern when implementing routine childhood pneumococcal conjugate vaccination programmes. Applying a concise predictive model, we present a ready-to-use quantitative tool to investigate the implications of serotype replacement on the net effectiveness of vaccination against invasive pneumococcal disease (IPD) and to guide in the selection of optimal vaccine serotype compositions. We utilise pre-vaccination data on pneumococcal carriage and IPD and assume partial or complete elimination of vaccine-type carriage, its replacement by non-vaccine-type carriage, and stable case-to-carrier ratios (probability of IPD per carriage episode). The model predicts that the post-vaccination IPD incidences in Finland for currently available vaccine serotype compositions can eventually decrease among the target age group of children <5 years of age by 75%. However, due to replacement through herd effects, the decrease among the older population is predicted to be much less (20-40%). We introduce a sequential algorithm for the search of optimal serotype compositions and assess the robustness of inferences to uncertainties in data and assumptions about carriage and IPD. The optimal serotype composition depends on the age group of interest and some serotypes may be highly beneficial vaccine types in one age category (e.g. 6B in children), while being disadvantageous in another. The net effectiveness will be improved only if the added serotype has a higher case-to-carrier ratio than the average case-to-carrier ratio of the current non-vaccine types and the degree of improvement in effectiveness depends on the carriage incidence of the serotype. The serotype compositions of currently available pneumococcal vaccines are not optimal and the effectiveness of vaccination in the population at large could be improved by including new serotypes in the vaccine (e.g. 22 and 9N).

Pneumococcal transmission and disease in silico: a microsimulation model of the indirect effects of vaccination.

BACKGROUND: The degree and time frame of indirect effects of vaccination (serotype replacement and herd immunity) are key determinants in assessing the net effectiveness of vaccination with pneumococcal conjugate vaccines (PCV) in control of pneumococcal disease. Using modelling, we aimed to quantify these effects and their dependence on coverage of vaccination and the vaccine's efficacy against susceptibility to pneumococcal carriage. METHODS AND FINDINGS: We constructed an individual-based simulation model that explores the effects of large-scale PCV programmes and applied it in a developed country setting (Finland). A population structure with transmission of carriage taking place within relevant mixing groups (families, day care groups, schools and neighbourhoods) was considered in order to properly assess the dependency of herd immunity on coverage of vaccination and vaccine efficacy against carriage. Issues regarding potential serotype replacement were addressed by employing a novel competition structure between multiple pneumococcal serotypes. Model parameters were calibrated from pre-vaccination data about the age-specific carriage prevalence and serotype distribution. The model predicts that elimination of vaccine-type carriage and disease among those vaccinated and, due to a substantial herd effect, also among the general population takes place within 5-10 years since the onset of a PCV programme with high (90%) coverage of vaccination and moderate (50%) vaccine efficacy against acquisition of carriage. A near-complete replacement of vaccine-type carriage by non-vaccine-type carriage occurs within the same time frame. CONCLUSIONS: The changed patterns in pneumococcal carriage after PCV vaccination predicted by the model are unequivocal. The overall effect on disease incidence depends crucially on the magnitude of age- and serotype-specific case-to-carrier ratios of the remaining serotypes relative to those of the vaccine types. Thus the availability of reliable data on the incidence of both pneumococcal carriage and disease is essential in assessing the net effectiveness of PCV vaccination in a given epidemiological setting.