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1.  Selective and Genetic Constraints on Pneumococcal Serotype Switching 
PLoS Genetics  2015;11(3):e1005095.
Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into “serogroups” based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such “serotype switching” events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage. Eleven of these were within-serogroup switches, representing a highly significant (p < 0.0001) enrichment based on the observed serotype distribution. Whereas the recombinations resulting in between-serogroup switches all spanned the entire cps locus, some of those that caused within-serogroup switches did not. However, higher rates of within-serogroup switching could not be fully explained by either more frequent, shorter recombinations, nor by genetic linkage to genes involved in β–lactam resistance. This suggested the observed pattern was a consequence of selection for preserving serogroup. Phenotyping of strains constructed to express different serotypes in common genetic backgrounds was used to test whether genotypes were physiologically adapted to particular serogroups. These data were consistent with epistatic interactions between the cps locus and the rest of the genome that were specific to serotype, but not serogroup, meaning they were unlikely to account for the observed distribution of capsule types. Exclusion of these genetic and physiological hypotheses suggested future work should focus on alternative mechanisms, such as host immunity spanning multiple serotypes within the same serogroup, which might explain the observed pattern.
Author Summary
Streptococcus pneumoniae is a major respiratory pathogen responsible for a high burden of morbidity and mortality worldwide. Current anti-pneumococcal vaccines target the bacterium’s polysaccharide capsule, of which at least 95 different variants (‘serotypes’) are known, which are classified into ‘serogroups’. Bacteria can change their serotype through genetic recombination, termed ‘switching’, which can allow strains to evade vaccine-induced immunity. By combining epidemiological data with whole genome sequencing, this work finds a robust and unexpected pattern of serotype switching in a sample of bacteria collected following the introduction of routine anti-pneumococcal vaccination: switching was much more likely to exchange one serotype for another within the same serogroup than expected by chance. Several hypotheses are presented and tested to explain this pattern, including limitations of genetic recombination, interactions between the genes that determine serotype and the rest of the genome, and the constraints imposed by bacterial metabolism. This provides novel information on the evolution of S. pneumoniae, particularly regarding how the bacterium might diversify as newer vaccines are introduced.
PMCID: PMC4380333  PMID: 25826208
2.  Impact of 13-Valent Pneumococcal Conjugate Vaccination on Streptococcus pneumoniae Carriage in Young Children in Massachusetts 
In April 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 for use in the United States. We evaluated rates of pneumococcal colonization, by serotype and antibiotic resistance, in Massachusetts communities where serial cross-sectional surveillance has been conducted for the past decade.
Nasopharyngeal swabs were obtained from children 0 to <7 years of age and seen by primary care providers for well child or acute illness visits in 2001, 2004, 2007, 2009, and 2011. Pneumococcal isolates were serotyped by Quellung reaction and classified as PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F), additional PCV13 serotypes (1, 3, 5, 6A, 7F, 19A), or non-PCV13 serotypes. Changes in colonization and impact of PCV13 were assessed using generalized linear mixed models, adjusting for known risk factors and accounting for clustering by community.
Introduction of PCV13 did not affect the rate of overall pneumococcal colonization (31% in 2011). Colonization with non-PCV13 serotypes increased between 2001 and 2011 for all children (odds ratio [OR] per year, 1.12; 95% confidence interval [CI], 1.10, 1.15; P < .0001). 19A remained the second most common serotype in 2011, although a decline from 2009 was observed. Penicillin (7%), erythromycin (28%), ceftriaxone (10%), and clindamycin (10%) nonsusceptibility were commonly identified, concentrated among a small number of serotypes (including 19A, 35B, 15B/C, and 15A). Among healthy children 6–23 months old, colonization with PCV13 serotypes was lower among recipients of PCV13 vaccine (adjusted OR, 0.30; 95% CI, 0.11, 0.78). This effect was not observed in 6- to 23-month-old children with a concomitant respiratory tract infection (adjusted OR 1.36; 95% CI, 0.66, 2.77) or children 2 to <7 years old (adjusted OR, 1.17; 95% CI, 0.58, 2.34).
13-Valent pneumococcal conjugate vaccine reduced the prevalence of colonization with PCV13 serotypes among children 6–23 months old, but its efficacy was not shown among older children.
PMCID: PMC3933044  PMID: 24567842
colonization; pneumococcal conjugate vaccine; Streptococcus pneumoniae
3.  Recent Trends in Outpatient Antibiotic Use in Children 
Pediatrics  2014;133(3):375-385.
The goal of this study was to determine changes in antibiotic-dispensing rates among children in 3 health plans located in New England [A], the Mountain West [B], and the Midwest [C] regions of the United States.
Pharmacy and outpatient claims from September 2000 to August 2010 were used to calculate rates of antibiotic dispensing per person-year for children aged 3 months to 18 years. Differences in rates by year, diagnosis, and health plan were tested by using Poisson regression. The data were analyzed to determine whether there was a change in the rate of decline over time.
Antibiotic use in the 3- to <24-month age group varied at baseline according to health plan (A: 2.27, B: 1.40, C: 2.23 antibiotics per person-year; P < .001). The downward trend in antibiotic dispensing slowed, stabilized, or reversed during this 10-year period. In the 3- to <24-month age group, we observed 5.0%, 9.3%, and 7.2% annual declines early in the decade in the 3 plans, respectively. These dropped to 2.4%, 2.1%, and 0.5% annual declines by the end of the decade. Third-generation cephalosporin use for otitis media increased 1.6-, 15-, and 5.5-fold in plans A, B, and C in young children. Similar attenuation of decline in antibiotic use and increases in use of broad-spectrum agents were seen in other age groups.
Antibiotic dispensing for children may have reached a new plateau. Along with identifying best practices in low-prescribing areas, decreasing broad-spectrum use for particular conditions should be a continuing focus of intervention efforts.
PMCID: PMC3934343  PMID: 24488744
antibiotics; otitis media; respiratory tract infections
4.  Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced 
The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced.
We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010–11 and used eBURST software to compare the pneumococcal population structure with that found in previous years.
One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones.
While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0797-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4336693  PMID: 25887323
Pneumococcal conjugate vaccine; Streptococcus pneumoniae; Colonization; Molecular epidemiology; MLST
5.  Adverse Events Associated with Prolonged Antibiotic Use 
The Infectious Diseases Society of America and US CDC recommend 60 days of ciprofloxacin, doxycycline or amoxicillin for anthrax prophylaxis. It is not possible to determine severe adverse drug event (ADE) risks from the few people thus far exposed to anthrax prophylaxis. This study’s objective was to estimate risks of severe ADEs associated with long-term ciprofloxacin, doxycycline and amoxicillin exposure using 3 large databases: one electronic medical record (General Practice Research Database) and two claims databases (UnitedHealthcare, HMO Research Network).
We include office visit, hospital admission and prescription data for 1/1/1999–6/30/2001. Exposure variable was oral antibiotic person-days (pds). Primary outcome was hospitalization during exposure with ADE diagnoses: anaphylaxis, phototoxicity, hepatotoxicity, nephrotoxicity, seizures, ventricular arrhythmia or infectious colitis.
We randomly sampled 999,773, 1,047,496 and 1,819,004 patients from Databases A, B and C respectively. 33,183 amoxicillin, 15,250 ciprofloxacin and 50,171 doxycycline prescriptions continued ≥30 days. ADE hospitalizations during long-term exposure were not observed in Database A. ADEs during long-term amoxicillin were seen only in Database C with 5 ADEs or 1.2(0.4–2.7) ADEs/100,000 pds exposure. Long-term ciprofloxacin showed 3 and 4 ADEs with 5.7(1.2–16.6) and 3.5(1.0–9.0) ADEs/100,000 pds in Databases B and C, respectively. Only Database B had ADEs during long-term doxycycline with 3 ADEs or 0.9(0.2–2.6) ADEs/100,000 pds. For most events, the incidence rate ratio, comparing >28 vs.1–28 pds exposure was <1, showing limited evidence for cumulative dose-related ADEs from long-term exposure.
Long-term amoxicillin, ciprofloxacin and doxycycline appears safe, supporting use of these medications if needed for large-scale post-exposure anthrax prophylaxis.
PMCID: PMC4269235  PMID: 18215001
Anti-infective agents; Anthrax prevention and control; Health services research; Databases; Bioterrorism
6.  Deceased Donor Liver Transplantation in Infants and Small Children: Are Partial Grafts Riskier Than Whole Organs? 
Infants have the highest waitlist mortality of all liver transplant candidates. While previous studies have demonstrated that young children may be at increased risk when receiving partial grafts from adult and adolescent deceased donors (DD), with few size-matched organs available, these grafts have increasingly been used to expand the pediatric donor pool. We aimed to determine the current adjusted risk of graft failure and mortality in young pediatric recipients of DD partial livers, and to determine if these risks have changed over time.
We analyzed 2,683 first-time DD liver-alone recipients under the age of 2 years in the UNOS database (1995-2010), including 1,118 DD partial livers and 1,565 DD whole organs. Transplant factors associated with graft loss on bivariate analyses (p<0.1) were included in multivariable proportional hazards models of graft and patient survival. Interaction analysis was used to examine risks over time (time-periods:1995-2000, 2001-2005, 2006-2010).
While there were significant differences in crude graft survival by graft type in 1995-2000 (p<.001), graft survival between partial and whole grafts was comparable in 2001-2005 (p=.43) and 2006-2010 (p=.36). Furthermore, while the adjusted hazards of partial graft failure and mortality were 1.40 (1.05-1.89) and 1.41 (.95-2.09) respectively in 1995-2000, the adjusted risk of graft failure and mortality was comparable between partial and whole organs in 2006-2010 (Graft failure HR .81 95%CI .56-1.18; Mortality HR 1.02 95%CI .66-1.71).
Deceased-donor partial liver transplantation has become less risky over time, and now has comparable outcomes to whole liver transplantation in infants and young children.
PMCID: PMC3837552  PMID: 23696310
Pediatrics; partial liver; risk factors; multivariate analysis; United Network of Organ Sharing
To examine barriers to health care transition reported by young adults with type 1 diabetes and associations between barriers and prolonged gaps between pediatric and adult diabetes care.
We surveyed young adults aged 22 to 30 years with type 1 diabetes about their transition experiences, including barriers to timely establishment of adult diabetes care. We evaluated relationships between barriers and gaps in care using multivariate logistic regression.
The response rate was 53% (258 of 484 eligible subjects). Respondents (62% female) were 26.7 ± 2.4 years old and transitioned to adult diabetes care at 19.5 ± 2.9 years. Reported barriers included lack of specific adult provider referral name (47%) or contact information (27%), competing life priorities (43%), difficulty getting an appointment (41%), feeling upset about leaving pediatrics (24%), and insurance problems (10%). In multivariate analysis, barriers most strongly associated with gaps in care >6 months were lack of adult provider name (odds ratio [OR], 6.1; 95% confidence interval [CI], 3.0–12.7) or contact information (OR, 5.3; 95% CI, 2.0–13.9), competing life priorities (OR, 5.2; 95% CI, 2.7–10.3), and insurance problems (OR, 3.5; 95% CI, 1.2–10.3). Overall, respondents reporting ≥1 moderate/major barrier (48%) had 4.7-fold greater adjusted odds of a gap in care >6 months (95% CI, 2.8–8.7).
Significant barriers to transition, such as a lack of specific adult provider referrals, may be addressed with more robust preparation by pediatric providers and care coordination. Further study is needed to evaluate strategies to improve young adult self-care in the setting of competing life priorities.
PMCID: PMC4034180  PMID: 23807526
8.  Attributable healthcare utilization and cost of pneumonia due to drug-resistant streptococcus pneumonia: a cost analysis 
The burden of disease due to S. pneumoniae (pneumococcus), particularly pneumonia, remains high despite the widespread use of vaccines. Drug resistant strains complicate clinical treatment and may increase costs. We estimated the annual burden and incremental costs attributable to antibiotic resistance in pneumococcal pneumonia.
We derived estimates of healthcare utilization and cost (in 2012 dollars) attributable to penicillin, erythromycin and fluoroquinolone resistance by taking the estimate of disease burden from a previously described decision tree model of pneumococcal pneumonia in the U.S. We analyzed model outputs assuming only the existence of susceptible strains and calculating the resulting differences in cost and utilization. We modeled the cost of resistance from delayed resolution of illness and the resulting additional health services.
Our model estimated that non-susceptibility to penicillin, erythromycin and fluoroquinolones directly caused 32,398 additional outpatient visits and 19,336 hospitalizations for pneumococcal pneumonia. The incremental cost of antibiotic resistance was estimated to account for 4% ($91 million) of direct medical costs and 5% ($233 million) of total costs including work and productivity loss. Most of the incremental medical cost ($82 million) was related to hospitalizations resulting from erythromycin non-susceptibility. Among patients under age 18 years, erythromycin non-susceptibility was estimated to cause 17% of hospitalizations for pneumonia and $38 million in costs, or 39% of pneumococcal pneumonia costs attributable to resistance.
We estimate that antibiotic resistance in pneumococcal pneumonia leads to substantial healthcare utilization and cost, with more than one-third driven by macrolide resistance in children. With 5% of total pneumococcal costs directly attributable to resistance, strategies to reduce antibiotic resistance or improve antibiotic selection could lead to substantial savings.
PMCID: PMC4029811  PMID: 24851182
Streptococcus pneumoniae; Antibiotic resistance; Healthcare utilization; DRSP
9.  PEDSnet: a National Pediatric Learning Health System 
A learning health system (LHS) integrates research done in routine care settings, structured data capture during every encounter, and quality improvement processes to rapidly implement advances in new knowledge, all with active and meaningful patient participation. While disease-specific pediatric LHSs have shown tremendous impact on improved clinical outcomes, a national digital architecture to rapidly implement LHSs across multiple pediatric conditions does not exist. PEDSnet is a clinical data research network that provides the infrastructure to support a national pediatric LHS. A consortium consisting of PEDSnet, which includes eight academic medical centers, two existing disease-specific pediatric networks, and two national data partners form the initial partners in the National Pediatric Learning Health System (NPLHS). PEDSnet is implementing a flexible dual data architecture that incorporates two widely used data models and national terminology standards to support multi-institutional data integration, cohort discovery, and advanced analytics that enable rapid learning.
PMCID: PMC4078288  PMID: 24821737
comparative effectivness research; distributed databases; data sharing; inflammatory bowel diseases; hypoplastic left heart syndrome; obesity
10.  Leveraging Text Messaging and Mobile Technology to Support Pediatric Obesity-Related Behavior Change: A Qualitative Study Using Parent Focus Groups and Interviews 
Text messaging (short message service, SMS) is a widely accessible and potentially cost-effective medium for encouraging behavior change. Few studies have examined text messaging interventions to influence child health behaviors or explored parental perceptions of mobile technologies to support behavior change among children.
Our aim was to examine parental acceptability and preferences for text messaging to support pediatric obesity-related behavior change.
We conducted focus groups and follow-up interviews with parents of overweight and obese children, aged 6-12 years, seen for “well-child” care in eastern Massachusetts. A professional moderator used a semistructured discussion guide and sample text messages to catalyze group discussions. Seven participants then received 3 weeks of text messages before a follow-up one-on-one telephone interview. All focus groups and interviews were recorded and transcribed verbatim. Using a framework analysis approach, we systematically coded and analyzed group and interview data to identify salient and convergent themes.
We reached thematic saturation after five focus groups and seven follow-up interviews with a total of 31 parents of diverse race/ethnicity and education levels. Parents were generally enthusiastic about receiving text messages to support healthy behaviors for their children and preferred them to paper or email communication because they are brief and difficult to ignore. Participants anticipated high responsiveness to messaging endorsed by their child’s doctor and indicated they would appreciate messages 2-3 times/week or more as long as content remains relevant. Suggestions for maintaining message relevance included providing specific strategies for implementation and personalizing information. Most felt the negative features of text messaging (eg, limited message size) could be overcome by providing links within messages to other media including email or websites.
Text messaging is a promising medium for supporting pediatric obesity-related behavior change. Parent perspectives could assist in the design of text-based interventions.
Trial Registration NCT01565161; (Archived by WebCite at
PMCID: PMC3869083  PMID: 24317406
child; obesity; overweight; health behavior; text messaging; telemedicine
11.  Population genomics of post-vaccine changes in pneumococcal epidemiology 
Nature genetics  2013;45(6):10.1038/ng.2625.
Whole genome sequencing of 616 asymptomatically carried pneumococci was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates revealed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant pre-vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the fall in pneumococcal disease rates after the vaccine’s introduction.
PMCID: PMC3725542  PMID: 23644493
12.  Population genomics of post-vaccine changes in pneumococcal epidemiology 
Nature genetics  2013;45(6):10.1038/ng.2625.
Whole genome sequencing of 616 asymptomatically carried pneumococci was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates revealed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant pre-vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the fall in pneumococcal disease rates after the vaccine’s introduction.
PMCID: PMC3725542  PMID: 23644493
13.  Transition experiences and health care utilization among young adults with type 1 diabetes 
The purpose of this study was to describe the current status of adult diabetes care in young adults with type 1 diabetes and examine associations between health care transition experiences and care utilization.
We developed a survey to assess transition characteristics and current care in young adults with type 1 diabetes. We mailed the survey to the last known address of young adults who had previously received diabetes care at a tertiary pediatric center.
Of 291 surveys sent, 83 (29%) were undeliverable and three (1%) were ineligible. Of 205 surveys delivered, 65 were returned (response rate 32%). Respondents (mean age 26.6 ± 3.0 years, 54% male, 91% Caucasian) transitioned to adult diabetes care at a mean age of 19.2 ± 2.8 years. Although 71% felt mostly/completely prepared for transition, only half received recommendations for a specific adult provider. Twenty-six percent reported gaps exceeding six months between pediatric and adult diabetes care. Respondents who made fewer than three diabetes visits in the year prior to transition (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.2–16.5) or cited moving/relocation as the most important reason for transition (OR 6.3, 95% CI 1.3–31.5) were more likely to report gaps in care exceeding six months. Patients receiving current care from an adult endocrinologist (79%) were more likely to report at least two diabetes visits in the past year (OR 6.0, 95% CI 1.5–24.0) compared with those receiving diabetes care from a general internist/adult primary care doctor (17%). Two-thirds (66%) reported receiving all recommended diabetes screening tests in the previous year, with no difference according to provider type.
In this sample, transition preparation was variable and one quarter reported gaps in obtaining adult diabetes care. Nevertheless, the majority endorsed currently receiving regular diabetes care, although visit frequency differed by provider type. Because locating patients after transition was incomplete, our findings suggest the need for standardized methods to track transitioning patients.
PMCID: PMC3749062  PMID: 23990711
type 1 diabetes mellitus; health care delivery; young adults; transition to adult care
14.  Health Care Transition in Patients With Type 1 Diabetes 
Diabetes Care  2012;35(8):1716-1722.
To examine characteristics of the transition from pediatric to adult care in emerging adults with type 1 diabetes and evaluate associations between transition characteristics and glycemic control.
We developed and mailed a survey to evaluate the transition process in emerging adults with type 1 diabetes, aged 22 to 30 years, receiving adult diabetes care at a single center. Current A1C data were obtained from the medical record.
The response rate was 53% (258 of 484 eligible). The mean transition age was 19.5 ± 2.9 years, and 34% reported a gap >6 months in establishing adult care. Common reasons for transition included feeling too old (44%), pediatric provider suggestion (41%), and college (33%). Less than half received an adult provider recommendation and <15% reported having a transition preparation visit or receiving written transition materials. The most recent A1C was 8.1 ± 1.3%. Respondents who felt mostly/completely prepared for transition had lower likelihood of a gap >6 months between pediatric and adult care (adjusted odds ratio 0.47 [95% CI 0.25–0.88]). In multivariate analysis, pretransition A1C (β = 0.49, P < 0.0001), current age (β = −0.07, P = 0.03), and education (β = −0.55, P = 0.01) significantly influenced current posttransition A1C. There was no independent association of transition preparation with posttransition A1C (β = −0.17, P = 0.28).
Contemporary transition practices may help prevent gaps between pediatric and adult care but do not appear to promote improvements in A1C. More robust preparation strategies and handoffs between pediatric and adult care should be evaluated.
PMCID: PMC3402251  PMID: 22699289
15.  Trends in Antibiotic Use in Massachusetts Children, 2000–2009 
Pediatrics  2012;130(1):15-22.
Antibiotic use rates have declined dramatically since the 1990s. We aimed to determine if, when, and at what level the decline in antibiotic-dispensing rates ended and which diagnoses contributed to the trends.
Antibiotic dispensings and diagnoses were obtained from 2 health insurers for 3- to <72-month-olds in 16 Massachusetts communities from 2000 to 2009. Population-based antibiotic-dispensing rates per person-year (p-y) were determined according to year (September–August) for 3 age groups. Fit statistics were used to identify the most likely year for a change in trend. Rates for the first and last years were compared according to antibiotic category and associated diagnosis.
From 2000–2001 to 2008–2009, the antibiotic-dispensing rate for 3- to <24-month-olds decreased 24% (2.3–1.8 antibiotic dispensings per p-y); for 24- to <48-month-olds, it decreased 18% (1.6–1.3 antibiotic dispensings per p-y); and for 48- to <72-month-olds, it decreased 20% (1.4–1.1 antibiotic dispensings per p-y). For 3- to <48-month-olds, rates declined until 2004–2005 and remained stable thereafter; the downward trend for 48- to <72-month-olds ended earlier in 2001–2002. Among 3- to <24-month-olds, first-line penicillin use declined 26%. For otitis media, the dispensing rate decreased 14% and the diagnosis rate declined 9%, whereas the treatment fraction was stable at 63%.
The downward trend in antibiotic dispensings to young children in these communities ended by 2004–2005. This trend was driven by a declining otitis media diagnosis rate. Continued monitoring of population-based dispensing rates will support efforts to avoid returning to previous levels of antibiotic overuse.
PMCID: PMC3382917  PMID: 22732172
antibiotic use; managed care programs; otitis media
16.  Pneumococcal Carriage and Antibiotic Resistance in Young Children before 13-Valent Conjugate Vaccine 
We sought to measure trends in Streptococcus pneumoniae (SP) carriage and antibiotic resistance in young children in Massachusetts communities after widespread adoption of heptavalent pneumococcal conjugate vaccine (PCV7) and before the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13).
We conducted a cross-sectional study including collection of questionnaire data and nasopharyngeal specimens among children <7 years in primary care practices from 8 Massachusetts communities during the winter season of 2008–9 and compared with to similar studies performed in 2001, 2003–4, and 2006–7. Antimicrobial susceptibility testing and serotyping were performed on pneumococcal isolates, and risk factors for colonization in recent seasons (2006–07 and 2008–09) were evaluated.
We collected nasopharyngeal specimens from 1,011 children, 290 (29%) of whom were colonized with pneumococcus. Non-PCV7 serotypes accounted for 98% of pneumococcal isolates, most commonly 19A (14%), 6C (11%), and 15B/C (11%). In 2008–09, newly-targeted PCV13 serotypes accounted for 20% of carriage isolates and 41% of penicillin non-susceptible S. pneumoniae (PNSP). In multivariate models, younger age, child care, young siblings, and upper respiratory illness remained predictors of pneumococcal carriage, despite near-complete serotype replacement. Only young age and child care were significantly associated with PNSP carriage.
Serotype replacement post-PCV7 is essentially complete and has been sustained in young children, with the relatively virulent 19A being the most common serotype. Predictors of carriage remained similar despite serotype replacement. PCV13 may reduce 19A and decrease antibiotic-resistant strains, but monitoring for new serotype replacement is warranted.
PMCID: PMC3288953  PMID: 22173142
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
17.  Carried Pneumococci in Massachusetts Children; The Contribution of Clonal Expansion and Serotype Switching 
PMCID: PMC3175614  PMID: 21085049
MLST; conjugate vaccination; Streptococcus pneumoniae; nasopharyngeal carriage
18.  Utilization of Healthcare Resources by U.S. Children and Adults with Inflammatory Bowel Disease 
Inflammatory bowel diseases  2011;17(1):62-68.
The inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC) affect over 1 million people in the United States, yet little is known about healthcare utilization by affected individuals.
1) To describe the healthcare utilization associated with IBD in an insured U.S. population. 2) To determine how sociodemographic factors impact healthcare utilization in this population.
Using an administrative database comprised of 87 health plans, we ascertained cases of CD and UC using an administrative definition. We identified inpatient, office-based, emergency, and endoscopy services occurring between 2003-2004 in IBD patients and matched controls. For each case, excess utilization was determined by subtracting the mean number of control visits from the number of case visits. Multivariable logistic and linear regressions were used to identify the sociodemographic factors associated with excess utilization.
We identified 9,056 CD patients and 10,364 UC patients. The mean number of annual excess hospitalizations, ED visits, and office visits per 100 patients for CD were 21.7, 20.1, and 493 respectively. These values for UC were 13.3, 10.3, and 364 respectively. In general, utilization was higher in CD compared with UC, and in younger patients compared with older patients. Utilization also varied by gender, geographical region, and insurance type (Medicaid versus commercial).
In the U.S., patients with IBD consume substantial healthcare resources. Resource utilization varies by patient age and disease type, and to a lesser extent, gender, geographical region, and insurance type. These findings may be used to inform health policy.
PMCID: PMC2962765  PMID: 20564532
Crohn’s disease; ulcerative colitis; healthcare utilization
19.  Serotype Specific Invasive Capacity and Persistent Reduction in Invasive Pneumococcal Disease 
Vaccine  2010;29(2):283-288.
Defining the propensity of Streptoccocus pneumoniae (SP) serotypes to invade sterile body sites following nasopharyngeal (NP) acquisition has the potential to inform about how much invasive pneumococcal disease (IPD) may occur in a typical population with a given distribution of carriage serotypes. Data from enhanced surveillance for IPD in Massachusetts children ≤7 years in 2003/04, 2006/07 and 2008/09 seasons and surveillance of SP NP carriage during the corresponding respiratory seasons in 16 Massachusetts communities in 2003/04 and 8 of the 16 communities in both 2006/07 and 2008/09 were used to compute a serotype specific “invasive capacity (IC)” by dividing the incidence of IPD due to serotype x by the carriage prevalence of that same serotype in children of the same age. A total of 206 IPD and 806 NP isolates of SP were collected during the study period. An approximate 50-fold variation in the point estimates between the serotypes having the highest (18C, 33F, 7F, 19A, 3 and 22F) and lowest (6C, 23A, 35F, 11A, 35B, 19F, 15A, and 15BC) IC was observed. Point estimates of IC for most of the common serotypes currently colonizing children in Massachusetts were low and likely explain the continued reduction in IPD from the pre-PCV era in the absence of specific protection against these serotypes. Invasive capacity differs among serotypes and as new pneumococcal conjugate vaccines are introduced, ongoing surveillance will be essential to monitor whether serotypes with high invasive capacity emerge (e.g. 33F, 22F) as successful colonizers resulting in increased IPD incidence due to replacement serotypes.
PMCID: PMC3139683  PMID: 21029807
Streptoccocus pneumoniae; serotype; invasive capacity
Vaccine  2010;28(30):4842-4846.
Pneumococcal type 1 pilus proteins have been proposed as potential vaccine candidates. Following conjugate pneumococcal vaccination, the prevalence of the pneumococcal type 1 pilus declined dramatically, a decline associated with the elimination of vaccine-type (VT) strains. Here we show that between 2004 and 2007, there has been a significant increase in pilus prevalence, now exceeding rates from the pre-conjugate vaccine era. This increase is primarily due to non-VT strains. These emerging piliated non-VT strains are mostly novel clones, with some exceptions. The rise in pilus type 1 frequency across multiple distinct genetic backgrounds suggests that the pilus may confer an intrinsic advantage.
PMCID: PMC2897942  PMID: 20434550
S. pneumoniae pilus; PCV7; vaccine- and non-vaccine-types
21.  Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete 
Epidemics  2010;2(2):80-84.
Invasive pneumococcal disease (IPD) has been reduced in the US following conjugate vaccination (PCV7) targeting seven pneumococcal serotypes in 2000. However, increases in IPD due to other serotypes have been observed, in particular 19A. How much this “serotype replacement” will erode the benefits of vaccination and over what timescale is unknown. We used a population genetic approach to test first whether the selective impact of vaccination could be detected in a longitudinal carriage sample, and secondly how long it persisted for following introduction of vaccine in 2000. To detect the selective impact of the vaccine we compared the serotype diversity of samples from pneumococcal carriage in Massachusetts children collected in 2001, 2004 and 2007 with others collected in the pre-vaccine era in Massachusetts, the UK and Finland. The 2004 sample was significantly (p >0.0001) more diverse than pre-vaccine samples, indicating the selective pressure of vaccination. The 2007 sample showed no significant difference in diversity from the pre-vaccine period, and exhibited similar population structure, but with different serotypes. In 2007 the carriage frequency of 19A was similar to that of the most common serotype in pre-vaccine samples. We suggest that serotype replacement involving 19A may be complete in Massachusetts due to similarities in population structure to pre-vaccine samples. These results suggest that the replacement phenomenon occurs rapidly with high vaccine coverage, and may allay concerns about future increases in disease due to 19A. For other serotypes, the future course of replacement disease remains to be determined.
PMCID: PMC2963072  PMID: 21031138
Streptococcus pneumoniae; Infectious disease epidemiology; Nasopharyngeal carriage; Population genetics
22.  Early Child Care and Adiposity at Ages 1 and 3 Years 
Pediatrics  2009;124(2):555-562.
The majority of infants in the United States are in non-parental child care, yet little is known about the effect of child care on development of obesity.
To examine the relationship between child care attendance from birth to 6 months and adiposity at 1 and 3 years of age.
We studied 1138 children from a prospective cohort of pregnant women and their offspring. The main exposure was time in child care from birth to 6 months of age, overall and by type of care: (1) child care center; (2) someone else’s home; and (3) child’s own home by nonparent. The main outcomes were weight-for-length (WFL) z score at 1 year and BMI z score at 3 years of age.
A total of 649 (57%) infants attended child care; 17% were cared for in a center, 27% in someone else’s home, and 21% in their own home by a nonparent. After adjustment for confounders, overall time in child care was associated with an increased WFL z score at 1 year and BMI z score at 3 years of age but not skinfold thicknesses. Center and own home care were not associated with the outcomes, but care in someone else’s home was associated with an increase in both the 1- and 3-year outcomes.
Child care in the first 6 months of life, especially in someone else’s home, was associated with an increased WFL z score at 1 year and BMI z score at 3 years of age.
PMCID: PMC3049895  PMID: 19651579
child care; childhood obesity; nutrition; physical activity; infancy
23.  Reducing the Prescribing of Heavily Marketed Medications: A Randomized Controlled Trial 
Prescription drug costs are a major component of health care expenditures, yet resources to support evidence-based prescribing are not widely available.
To evaluate the effectiveness of computerized prescribing alerts, with or without physician-led group educational sessions, to reduce the prescribing of heavily marketed hypnotic medications.
Cluster-randomized controlled trial.
We randomly allocated 14 internal medicine practice sites to receive usual care, computerized prescribing alerts alone, or alerts plus group educational sessions.
Proportion of heavily marketed hypnotics prescribed before and after the implementation of computerized alerts and educational sessions.
Main Results
The activation of computerized alerts held the prescribing of heavily marketed hypnotic medications at pre-intervention levels in both the alert-only group (adjusted risk ratio [RR] 0.97; 95% CI 0.82–1.14) and the alert-plus-education group (RR 0.98; 95% CI 0.83–1.17) while the usual-care group experienced an increase in prescribing (RR 1.31; 95% CI 1.08–1.60). Compared to the usual-care group, the relative risk of prescribing heavily marketed medications was less in both the alert-group (Ratio of risk ratios [RRR] 0.74; 95% CI 0.57–0.96) and the alert-plus-education group (RRR 0.74; 95% CI 0.58–0.97). The prescribing of heavily marketed medications was similar in the alert-group and alert-plus-education group (RRR 1.02; 95% CI 0.80–1.29). Most clinicians reported that the alerts provided useful prescribing information (88%) and did not interfere with daily workflow (70%).
Computerized decision support is an effective tool to reduce the prescribing of heavily marketed hypnotic medications in ambulatory care settings.
Trial Registration Identifier: NCT00788346.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-009-1013-x) contains supplementary material, which is available to authorized users.
PMCID: PMC2710467  PMID: 19475459
prescription drugs; effectiveness; marketed medications; prescribing; decision support; computerized alerts
24.  Continued Impact of Pneumococcal Conjugate Vaccine on Carriage in Young Children 
Pediatrics  2009;124(1):e1-11.
The goals were to assess serial changes in Streptococcus pneumoniae serotypes and antibiotic resistance in young children and to evaluate whether risk factors for carriage have been altered by heptavalent pneumococcal conjugate vaccine (PCV7).
Nasopharyngeal specimens and questionnaire/medical record data were obtained from children 3 months to <7 years of age in primary care practices in 16 Massachusetts communities during the winter seasons of 2000–2001 and 2003–2004 and in 8 communities in 2006–2007. Antimicrobial susceptibility testing and serotyping were performed with S pneumoniae isolates.
We collected 678, 988, and 972 specimens during the sampling periods in 2000–2001, 2003–2004, and 2006–2007, respectively. Carriage of non-PCV7 serotypes increased from 15% to 19% and 29% (P < .001), with vaccine serotypes decreasing to 3% of carried serotypes in 2006–2007. The relative contribution of several non-PCV7 serotypes, including 19A, 35B, and 23A, increased across sampling periods. By 2007, commonly carried serotypes included 19A (16%), 6A (12%), 15B/C (11%), 35B (9%), and 11A (8%), and high-prevalence serotypes seemed to have greater proportions of penicillin nonsusceptibility. In multivariate models, common predictors of pneumococcal carriage, such as child care attendance, upper respiratory tract infection, and the presence of young siblings, persisted.
The virtual disappearance of vaccine serotypes in S pneumoniae carriage has occurred in young children, with rapid replacement with penicillin-nonsusceptible nonvaccine serotypes, particularly 19A and 35B. Except for the age group at highest risk, previous predictors of carriage, such as child care attendance and the presence of young siblings, have not been changed by the vaccine.
PMCID: PMC2782668  PMID: 19564254
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
25.  Increase in the Prevalence of the Newly Discovered Pneumococcal Serotype 6C in the Nasopharynx after Introduction of Pneumococcal Conjugate Vaccine 
The Journal of infectious diseases  2009;199(3):320-325.
Because pneumococcal serotype 6C was previously not distinguished from serotype 6A, the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) on the carriage of serotype 6C is unknown.
The nasopharyngeal (NP) prevalence of the 6C serotype was determined using 1326 pneumococcal isolates collected from 7 cohorts of Massachusetts children between 1994 and 2007. Initially, the isolates were serotyped using the quellung reaction; subsequently, stored specimens of all putative 6A isolates were tested for 6C using monoclonal antibodies. The opsonophagocytic and antibiotic susceptibilities of the isolates were determined.
The prevalence of 6A was 9.6% (33/343) before 2001, 8.0% (18/226) in 2004, and 2.9% (12/416) in 2007. In contrast, the prevalence of 6C was 0.6% (2/343) before 2001, 2.2% (5/226) in 2004, and 8.7% (36/416) in 2007 (P < .001 for 2/343 vs. 36/416). 6C isolates from 2007 were more susceptible to antibiotics than were 6A isolates. PCV7 induced a low ability to opsonize different isolates of 6C.
Among NP isolates, the prevalence of 6C isolates has increased and the prevalence of 6A isolates has decreased since the introduction of PCV7 in Massachusetts in 2000. The observed increase in serotype 6C prevalence may be explained by the induction by PCV7 of low amounts of functional anti-6C antibody, compared with anti-6A and anti-6B antibodies.
PMCID: PMC2743180  PMID: 19099489

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