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1.  Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites 
PLoS Medicine  2013;10(9):e1001517.
In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs.
Please see later in the article for the Editors' Summary
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.
Methods and Findings
Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]).
Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used.
Please see later in the article for the Editors' Summary
Editors’ Summary
Pneumococcal disease–a major cause of illness and death in children and adults worldwide–is caused by Streptococcus pneumoniae, a bacterium that often colonizes the nose and throat harmlessly. Unfortunately, S. pneumoniae occasionally spreads into the lungs, bloodstream, or covering of the brain, where it causes pneumonia, septicemia, and meningitis, respectively. These invasive pneumococcal diseases (IPDs) can usually be successfully treated with antibiotics but can be fatal. Consequently, it is better to avoid infection through vaccination. Vaccination primes the immune system to recognize and attack disease-causing organisms (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 or “serotypes,” each characterized by a different antigenic polysaccharide (complex sugar) coat, vaccines that protect against S. pneumoniae have to include multiple serotypes. Thus, the pneumococcal conjugate vaccine PCV7, which was introduced into the US infant immunization regimen in 2000, contains polysaccharides from the seven S. pneumoniae serotypes mainly responsible for IPD in the US at that time.
Why Was This Study Done?
Vaccination with PCV7 was subsequently introduced in several other high- and middle-income countries, and IPD caused by the serotypes included in the vaccine declined substantially in children and in adults (because of reduced bacterial transmission and herd protection) in the US and virtually all these countries. However, increases in IPD caused by non-vaccine serotypes occurred in some settings, presumably because of “serotype replacement.” PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes. Consequently, after vaccination, previously less common, non-vaccine serotypes can colonize the nose and throat, some of which can cause IPD. In July 2010, a World Health Organization expert consultation on serotype replacement called for a comprehensive analysis of the magnitude and variability of pneumococcal serotype replacement following PCV7 use to help guide the introduction of PCVs in low-income countries, where most pneumococcal deaths occur. In this pooled analysis of data from multiple surveillance sites, the researchers investigate serotype-specific changes in IPD after PCV7 introduction using a standardized approach.
What Did the Researchers Do and Find?
The researchers identified 21 databases that had data about the rate of IPD for at least 2 years before and 1 year after PCV7 introduction. They estimated whether changes in IPD rates had occurred after PCV7 introduction by calculating site-specific rate ratios–the observed IPD rate for each post-PCV7 year divided by the expected IPD rate in the absence of PCV7 extrapolated from the pre-PCV7 rate. Finally, they used a statistical approach (random effects meta-analysis) to estimate summary (pooled) rate ratios. For children under 5 years old, the overall number of observed cases of IPD in the first year after the introduction of PCV7 was about half the expected number; this reduction in IPD continued through year 7 after PCV7 introduction. Notably, the rate of IPD caused by the S. pneumonia serotypes in PCV7 decreased every year, but the rate of IPD caused by non-vaccine serotypes increased annually. By year 7, the number of cases of IPD caused by non-vaccine serotypes was 3-fold higher than expected, but was still smaller than the decrease in vaccine serotypes, thereby leading to the decrease in overall IPD. Finally, smaller decreases in overall IPD also occurred among adults but occurred later than in children 2 years or more after PCV7 introduction.
What Do These Findings Mean?
These findings show that consistent, rapid, and sustained decreases in overall IPD and in IPD caused by serotypes included in PCV7 occurred in children and thus support the use of PCVs. The small increases in IPD caused by non-vaccine serotypes that these findings reveal are likely to be the result of serotype replacement, but changes in antibiotic use and other factors may also be involved. These findings have several important limitations, however. For example, PCV7 is no longer made and extrapolation of these results to newer PCV10 and PCV13 formulations should be done cautiously. On the other hand, many of the serotypes causing serotype replacement after PCV7 are included in these higher valency vaccines. Moreover, because the data analyzed in this study mainly came from high-income countries, these findings may not be generalizable to low-income countries. Nevertheless, based on their analysis, the researchers make recommendations for the collection and analysis of IPD surveillance data that should allow valid interpretations of the effect of PCVs on IPD to be made, an important requisite for making sound policy decisions about vaccination against pneumococcal disease.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
The International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health has more information on introduction of pneumococcal conjugate vaccines in low-income countries
PMCID: PMC3782411  PMID: 24086113
2.  Failure of introduction of food allergens after negative oral food challenge tests in children 
European Journal of Pediatrics  2015;174(8):1093-1099.
One of the purposes to perform an oral food challenge (FC) test is to avoid unnecessary elimination of food allergens. In case of a negative FC test result, the food can be introduced. It is, however, unknown if patients act according to the outcome of the test. This study evaluates the rate of introduction of peanut, hazelnut, cow’s milk or hen’s egg allergens after a negative FC test. We investigated the introduction rate of children (0–18 years) with a negative FC test visiting the Department of Allergology, Erasmus Medical Centre Rotterdam from 2008 till 2013 and the factors that influence the rate of introduction. Patients were asked to complete a comprehensive questionnaire about their FC test. In total, 157 (38 % girls, mean age during challenge 6.9 years) participated in the study. Of these FC tests, 104 (56 %) were followed by a successful introduction, 30 (16 %) by a partly introduction (traces or processed foods) and 52 (28 %) by a failed introduction. Peanut and hazelnut showed a statistically significant lower successful introduction rate. Age, gender, symptoms during FC test, dietary advice and time period to introduction significantly influenced the rate of introduction. One fourth of the children with failure of introducing foods experienced symptoms during the introduction.
Conclusion: More than one quarter of all children with a negative FC test result did not introduce the food. The FC test in its current form does not achieve its objective for this group of children. What is Known: • When the outcome of a food challenge test is negative, the food should be introduced in the diet of the child. • Failure of this introduction has negative consequences for the health of the child. What is New: • Failure of introduction of foods after a negative challenge test is reported in almost 25 % of the challenged children. • Failure of introduction after a negative challenge test is significant associated with gender, age, allergens, symptoms during OFC (according to the parents), advice, time start eating the food, and symptoms during introduction.
PMCID: PMC4516899  PMID: 25762026
Children; Failed introduction; Food allergy; Oral food challenge test
3.  Physiological and Behavioral Effects of Social Introduction on Adult Male Rhesus Macaques 
American journal of primatology  2008;70(6):542-550.
Pair housing of laboratory macaques is widely considered to lead to positive changes in well-being, yet the process of introduction is viewed as potentially stressful and risk-prone. Behavioral and physiological data were collected on eight adult male rhesus macaques before, during, and after the process of introduction, in order to measure the initial stress of introduction as well as long-term changes in well-being. Socially experienced subjects, all implanted with biotelemetry devices, were studied in five successive phases: baseline (singly housed), 1 day each of protected contact and full contact introduction, post-introduction (1–3 weeks after introduction), and settled pairs (≥20 weeks after introduction). One hundred and seventy-six hours of behavioral data and 672 hr of heart rate data were analyzed. Fecal cortisol was also measured for the baseline, post-introduction, and settled pair phases. All introductions were successful and subjects showed no physiological or behavioral signs of stress, such as increased heart rate, abnormal behavior, or psychological indices of distress (depressive/anxiety-related behavior). Agonism was minimal throughout the introduction process and over the subsequent months; only one wound was incurred over the course of the study. Levels of abnormal behaviors, psychological indices of distress, locomotion, inactivity, and affiliation showed improvements within several weeks after introduction; these changes were still present 5–9 months later for the latter two categories. Heart rates during introduction fell significantly in the settled pair phase, and also varied predictably with time of day. Fecal cortisol levels were lower in settled pairs than in single housing. The fact that reductions in abnormal behavior did not persist over the long term may have been confounded by increasing duration of time spent caged. The results of this study may be of practical use for designing and monitoring social introductions and suggest that managers should not dismiss the feasibility of successful pairing of adult male rhesus macaques.
PMCID: PMC2863312  PMID: 18189243
Rhesus macaques; social introductions; biotelemetry; stress
4.  Risk of African swine fever introduction into the European Union through transport-associated routes: returning trucks and waste from international ships and planes 
The uncontrolled presence of African swine fever (ASF) in Russian Federation (RF) poses a serious risk to the whole European Union (EU) pig industry. Although trade of pigs and their products is banned since the official notification in June 2007, the potential introduction of ASF virus (ASFV) may occur by other routes, which are very frequent in ASF, and more difficult to control, such as contaminated waste or infected vehicles. This study was intended to estimate the risk of ASFV introduction into the EU through three types of transport routes: returning trucks, waste from international ships and waste from international planes, which will be referred here as transport-associated routes (TAR). Since no detailed and official information was available for these routes, a semi-quantitative model based on the weighted combination of risk factors was developed to estimate the risk of ASFV introduction by TAR. Relative weights for combination of different risk factors as well as validation of the model results were obtained by an expert opinion elicitation.
Model results indicate that the relative risk for ASFV introduction through TAR in most of the EU countries (16) is low, although some countries, specifically Poland and Lithuania, concentrate high levels of risk, the returning trucks route being the analyzed TAR that currently poses the highest risk for ASFV introduction into the EU. The spatial distribution of the risk of ASFV introduction varies importantly between the analyzed introduction routes. Results also highlight the need to increase the awareness and precautions for ASF prevention, particularly ensuring truck disinfection, to minimize the potential risk of entrance into the EU.
This study presents the first assessment of ASF introduction into the EU through TAR. The innovative model developed here could be used in data scarce situations for estimating the relative risk associated to each EU country. This simple methodology provides a rapid and easy to interpret results on risk that may be used for a target and cost-effective allocation of resources to prevent disease introduction.
PMCID: PMC3485109  PMID: 22935221
African swine fever; Risk assessment; Transport; Trucks; Waste disposal
5.  High genetic diversity is not essential for successful introduction 
Ecology and Evolution  2013;3(13):4501-4517.
Some introduced populations thrive and evolve despite the presumed loss of diversity at introduction. We aimed to quantify the amount of genetic diversity retained at introduction in species that have shown evidence of adaptation to their introduced environments. Samples were taken from native and introduced ranges of Arctotheca populifolia and Petrorhagia nanteuilii. Using microsatellite data, we identified the source for each introduction, estimated genetic diversity in native and introduced populations, and calculated the amount of diversity retained in introduced populations. These values were compared to those from a literature review of diversity in native, confamilial populations and to estimates of genetic diversity retained at introduction. Gene diversity in the native range of both species was significantly lower than for confamilials. We found that, on average, introduced populations showing evidence of adaptation to their new environments retained 81% of the genetic diversity from the native range. Introduced populations of P. nanteuilii had higher genetic diversity than found in the native source populations, whereas introduced populations of A. populifolia retained only 14% of its native diversity in one introduction and 1% in another. Our literature review has shown that most introductions demonstrating adaptive ability have lost diversity upon introduction. The two species studied here had exceptionally low native range genetic diversity. Further, the two introductions of A. populifolia represent the largest percentage loss of genetic diversity in a species showing evidence of substantial morphological change in the introduced range. While high genetic diversity may increase the likelihood of invasion success, the species examined here adapted to their new environments with very little neutral genetic diversity. This finding suggests that even introductions founded by small numbers of individuals have the potential to become invasive.
PMCID: PMC3856749  PMID: 24340190
Asteraceae; biological invasions; caryophyllaceae; genetic diversity; microsatellite; rapid evolution
6.  Invasive Pneumococcal Disease in Infants Younger Than 90 Days Before and After Introduction of PCV7 
Pediatrics  2013;132(1):e17-e24.
Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) changed the epidemiology of invasive pneumococcal disease (IPD). We evaluated the changes that occurred after PCV7 introduction among Utah infants aged 1 to 90 days, too young to be fully immunized.
We identified children <18 years with culture-confirmed IPD from 1997–2010. We analyzed demographic, clinical, and serotype data for infants aged 1–90 days. The pre– and post–vaccine introduction periods spanned 1997–2000 and 2001–2010, respectively.
Of 513 children with IPD, 36 were 1 to 90 days and accounted for 7% of IPD cases in both the pre– and post–vaccine introduction period. The pre–vaccine IPD incidence rate was 5.0 per 100 000 live births, and was unchanged in the post–vaccine introduction period. IPD caused by PCV7 serotypes decreased by 74% (from 2.2 to 0.58 per 100 000), whereas non-vaccine serotype IPD increased by 57% (from 2.8 to 4.4 per 100 000). Sixteen infants (44%) required intensive care, and 3 (8%) died. Bacteremia without focus (56%) and meningitis (44%) were the predominant syndromes in the pre– and post–vaccine introduction periods, respectively. In the post–vaccine introduction period, serotype 7F was the most common serotype among infants and was responsible for 50% of meningitis.
The incidence of IPD in Utah infants aged 1 to 90 days caused by PCV7 serotypes decreased after PCV7 introduction, but overall incidence was unchanged. In the post–vaccine introduction period, serotype 7F predominated in this age group and was associated with meningitis.
PMCID: PMC3691535  PMID: 23733800
invasive pneumococcal disease; Streptococcus pneumoniae; infant; pneumococcal conjugate vaccine
7.  Predictors for early introduction of solid food among Danish mothers and infants: an observational study 
BMC Pediatrics  2014;14:243.
Early introduction of complementary feeding may interfere with breastfeeding and the infant’s self-controlled appetite resulting in increased growth. The aim of the present study was to investigate predictors for early introduction of solid food.
In an observational study Danish mothers filled in a self-administered questionnaire approximately six months after birth. The questionnaire included questions about factors related to the infant, the mother, attachment and feeding known to influence time for introduction of solid food. The study population consisted of 4503 infants. Data were analysed using ordered logistic regression models. Outcome variable was time for introduction to solid food.
Almost all of the included infants 4386 (97%) initiated breastfeeding. At weeks 16, 17–25, 25+, 330 infants (7%); 2923 (65%); and 1250 (28%), respectively had been introduced to solid food. Full breastfeeding at five weeks was the most influential predictor for later introduction of solid food (OR = 2.52 CI: 1.93-3.28). Among infant factors male gender, increased gestational age at birth, and higher birth weight were found to be statistically significant predictors. Among maternal factors, lower maternal age, higher BMI, and being primipara were significant predictors, and among attachment factors mother’s reported perception of the infant as being temperamental, and not recognising early infant cues of hunger were significant predictors for earlier introduction of solid food. Supplementary analyses of interactions between the predictors showed that the association of maternal perceived infant temperament on early introduction was restricted to primiparae, that the mother’s pre-pregnancy BMI had no impact if the infant was fully breastfed at week five, and that birth weight was only associated if the mother had reported early uncertainty in recognising infant’s cues of hunger.
Breastfeeding was the single most powerful indicator for preventing early introduction to solid food. Modifiable predictors pointed to the importance of supporting breastfeeding and educating primipara and mothers with low birth weight infants to be able to read and respond to their infants’ cues to prevent early introduction to solid food.
PMCID: PMC4263048  PMID: 25270266
Infant feeding practices; Breast-feeding; Introduction of complementary feeding; Solid food; Infant temperament; Risk factors
8.  A spatiotemporal model to assess the introduction risk of African horse sickness by import of animals and vectors in France 
BMC Veterinary Research  2015;11:127.
African horse sickness (AHS) is a major, Culicoides-borne viral disease in equines whose introduction into Europe could have dramatic consequences. The disease is considered to be endemic in sub-Saharan Africa. Recent introductions of other Culicoides-borne viruses (bluetongue and Schmallenberg) into northern Europe have highlighted the risk that AHS may arrive in Europe as well. The aim of our study was to provide a spatiotemporal quantitative risk model of AHS introduction into France. The study focused on two pathways of introduction: the arrival of an infectious host (PW-host) and the arrival of an infectious Culicoides midge via the livestock trade (PW-vector). The risk of introduction was calculated by determining the probability of an infectious animal or vector entering the country and the probability of the virus then becoming established: i.e., the virus’s arrival in France resulting in at least one local equine host being infected by one local vector. This risk was assessed using data from three consecutive years (2010 to 2012) for 22 regions in France.
The results of the model indicate that the annual risk of AHS being introduced to France is very low but that major spatiotemporal differences exist. For both introduction pathways, risk is higher from July to October and peaks in July. In general, regions with warmer climates are more at risk, as are colder regions with larger equine populations; however, regional variation in animal importation patterns (number and species) also play a major role in determining risk. Despite the low probability that AHSV is present in the EU, intra-EU trade of equines contributes most to the risk of AHSV introduction to France because it involves a large number of horse movements.
It is important to address spatiotemporal differences when assessing the risk of ASH introduction and thus also when implementing efficient surveillance efforts. The methods and results of this study may help develop surveillance techniques and other risk reduction measures that will prevent the introduction of AHS or minimize AHS’ potential impact once introduced, both in France and the rest of Europe.
Electronic supplementary material
The online version of this article (doi:10.1186/s12917-015-0435-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4455332  PMID: 26040321
African horse sickness; Equine movements; Import risk assessment; Risk of introduction; Culicoides; Quantitative risk; Midge
9.  Impact of the introduction of pneumococcal conjugate vaccine on immunization coverage among infants 
BMC Pediatrics  2005;5:43.
The introduction of pneumococcal conjugate vaccine (PCV) to the U.S. recommended childhood immunization schedule in the year 2000 added three injections to the number of vaccinations a child is expected to receive during the first year of life. Surveys have suggested that the addition of PCV has led some immunization providers to move other routine childhood vaccinations to later ages, which could increase the possibility of missing these vaccines. The purpose of this study was to evaluate whether introduction of PCV affected immunization coverage for recommended childhood vaccinations among 13-month olds in four large provider groups.
In this retrospective cohort study, we analyzed computerized data on vaccinations for 33,319 children in four large provider groups before and after the introduction of PCV. The primary outcome was whether the child was up to date for all non-PCV recommended vaccinations at 13 months of age. Logistic regression was used to evaluate the association between PCV introduction and the primary outcome. The secondary outcome was the number of days spent underimmunized by 13 months. The association between PCV introduction and the secondary outcome was evaluated using a two-part modelling approach using logistic and negative binomial regression.
Overall, 93% of children were up-to-date at 13 months, and 70% received all non-PCV vaccinations without any delay. Among the entire study population, immunization coverage was maintained or slightly increased from the pre-PCV to post-PCV periods. After multivariate adjustment, children born after PCV entered routine use were less likely to be up-to-date at 13 months in one provider group (Group C: OR = 0.5; 95% CI: 0.3 – 0.8) and were less likely to have received all vaccine doses without any delay in two Groups (Group B: OR = 0.4, 95% CI: 0.3 – 0.6; Group C: OR = 0.5, 95% CI: 0.4 – 0.7). This represented 3% fewer children in Group C who were up-to-date and 14% (Group C) to 16% (Group B) fewer children who spent no time underimmunized at 13 months after PCV entered routine use compared to the pre-PCV baseline. Some disruptions in immunization delivery were also observed concurrent with temporary recommendations to suspend the birth dose of hepatitis B vaccine, preceding the introduction of PCV.
These findings suggest that the introduction of PCV did not harm overall immunization coverage rates in populations with good access to primary care. However, we did observe some disruptions in the timely delivery of other vaccines coincident with the introduction of PCV and the suspension of the birth dose of hepatitis B vaccine. This study highlights the need for continued vigilance in coming years as the U.S. introduces new childhood vaccines and policies that may change the timing of existing vaccines.
PMCID: PMC1314888  PMID: 16313673
10.  Early Life Eczema, Food Introduction, and Risk of Food Allergy in Children 
The effect of food introduction timing on the development of food allergy remains controversial. We sought to examine whether the presence of childhood eczema changes the relationship between timing of food introduction and food allergy. The analysis includes 960 children recruited as part of a family-based food allergy cohort. Food allergy was determined by objective symptoms developing within 2 hours of ingestion, corroborated by skin prick testing/specific IgE. Physician diagnosis of eczema and timing of formula and solid food introduction were obtained by standardized interview. Cox Regression analysis provided hazard ratios for the development of food allergy for the same subgroups. Logistic regression models estimated the association of eczema and formula/food introduction with the risk of food allergy, individually and jointly. Of the 960 children, 411 (42.8%) were allergic to 1 or more foods and 391 (40.7%) had eczema. Children with eczema had a 8.4-fold higher risk of food allergy (OR, 95% CI: 8.4, 5.9–12.1). Among all children, later (>6 months) formula and rice/wheat cereal introduction lowered the risk of food allergy. In joint analysis, children without eczema who had later formula (OR, 95% CI: 0.5, 0.3–0.9) and later (>1 year) solid food (OR, 95% CI: 0.5, 0.3–0.95) introduction had a lower risk of food allergy. Among children with eczema, timing of food or formula introduction did not modify the risk of developing food allergy. Later food introduction was protective for food allergy in children without eczema but did not alter the risk of developing food allergy in children with eczema.
PMCID: PMC3281290  PMID: 22375277
11.  Gene-drive in age-structured insect populations 
Evolutionary Applications  2008;2(2):143-159.
To date, models of gene-drive mechanisms proposed for replacing wild-type mosquitoes with transgenic strains that cannot transmit diseases have assumed no age or mating structure. We developed a more detailed model to analyze the effects of age and mating-related factors on the number of engineered insects that must be introduced into a wild population to achieve successful gene-drive based on the Medea and engineered underdominance mechanisms. We found that models without age-structure and mating details can substantially overestimate or underestimate the numbers of engineered insects that must be introduced. In general, introduction thresholds are lowest when young adults are introduced. When both males and females are introduced, assortative mating by age has little impact on the introduction threshold unless the introduced females have diminished reproductive ability because of their age. However, when only males are introduced, assortative mating by age is generally predicted to increase introduction thresholds. In most cases, introduction thresholds are much higher for male-only introductions than for both-sex introductions, but when mating is nearly random and the introduced insects are adults with Medea constructs, male-only introductions can have somewhat lower thresholds than both-sex introductions. Results from this model suggest specific parameters that should be measured in field experiments.
PMCID: PMC3352368  PMID: 25567857
assortative mating; fitness cost; genetic control; mosquito; release threshold
12.  Reduction in Clostridium difficile Infection Rates after Mandatory Hospital Public Reporting: Findings from a Longitudinal Cohort Study in Canada 
PLoS Medicine  2012;9(7):e1001268.
A population-based study conducted by Nick Daneman and colleagues in Ontario, Canada reports on the association between population reporting of hospital infection rates and a reduction in population burden of Clostridium difficile colitis.
The role of public reporting in improving hospital quality of care is controversial. Reporting of hospital-acquired infection rates has been introduced in multiple health care systems, but its relationship to infection rates has been understudied. Our objective was to determine whether mandatory public reporting by hospitals is associated with a reduction in hospital rates of Clostridium difficile infection.
Methods and Findings
We conducted a longitudinal, population-based cohort study in Ontario (Canada's largest province) between April 1, 2002, and March 31, 2010. We included all patients (>1 y old) admitted to 180 acute care hospitals. Using Poisson regression, we developed a model to predict hospital- and age-specific monthly rates of C. difficile disease per 10,000 patient-days prior to introduction of public reporting on September 1, 2008. We then compared observed monthly rates of C. difficile infection in the post-intervention period with rates predicted by the pre-intervention predictive model. In the pre-intervention period there were 33,634 cases of C. difficile infection during 39,221,113 hospital days, with rates increasing from 7.01 per 10,000 patient-days in 2002 to 10.79 in 2007. In the first calendar year after the introduction of public reporting, there was a decline in observed rates of C. difficile colitis in Ontario to 8.92 cases per 10,000 patient-days, which was significantly lower than the predicted rate of 12.16 (95% CI 11.35–13.04) cases per 10,000 patient-days (p<0.001). Over this period, public reporting was associated with a 26.7% (95% CI 21.4%–31.6%) reduction in C. difficile cases, or a projected 1,970 cases averted per year (95% CI 1,476–2,500). The effect was specific to C. difficile, with rates of community-acquired gastrointestinal infections and urinary tract infections unchanged. A limitation of our study is that this observational study design cannot rule out the influence of unmeasured temporal confounders.
Public reporting of hospital C. difficile rates was associated with a substantial reduction in the population burden of this infection. Future research will be required to discern the direct mechanism by which C. difficile infection rates may have been reduced in response to public reporting.
Please see later in the article for the Editors' Summary
Editors' Summary
A stay in hospital can be lifesaving but can expose people to health care–associated infections. One of these—Clostridium difficile infection—is a major cause of infectious disease illness and death in developed countries. C. difficile bacteria cause diarrhea and, more rarely, life-threatening inflammation of the gut (colitis). They are present in the gut of about 3% of adults but do not normally cause any problems because other “good” bacteria keep them in check. However, antibiotics destroy these good bacteria, and if a person who has taken antibiotics becomes infected with C. difficile before good bacteria repopulate the gut, C. difficile can multiply rapidly and produce toxins that cause illness. Because C. difficile is usually acquired from other infected patients and their contaminated environments, and because antibiotic use is highly prevalent in hospitals, most C. difficile infections are acquired in hospitals and nursing homes. Infections can be prevented by practicing good hygiene in health care environments (for example, washing hands regularly with soap and water), by isolating patients who are infected with C. difficile, and by prescribing antibiotics for other infections sparingly.
Why Was This Study Done?
Hospitals often need encouragement to improve infection control and other aspects of care. One potential way to improve the quality of hospital care is mandatory public reporting of measures of care quality. This intervention may help hospitals identify areas of poor performance to target for improvement or may motivate them to improve care quality to avoid the shame of a bad performance report. Although many health care systems have introduced public reporting of hospital-acquired infections, the effects of this intervention have been poorly studied. In this longitudinal cohort study, the researchers use population-based health care data to evaluate the impact of the introduction of mandatory hospital public reporting of the rates of hospital-acquired C. difficile infection in Ontario, Canada. Since September 1, 2008, hospitals in Ontario have been required to send monthly data on hospital-acquired C. difficile infections to the Ontario Ministry of Health and Long-Term Care for posting on a public website.
What Did the Researchers Do and Find?
The researchers used health care administrative data for all patients older than one year admitted to acute care hospitals in Ontario between April 1, 2002, and March 31, 2010, to develop a model to predict monthly rates of C. difficile disease per 10,000 patient-days based on rates in the period before the introduction of public reporting. They then compared the observed rates of C. difficile disease after the introduction of public reporting with the rates predicted by this model. In the pre-intervention period, there were nearly 34,000 cases of C. difficile disease during about 39 million hospital days. Rates of C. difficile disease increased from 7.01 cases per 10,000 patient-days in 2002 to 10.79 cases per 10,000 patient-days in 2007. After the introduction of public reporting, the C. difficile disease rate fell to 8.92 cases per 10,000 patient-days, which is significantly (that is, unlikely to have occurred by chance) lower than the 12.16 cases per 10,000 patient-days predicted by the pre-intervention model. Finally, the researchers estimate that public reporting was associated with a 26.6% reduction in C. difficile disease cases and that it averted about 1,900 cases per year.
What Do These Findings Mean?
These findings suggest that mandatory public reporting of hospital rates of C. difficile disease may reduce the population burden of this serious infection. Because this is an observational study, these findings do not prove that the introduction of mandatory public reporting actually caused a reduction in infection rates. Some other uncharacterized factor might be responsible for the decrease in C. difficile disease in Ontario hospitals since late 2008. Moreover, the many assumptions included in the predictive model means that the estimated number of cases averted by the introduction of public reporting may be inaccurate. Although further research is needed to determine how public reporting might affect C. difficile disease rates, the researchers suggest that, in this study, mandatory public reporting may have increased the prominence of C. difficile on hospital quality improvement agendas and may have motivated hospitals to adhere more closely to best practices in C. difficile prevention.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides detailed information about C. difficile infection, including an article called Making Health Care Safer: Stopping C. difficile Infections
The UK National Health Service Choices website provides information about C. difficile infections
The Health Protection Agency provides information about mandatory reporting of C. difficile infections in England and Wales and a fact sheet on C. difficile
Information about public reporting of hospital C. difficile rates in Ontario is available (in English and French)
MedlinePlus provides links to further resources about C. difficile infections (in English and Spanish)
The UK Clostridium Difficle Support website has a forum containing personal stories about C. difficile infection
PMCID: PMC3398960  PMID: 22815656
13.  The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models 
PLoS Medicine  2014;11(3):e1001610.
Using different approaches to investigate HIV transmission patterns, Justin Lessler and colleagues find that extra-community HIV introductions are frequent and likely play a role in sustaining the epidemic in the Rakai community.
Please see later in the article for the Editors' Summary
It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities—home to two-thirds of the African population—is driven by intra-community sexual networks versus viral introductions from outside of communities.
Methods and Findings
We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7–3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%–42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%–70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai.
Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities.
Please see later in the article for the Editors' Summary
Editors' Summary
About 35 million people (25 million of whom live in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. HIV infection can be controlled by taking antiretroviral drugs (antiretroviral therapy, or ART) daily throughout life. Although originally available only to people living in wealthy countries, recent political efforts mean that 9.7 million people in low- and middle-income countries now have access to ART. However, ART does not cure HIV infection, so prevention of viral transmission remains extremely important. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having one or a few partners, and by using condoms. Male circumcision also reduces HIV transmission. In addition to reducing illness and death among HIV-positive people, ART also reduces HIV transmission.
Why Was This Study Done?
Effective HIV control requires an understanding of how HIV spreads through sexual networks. These networks include sexual partnerships between individuals in households, between community members in different households, and between individuals from different communities. Local sexual networks (household and intra-community sexual partnerships) are sometimes assumed to be the dominant driving force in HIV spread in sub-Saharan Africa, but are viral introductions from sexual partnerships with individuals outside the community also important? This question needs answering because the effectiveness of interventions such as ART as prevention partly depends on how many new infections in an intervention area are attributable to infection from partners residing in that area and how many are attributable to infection from partners living elsewhere. Here, the researchers use three analytical methods—spatial clustering statistics, viral phylogenetics, and egocentric transmission modeling—to ask whether HIV transmission in rural Uganda is driven predominantly by intra-community sexual networks. Spatial clustering analysis uses the geographical coordinates of households to measure the tendency of HIV-infected people to cluster spatially at scales consistent with community transmission. Viral phylogenetic analysis examines the genetic relatedness of viruses; if transmission is through local networks, viruses in newly infected individuals should more closely resemble viruses in other community members than those in people outside the community. Egocentric transmission modelling uses information on the locations of recent sexual partners to estimate the proportions of new transmissions from household, intra-community, and extra-community partners.
What Did the Researchers Do and Find?
The researchers applied their three analytical methods to data collected from 14,594 individuals living in 46 communities (governmental administrative units) in Rakai District, Uganda. Spatial clustering analysis indicated that individuals who lived in households with individuals with incident HIV (newly diagnosed) or prevalent HIV (previously diagnosed) were 3.2 times more likely than the general population to be HIV-positive themselves. Spatial clustering outside households was relatively weak, however, and was confined to distances of less than half a kilometer. Viral phylogenetic analysis indicated that 44% of phylogenetic clusters (viruses with related genetic sequences found in more than one individual) were within households, but that 40% of clusters crossed community borders. Finally, analysis of the locations of self-reported sexual partners indicated that 39% of new viral transmissions occurred within stable household partnerships, but that among people newly infected by extra-household partners, nearly two-thirds were infected by partners from outside their community.
What Do These Findings Mean?
The results of all three analyses suggest that HIV introductions into communities are frequent and are likely to play an important role in sustaining HIV transmission in the Rakai District. Specifically, within this rural HIV-endemic region (a region where HIV infection is always present), viral introductions combined with intra-household transmission account for the majority of new infections, although community-based sexual networks also play a critical role in HIV transmission. These findings may not be generalizable to the broader Ugandan population or to other regions of Africa, and their accuracy is likely to be limited by the use of self-reported sexual partner data. Nevertheless, these findings indicate that the dynamics of HIV transmission in rural Uganda (and probably elsewhere) are complex. Consequently, to halt the spread of HIV, prevention efforts will need to be implemented at spatial scales broader than individual communities, and key populations that are likely to introduce HIV into communities will need to be targeted.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda and on HIV prevention strategies (in English and Spanish)
The UNAIDS Report on the Global AIDS Epidemic 2013 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Center for AIDS Prevention Studies (University of California, San Francisco) has a fact sheet about sexual networks and HIV prevention
Wikipedia provides information on spatial clustering analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
Personal stories about living with HIV/AIDS are available through Avert, NAM/aidsmap, and Healthtalkonline
PMCID: PMC3942316  PMID: 24595023
14.  The introduction of solids in relation to asthma and eczema 
Archives of Disease in Childhood  2004;89(4):303-308.
Background: Despite scarce scientific evidence, current feeding guidelines recommend delayed introduction of solids for the prevention of asthma and allergy.
Aims: To explore whether late introduction of solids is protective against the development of asthma, eczema, and atopy.
Methods: A total of 642 children were recruited before birth and followed to the age of 5½ years. Main outcome measures were: doctor's diagnosis of eczema ever, atopy according to skin prick test results against inhalant allergens, preschool wheezing, transient wheezing, all defined at age 5–5½ years. Introduction of solids as main exposure measure was assessed retrospectively at age 1 year.
Results: There was no evidence for a protective effect of late introduction of solids for the development of preschool wheezing, transient wheezing, atopy, or eczema. On the contrary, there was a statistically significant increased risk of eczema in relation to late introduction of egg (aOR 1.6, 95% CI 1.1 to 2.4) and milk (aOR 1.7, 95% CI 1.1 to 2.5). Late introduction of egg was furthermore associated with a non-significant increased risk of preschool wheezing (aOR 1.5, 95% CI 0.92 to 2.4). There was no statistical evidence of feeding practices playing a different role in the development of asthma and eczema after stratification for parental asthma and atopy status.
Conclusions: Results do not support the recommendations given by present feeding guidelines stating that a delayed introduction of solids is protective against the development of asthma and allergy.
PMCID: PMC1719882  PMID: 15033835
15.  Predictors of the early introduction of solid foods in infants: results of a cohort study 
BMC Pediatrics  2009;9:60.
The early introduction of solid foods before 4 months of age has been associated with an increased risk of diarrhoea in infancy and a greater risk of wheeze and increased percentage body fat and weight in childhood. The purpose of this study was to identify the level of compliance with national recommendations related to the timing of the introduction of solid foods and to describe the maternal and infant characteristics associated with the timing of the introduction of solids.
Subjects were 519 participants in the second longitudinal Perth Infant Feeding Study (PIFS II) recruited from two maternity hospitals in Perth, Western Australia in 2002/3. Data collected prior to, or shortly after discharge from hospital, and at 4, 10, 16, 22, 32, 40 and 52 weeks postpartum included timing of the introduction of solid foods and a variety of maternal and infant characteristics associated with the introduction of solid foods. Multivariate logistic regression was used to identify those factors associated with the risk of introducing solid foods early, which for the purposes of this study was defined as being before 17 weeks.
The median age of introduction of solid foods was 17.6 weeks. In total, 44% of infants had received solids before 17 weeks and 93% of infants had received their first solids before 26 weeks of age. The strongest independent predictors of the early introduction of solids were young maternal age, mother smoking prior to pregnancy and not fully breastfeeding at 4 weeks postpartum. In general, mothers introduced solids earlier than recommended because they perceived their baby to either need them or be ready for them.
This study showed a high level of non-compliance among Australian mothers with the infant feeding recommendation related to the timing of solids that was current at the time. In order to improve compliance health professionals need to be aware of those groups least likely to comply with recommendations and their reasons for non-compliance. Infant feeding recommendations need to be evidence-based, uniformly supported by professionals and widely, clearly and consistently articulated if higher rates of compliance are to be achieved in the future.
PMCID: PMC2754451  PMID: 19772610
16.  Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis 
PLoS Medicine  2010;7(4):e1000256.
Beate Sander and colleagues assess the cost-effectiveness of the program that provides free seasonal influenza vaccines to the entire population of Ontario, Canada.
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Annual outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—make millions of people ill and kill about 500,000 individuals every year. In doing so, they impose a considerable economic burden on society in terms of health care costs and lost productivity. Influenza epidemics occur because small but frequent changes in the viral proteins to which the immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can boost this natural immunity and greatly reduce a person's chances of catching influenza. Consequently, many countries run seasonal influenza vaccine programs. These programs usually target people at high risk of complications from influenza and individuals likely to come into close contact with them, and people who provide essential community services. So, for example, in most Canadian provinces, targeted influenza immunization programs (TIIPs) offer free influenza vaccinations to people aged 65 years or older, to people with chronic medical conditions, and to health care workers.
Why Was This Study Done?
Some experts argue, however, that universal vaccination might provide populations with better protection from influenza. In 2000, the province of Ontario in Canada decided, therefore, to introduce a universal influenza immunization program (UIIP) to provide free influenza vaccination to everyone older than 6 months, the first large program of this kind in the world. A study published in 2008 showed that, following the introduction of the UIIP, vaccination rates in Ontario increased more than in other Canadian provinces. In addition, deaths from influenza and influenza-related use of health care facilities decreased more in Ontario than in provinces that continued to offer a TIIP. But is universal influenza vaccination good value for money? In this study, the researchers evaluate the cost-effectiveness of the Ontario UIIP by comparing the health outcomes and costs associated with its introduction with the health outcomes and costs associated with a hypothetical continuation of targeted influenza immunization.
What Did the Researchers Do and Find?
The researchers used data on TIIP and UIIP vaccine uptake, physician visits, emergency department visits, hospitalizations for influenza, and deaths from influenza between 1997 and 2004 in Ontario and in nine Canadian states offering TIIPs, and Ontario cost data, in their “cost-utility” analysis. This type of analysis estimates the additional cost required to generate a year of perfect health (a quality-adjusted life-year or QALY) through the introduction of an intervention. QALYs are calculated by multiplying the time spent in a certain health state by a measure of the quality of that health state. The researchers report that the cost of Ontario's UIIP was about twice as much as the cost of a TIIP for the province. However, the introduction of the UIIP reduced the number of influenza cases by nearly two-thirds and reduced deaths from influenza by more than a quarter compared with what would have been expected had the province continued to offer a TIIP, an overall saving of 1,134 QALYs. Furthermore, the reduction in influenza cases halved influenza-related health care costs, mainly because of reductions in hospitalization. Overall, this means that the additional cost to Ontario of saving one QALY through the introduction of the UIIP was Can$10,797, an “incremental cost-effectiveness ratio” of $10,797 per QALY gained.
What Do These Findings Mean?
In Canada, an intervention is considered cost-effective from the point of view of a health care purchaser if it costs less than Canadian $50,000 to gain one QALY. These findings indicate, therefore, that for Ontario the introduction of the UIIP is economically attractive. Indeed, the researchers calculate that even if the costs of the UIIP were to double, the additional cost of saving one QALY by introducing universal immunization would remain below $50,000. Other “sensitivity” analyses undertaken by the researchers also indicate that universal immunization is likely to be effective and cost-effective in Ontario if other key assumptions and/or data included in the calculations are varied within reasonable limits. Given these findings, the researchers suggest that a UIIP might be an appealing intervention in other Canadian provinces and in other high-income countries where influenza transmission and health-care costs are broadly similar to those in Ontario.
Additional Information
Please access these Web sites via the online version of this summary at
A PLoS Medicine Research Article by Kwong and colleagues describes how the introduction of universal influenza immunization in Ontario altered influenza-related health care use and deaths in the province
Wikipedia pages are available on QALYs and on cost-utility analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Bandolier, an independent online journal about evidence-based health-care, provides information about QALYs and their use in cost-utility analysis
The UK National Institute for Health and Clinical Excellence has a webpage on Measuring effectiveness and cost-effectiveness: the QALY
PMCID: PMC2850382  PMID: 20386727
17.  Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis 
PLoS Medicine  2011;8(4):e1001024.
A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age.
In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings
National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ∼1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
Please see later in the article for the Editors' Summary
Editors' Summary
Diarrheal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. As highlighted in a recent PLoS Medicine series, access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation.
Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country's national immunization programs.
Why Was This Study Done?
Although the protective effect of rotavirus vaccines has been assessed in various high-, middle-, and low-income settings, for reasons that remain unclear, the efficacy of live, oral rotavirus vaccines appears to be dependent on geographical location and correlated to the socioeconomic status of the population. Because of these concerns, evaluating the health impact of large-scale rotavirus vaccine programs and ensuring their equity in a real-world setting (rather than in clinical trial conditions) is important.
Therefore, the researchers addressed this issue by conducting this study to evaluate the effect of rotavirus vaccination on mortality and hospital admissions for diarrhea due to all causes among young children in the five regions of Brazil. The researchers chose to do this study in Brazil because of the high incidence of diarrhea-related deaths and hospital admissions and because five years ago, in July 2006, the Brazilian Ministry of Health introduced the single-strain rotavirus vaccine simultaneously in all 27 states through its national immunization program—allowing for “before” and “after” intervention analysis.
What Did the Researchers Do and Find?
The researchers obtained data on diarrheal deaths and hospital admissions in children aged under five years for the period 2002–2005 and 2007–2009 and data on rotavirus vaccination rates. The researchers got the data on diarrhea deaths from the Brazilian Mortality Information System—the national database of information collected from death certificates that covers 90% of all deaths in Brazil. The data on hospital admissions came from the electronic Hospital Information System of Brazil's Unified Health System (Sistema Unico de Saúde, SUS)—the publicly funded health-care system that covers roughly 70% of the hospitalizations and includes information on all admissions (from public hospitals and some private hospitals) authorized for payment by the Unified Health System. The researchers got regional rotavirus vaccination coverage estimates for 2007–2009 from the information department of the Ministry of Health, and estimated coverage of the two doses of oral rotavirus vaccine by taking the annual number of second doses administered divided by the number of infants in the region.
In 2007, an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009, this proportion rose to 84% of children younger than one year of age. The researchers found that in the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were respectively 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrhea deaths and 130,000 fewer admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not eligible for vaccination during the study period (aged 2–4 years).
What Do These Findings Mean?
These findings suggest that the introduction of rotavirus vaccination in all areas of Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children aged under five years. These real-world impact data are consistent with the clinical trials and strengthen the evidence base for rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
These findings have important global policy implications. In middle-income countries, such as Brazil, that are not eligible for financial support from donors, the potential reductions in admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these still relatively expensive vaccines.
Additional Information
Please access these Web sites via the online version of this summary at
PLoS Medicine has published a series on water and sanitation
More information is available from the World Health Organization on diarrheal illness in children
More information is available about rotavirus vaccines from the World Health Organization, the US Centers for Disease Control and Prevention, and the Rotavirus Vaccine Program
PMCID: PMC3079643  PMID: 21526228
18.  Modeling Dynamic Introduction of Chikungunya Virus in the United States 
Chikungunya is a mosquito-borne viral infection of humans that previously was confined to regions in central Africa. However, during this century, the virus has shown surprising potential for geographic expansion as it invaded other countries including more temperate regions. With no vaccine and no specific treatment, the main control strategy for Chikungunya remains preventive control of mosquito populations. In consideration for the risk of Chikungunya introduction to the US, we developed a model for disease introduction based on virus introduction by one individual. Our study combines a climate-based mosquito population dynamics stochastic model with an epidemiological model to identify temporal windows that have epidemic risk. We ran this model with temperature data from different locations to study the geographic sensitivity of epidemic potential. We found that in locations with marked seasonal variation in temperature there also was a season of epidemic risk matching the period of the year in which mosquito populations survive and grow. In these locations controlling mosquito population sizes might be an efficient strategy. But, in other locations where the temperature supports mosquito development all year the epidemic risk is high and (practically) constant. In these locations, mosquito population control alone might not be an efficient disease control strategy and other approaches should be implemented to complement it. Our results strongly suggest that, in the event of an introduction and establishment of Chikungunya in the US, endemic and epidemic regions would emerge initially, primarily defined by environmental factors controlling annual mosquito population cycles. These regions should be identified to plan different intervention measures. In addition, reducing vector: human ratios can lower the probability and magnitude of outbreaks for regions with strong seasonal temperature patterns. This is the first model to consider Chikungunya risk in the US and can be applied to other vector borne diseases.
Author Summary
Chikungunya fever is a mosquito-borne viral infection showing a surprising potential for geographic expansion. Similar to other tropical infectious diseases having no vaccine and no specific treatment, the main control strategy for Chikungunya remains reduction of mosquito population size. We developed a model for disease introduction that combines a climate based mosquito population dynamics stochastic model with an epidemiological model in order to identify temporal windows during which disease introduction through one exposed individual might compromise the health status of the entire human population. We ran this model with temperature data from different locations showing the geographic sensitivity of this risk. The identification of temporal windows with epidemic risk at different spatial locations is key to guiding mosquito population control campaigns. Locations with marked seasonal variation also have a season with high epidemic risk matching the period in which mosquito populations survive and grow, therefore controlling mosquito population sizes might be an optimal strategy in those areas. However, locations with other temperature patterns may need additional control strategies to avoid epidemics. To our knowledge, this is the first model to explore Chikungunya introduction in the USA. Our modeling approach can be used for other vector borne diseases and can be expanded to compare the outcome with different control strategies.
PMCID: PMC3510155  PMID: 23209859
19.  New parasites and predators follow the introduction of two fish species to a subarctic lake: implications for food-web structure and functioning 
Oecologia  2012;171(4):993-1002.
Introduced species can alter the topology of food webs. For instance, an introduction can aid the arrival of free-living consumers using the new species as a resource, while new parasites may also arrive with the introduced species. Food-web responses to species additions can thus be far more complex than anticipated. In a subarctic pelagic food web with free-living and parasitic species, two fish species (arctic charr Salvelinus alpinus and three-spined stickleback Gasterosteus aculeatus) have known histories as deliberate introductions. The effects of these introductions on the food web were explored by comparing the current pelagic web with a heuristic reconstruction of the pre-introduction web. Extinctions caused by these introductions could not be evaluated by this approach. The introduced fish species have become important hubs in the trophic network, interacting with numerous parasites, predators and prey. In particular, five parasite species and four predatory bird species depend on the two introduced species as obligate trophic resources in the pelagic web and could therefore not have been present in the pre-introduction network. The presence of the two introduced fish species and the arrival of their associated parasites and predators increased biodiversity, mean trophic level, linkage density, and nestedness; altering both the network structure and functioning of the pelagic web. Parasites, in particular trophically transmitted species, had a prominent role in the network alterations that followed the introductions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00442-012-2461-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3612402  PMID: 23053223
Non-native species; Pelagic community; Species additions; Topology; Trophic interactions
20.  Introduction of New Vaccines: Decision-making Process in Bangladesh 
The understanding of the decision-making process in the introduction of new vaccines helps establish why vaccines are adopted or not. It also contributes to building a sustainable demand for vaccines in a country. The purpose of the study was to map and analyze the formal decision-making process in relation to the introduction of new vaccines within the context of health policy and health systems and identify the ways of making decisions to introduce new vaccines in Bangladesh. During February-April 2011, a qualitative assessment was made at the national level to evaluate the decision-making process around the adoption of new vaccines in Bangladesh. The study population included: policy-level people, programme heads or associates, and key decision-makers of the Government, private sector, non-governmental organizations, and international agencies at the national level. In total, 13 key informants were purposively selected. Data were collected by interviewing key informants and reviewing documents. Data were analyzed thematically. The findings revealed that the actors from different sectors at the policy level were involved in the decision-making process in the introduction of new vaccines. They included policy-makers from the ministries of health and family welfare, finance, and local government and rural development; academicians; researchers; representatives from professional associations; development partners; and members of different committees on EPI. They contributed to the introduction of new vaccines in their own capacity. The burden of disease, research findings on vaccine-preventable diseases, political issues relating to outbreaks of certain diseases, initiatives of international and local stakeholders, pressure of development partners, the Global Alliance for Vaccines and Immunization (GAVI) support, and financial matters were the key factors in the introduction of new vaccines in Bangladesh. The slow introduction and uptake of new vaccines is a concern in the country. Rapid action on the application of GAVI support and less time taken by the Government in processing the implementation and administrative work may expedite the introduction of new vaccines in future in this country.
PMCID: PMC3702342  PMID: 23930339
Decision-making; Qualitative research; Vaccines; Bangladesh
21.  Family and infant characteristics associated with timing of core and non-core food introduction in early childhood 
To identify family and infant characteristics associated with timing of introduction of two food types: core foods (nutrient-dense) and non-core foods (nutrient-poor) in a population-based sample of mothers and infants.
Participants were 1861 mothers and infants from the Gemini twin birth cohort (one child per family). Family and infant characteristics were assessed when the infants were around 8 months old. Timing of introducing core and non-core foods was assessed at 8 and 15 months. As the distributions of timing were skewed, three similar-sized groups were created for each food type: earlier (core: 1–4 months; non-core: 3–8 months), average (core: 5 months; non-core: 9–10 months), and later introduction (core: 6–12 months; non-core: 11–18 months). Ordinal logistic regression was used to examine predictors of core and non-core food introduction, with bootstrapping to test for differences between the core and non-core models.
Younger maternal age, lower education level, and higher maternal BMI were associated with earlier core and non-core food introduction. Not breastfeeding for at least 3 months and higher birth weight were specifically associated with earlier introduction of core foods. Having older children was specifically associated with earlier introduction of non-core foods.
There are similarities and differences in the characteristics associated with earlier introduction of core and non-core foods. Successful interventions may require a combination of approaches to target both food types.
PMCID: PMC3674911  PMID: 23486509
Infant feeding; core foods; non-core foods
22.  Spatial Genetic Heterogeneity in Populations of a Newly Invasive Whitefly in China Revealed by a Nation-Wide Field Survey 
PLoS ONE  2013;8(11):e79997.
Even though introductions of exotic species provide ready-made experiments of rapid evolution, few studies have examined the genetic structure of an exotic species shortly after its initial introduction and subsequent spread. To determine the genetic structure of its populations during the initial introduction, we investigated the invasive sweet potato whitefly (Bemisia tabaci Q, commonly known as B. tabaci biotype Q) in China, which was introduced in approximately 2003. A total of 619 B. tabaci Q individuals in 20 provinces throughout China were collected and analyzed using five microsatellite loci.
The introduced populations of B. tabaci Q in China represent eight genetic clusters with different geographic distributions. The populations in Yunnan Province, where B. tabaci Q was first detected, are genetically different from the other populations in China.
The introduced populations of B. tabaci Q in China have high spatial genetic heterogeneity. Additional research is required to determine whether the heterogeneity results from multiple introductions, rapid evolution following one or few introductions, or some combination of multiple introductions and rapid evolution. The heterogeneity, however, is inconsistent with a single introduction at Yunnan Province, where B. tabaci Q was first detected, followed by spread.
PMCID: PMC3841195  PMID: 24302995
23.  The timing of introduction of pharmaceutical innovations in seven European countries 
Rationale, aims and objectives
Differences in the performance of medical care may be due to variation in the introduction and diffusion of medical innovations. The objective of this paper is to compare seven European countries (United Kingdom, the Netherlands, West Germany, France, Spain, Estonia and Sweden) with regard to the year of introduction of six specific pharmaceutical innovations (antiretroviral drugs, cimetidine, tamoxifen, cisplatin, oxalaplatin and cyclosporin) that may have had important population health impacts.
We collected information on introduction and further diffusion of drugs using searches in the national and international literature, and questionnaires to national informants. We combined various sources of information, both official years of registration and other indicators of introduction (clinical trials, guidelines, evaluation reports, sales statistics).
Results and conclusions
The total length of the period between first and last introduction varied between 8 years for antiretroviral drugs and 22 years for cisplatin. Introduction in Estonia was generally delayed until the 1990s. The average time lags were smallest in France (2.2 years), United Kingdom (2.8 years) and the Netherlands (3.5 years). Similar rank orders were seen for year of registration suggesting that introduction lags are not only explained by differences in the process of registration. We discuss possible reasons for these between-country differences and implications for the evaluation of medical care.
PMCID: PMC4282430  PMID: 24750393
health systems; medical care; mortality; outcome measures; pharmaceuticals; quality of care
24.  Effect of chlorocamphene on the isoenzyme spectrum of lactate dehydrogenase in rat serum and liver. 
Rats were used to study the general activity and the isoenzyme spectrum of lactate dehydrogenase (LDH) during single-instance and long-term introduction of polychlorocamphene. Total lactate dehydrogenase activity decreases in the liver during the single-instance introduction of half the LD50 (120 mg/kg). The isoenzyme spectrum of LDH is characterized by an increase in the quantity of LDH1, LDH2, and LDH3 and by a decrease in the amount of LDH4. The overall LDH activity does not change in blood serum. The isoform ratio changes insignificantly and LDH1 falls, but normalized 15 days after the introduction of the compound. Long-term introduction of polychlorocamphene at levels 1/100 the LD50 dose over 1.3 and 6 months causes a reduction in the overall LDH activity, both in the liver and in the serum. A decrease in the activity of the basic LDH isoenzyme of the liver (LDH5) and a sharp increase in LDH3 are characteristic for the isoenzyme spectrum of the liver. LDH1 and LDH4 decrease and LDH2 and LDH3 increase in blood serum. Beginning with the third month of polychlorocamphene introduction, LDH1 tends to return to normal levels. LDH2, LDH3, and LDH4 do return to normal levels, while LDH5 increases regularly. This results in a reduction of the number of H subunits and an increase of M subunits. This is characteristic of hypoxic states. On comparing the changes in the LDH enzymes of the liver and blood serum, it can be considered that the introduction of polychlorocamphene does not result in an increase in the permeability of the cellular membranes of the liver for LDH isoenzymes, while the observed isoenzyme spectrum shifts in blood serum are either the result of the biosynthesis of the isoforms of this enzyme changed by the compound or the result of the permeability for them of cells of other tissues.
PMCID: PMC1475013  PMID: 1269500
25.  Changes in hospital costs after introducing an intermediate care unit: a comparative observational study 
Critical Care  2008;12(3):R68.
The high cost of critical care resources has resulted in strategies to reduce the costs of ruling out low-risk patients by developing intermediate care units (IMCs). The aim of this study was to compare changes in total hospital costs for intensive care patients before and after the introduction of an IMC at the University Hospital Maastricht.
The design was a comparative longitudinal study. The setting was a university hospital with a mixed intensive care unit (ICU), an IMC, and general wards. Changes in total hospital costs were measured for patients who were admitted to the ICU before and after the introduction of the IMC. The comparison of interest was the opening of a six-bed mixed IMC.
The mean total hospital cost per patient increased significantly. Before the introduction of the IMC, the total hospital cost per patient was €12,961 (± €14,530) and afterwards it rose to €16,513 (± €17,718). Multiple regression analysis was used to determine to what extent patient characteristics explained these higher hospital costs using mortality, type of stay, diagnostic categories, length of ICU and ward stay, and the Therapeutic Intervention Scoring System (TISS) as predictors. More surgical patients, greater requirements of therapeutic interventions on the ICU admission day, and longer ICU stay in patients did explain the increase in hospital costs, rather than the introduction of the IMC.
After the introduction of the IMC, the higher mean total hospital costs for patients with a high TISS score and longer ICU stay explained the cost increase.
PMCID: PMC2481456  PMID: 18482443

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