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Carlos R Oliveira,1,2 Eugene D Shapiro,1,3 Daniel M Weinberger3 1Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA; 2Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA; 3Department of Epidemiology of Microbial Diseases, Yale University School of Public Health, New Haven, CT, USACorrespondence: Carlos R Oliveira, Yale University School of Medicine, 464 Congress Avenue, Suite 204, New Haven, CT, 06520, USA, Tel +1 203 785 5474, Email carlos.oliveira@yale.eduPurpose: Vaccine effectiveness (VE) studies are often conducted after the introduction of new vaccines to ensure they provide protection in real-world settings. Control of confounding is often needed during the analyses, which is most efficiently done through multivariable modeling. When many confounders are being considered, it can be challenging to know which variables need to be included in the final model. We propose an intuitive Bayesian model averaging (BMA) framework for this task.Patients and Methods: Data were used from a matched case–control study that aimed to assess the effectiveness of the Lyme vaccine post-licensure. Cases were residents of Connecticut, 15– 70 years of age with confirmed Lyme disease. Up to 2 healthy controls were matched to each case subject by age. All participants were interviewed, and medical records were reviewed to ascertain immunization history and evaluate potential confounders. BMA was used to systematically search for potential models and calculate the weighted average VE estimate from the top subset of models. The performance of BMA was compared to three traditional single-best-model-selection methods: two-stage selection, stepwise elimination, and the leaps and bounds algorithm.Results: The analysis included 358 cases and 554 matched controls. VE ranged between 56% and 73% and 95% confidence intervals crossed zero in < 5% of all candidate models. Averaging across the top 15 models, the BMA VE was 69% (95% CI: 18– 88%). The two-stage, stepwise, and leaps and bounds algorithm yielded VE of 71% (95% CI: 21– 90%), 73% (95% CI: 26– 90%), and 74% (95% CI: 27– 91%), respectively.Conclusion: This paper highlights how the BMA framework can be used to generate transparent and robust estimates of VE. The BMA-derived VE and confidence intervals were similar to those estimated using traditional methods. However, by incorporating model uncertainty into the parameter estimation, BMA can lend additional rigor and credibility to a well-designed study.Keywords: Bayesian model averaging, model uncertainty, vaccine effectiveness, Lyme vaccine

After the manufacture of Lyme vaccine was discontinued in 2002, strategies to prevent Lyme disease (LD) have focused on personal protective measures. Effectiveness of these measures has not been conclusively demonstrated. The aim of our case-control study was to assess the effectiveness of personal preventive measures in a highly disease-endemic area. Case-patients were persons with LD reported to Connecticut's Department of Public Health and classified as having definite, possible, or unlikely LD. Age-matched controls without LD were identified. Study participants were interviewed to assess the practice of preventive measures and to obtain information on occupational and recreational risk factors. Use of protective clothing was 40% effective; routine use of tick repellents on skin or clothing was 20% effective. Checking one's body for ticks and spraying property with acaricides were not effective. We concluded that use of protective clothing and of tick repellents (on skin or clothing) are effective in preventing LD. [ABSTRACT FROM AUTHOR]

Objective: We sought to evaluate the validity of retrieving data from a commercial, outpatient electronic medical record (EMR) to assess the management of pharyngitis, an important measure of quality of healthcare in pediatrics and a new measure for the Health Plan Employer Data and Information Set (HEDIS).Methods: For children ages 3-18 years, we electronically identified clinical encounters with diagnoses of pharyngitis using 3 different strategies (an EMR-based strategy, an administrative data-based strategy, and a reference strategy which used medical record review). By each strategy, we calculated the proportion of episodes of pharyngitis during 1 year for which management of pharyngitis adhered to published guidelines.Results: Among 479 total episodes of pharyngitis, 434 (91%) were from the EMR-based strategy and 281 (59%) from the administrative data-based strategy. Review of the records (the reference strategy) found that 391 of 479 (82%) were confirmed episodes of pharyngitis. A diagnostic test for group A streptococcus (GAS) was performed at 310 of 434 (71%) of episodes identified by the EMR-based strategy and at 214 of 281 (76%) of episodes by the administrative data-based strategy (P = 0.045). By the reference strategy, a diagnostic test was done in 301 of 391 (77%); more than at episodes found by the EMR-based strategy (71%, P < 0.001).Conclusions: The EMR-based strategy resulted in a statistically different proportion of episodes having diagnostic testing for GAS compared with a reference strategy. Complete evaluations to validate strategies for extracting data from electronic databases are necessary before assuming that measures of quality of care will be the same regardless of the source of data. [ABSTRACT FROM AUTHOR]

To compare the sensitivity of a new ELISA for IgM antibodies to Borrelia burgdorferi that uses a recombinant outer surface protein C (rOspC) with those of a whole cell (WC) ELISA and an immunoblot assay for the diagnosis of early Lyme disease, serum specimens from 82 consecutive patients with physician-documented erythema migrans were analyzed. To compare the specificities of the three assays, serum specimens from 50 patients without a history of Lyme disease and from an area in which B. burgdorferi is not endemic were analyzed. The sensitivities of the WC ELISA, immunoblot assay, and IgM rOspC ELISA were 28%, 29%, and 46%, respectively, while the specificities were 100%, 100%, and 98%, respectively. The IgM rOspC ELISA is a convenient, readily automated, easily standardized serologic test that is significantly more sensitive for the diagnosis of early Lyme disease than either WC ELISA or immunoblot assay. [ABSTRACT FROM AUTHOR]

Health care provider recommendations are among the most important factors influencing parents' decisions to vaccinate their adolescents. However, delivery of high-quality health care provider recommendations for vaccination is not universal. There is wide variation in the strength, timeliness and consistency of the delivery of recommendations for all adolescent vaccines. The factors that influence health care providers' recommendations are multi-level and can be conceptualized in much the same way as vaccine acceptance among parents. Health care providers are influenced by their own attitudes and beliefs about a vaccine and also by the patient they are treating and by the community in which they practice as well as state and national level vaccine policy. We propose a multi-level framework for understanding the factors that influence health care providers' recommendations at the individual, interpersonal and community level to both develop and adapt interventions to improve providers' recommendations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Surveillance for respiratory syncytial virus (RSV) likely captures just a fraction of the burden of disease. Understanding the burden of hospitalizations and disparities between populations can help to inform upcoming RSV vaccine programs and to improve surveillance., Methods: We obtained monthly age-, ZIP code- and cause-specific hospitalizations in New York, New Jersey, and Washington from the US State Inpatient Databases (2005-2014). We estimated the incidence of respiratory hospitalizations attributable to RSV by age and by socioeconomic status using regression models. We compared the estimated incidence and the recorded incidence (based on ICD9-CM) of RSV hospitalizations to estimate the under-recorded ratio in different subpopulations., Results: The estimated annual incidence of respiratory hospitalizations due to RSV was highest among infants < 1 year of age with low socioeconomic status (2800, 95% CrI [2600, 2900] per 100,000 person-years). We also estimated a considerable incidence in older adults (≥ 65 years of age), ranging from 130 to 960 per 100,000 person-years across different socioeconomic strata. The incidence of hospitalization recorded as being due to RSV represented a significant undercount, particularly in adults. Less than 5% of the estimated RSV hospitalizations were captured for those ≥ 65 years of age., Conclusions: RSV causes a considerable burden of hospitalization in young children and in older adults in the US, with variation by socioeconomic group. Recorded diagnoses substantially underestimate the incidence of hospitalization due to RSV in older adults., (© 2022. The Author(s).)

Importance: The emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2 has led to increases in both infections and hospitalizations among adolescents. Little is known about the effectiveness of the BNT162b2 vaccine in adolescents in the general population, as opposed to a clinical trial population., Objective: To estimate the effectiveness of the BNT162b2 vaccine in adolescents aged 12 to 18 years., Design, Setting, and Participants: This was a matched case-control study among adolescents (aged 12-18 years) who had results from a SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test. Immunization histories, relevant clinical data, and RT-PCR test results were obtained from the Yale New Haven Health System's medical records between June 1, 2021, and August 15, 2021, when the Delta variant caused 92% of infections in Connecticut. Case participants were defined as adolescents who had a positive test result and an associated medical encounter. Control participants were defined as those who had a negative test result and were matched to a case participant by age, county of residence, and date of testing., Exposures: Adolescents were defined as fully immunized if they had received 2 doses of vaccine at least 14 days before focal time., Main Outcomes and Measures: The primary outcome measured was SARS-CoV-2 infection confirmed by RT-PCR. The vaccine's effectiveness (VE) was estimated using matched odds ratios from conditional logistic regression models. Secondary measures included estimated VE by clinical symptoms, number of vaccine doses received, and elapsed time from immunization., Results: A total of 6901 adolescents were tested for SARS-CoV-2. The final sample comprised 186 case participants and 356 matched control participants. The median age was 14 (IQR, 13-16) years, 262 (48%) identified as female, 81 (15%) as Black, 82 (15%) as Hispanic, and 297 (55%) as White. Overall, 134 (25%) were fully immunized (case participants, 10 [5%]; control participants, 124 [35%]). The median time between immunization and the SARS-CoV-2 test was 62 days (range, 17-129 days). Within 4 months of receiving 2 doses, VE against any infection was estimated to be 91% (95% CI, 80%-96%); against asymptomatic infection, 85% (95% CI, 57%-95%). Effectiveness after a single dose was estimated to be 74% (95% CI, 18%-92%)., Conclusions and Relevance: In this retrospective case-control study of US adolescents, 2 doses of BNT162b2 vaccine appeared to provide excellent protection for at least 4 months after immunization against both symptomatic and asymptomatic SARS-CoV-2 infections.

Importance: Respiratory syncytial virus (RSV) is a leading cause of hospitalizations in young children. RSV largely disappeared in 2020 owing to precautions taken because of the COVID-19 pandemic. Estimating the timing and intensity of the reemergence of RSV and the age groups affected is crucial for planning for the administration of prophylactic antibodies and anticipating hospital capacity., Objective: To examine the association of different factors, including mitigation strategies, duration of maternal-derived immunity, and importation of external infections, with the dynamics of reemergent RSV epidemics., Design, Setting, and Participants: This simulation modeling study used mathematical models to reproduce the annual epidemics of RSV before the COVID-19 pandemic in New York and California. These models were modified to project the trajectory of RSV epidemics from 2020 to 2025 under different scenarios with varying stringency of mitigation measures for SARS-CoV-2. Simulations also evaluated factors likely to affect the reemergence of RSV epidemics, including introduction of the virus from out-of-state sources and decreased transplacentally acquired immunity in infants. Models using parameters fitted to similar inpatient data sets from Colorado and Florida were used to illustrate these associations in populations with biennial RSV epidemics and year-round RSV circulation, respectively. Statistical analysis was performed from February to October 2021., Main Outcomes and Measures: The primary outcome of this study was defined as the estimated number of RSV hospitalizations each month in the entire population. Secondary outcomes included the age distribution of hospitalizations among children less than 5 years of age, incidence of any RSV infection, and incidence of RSV lower respiratory tract infection., Results: Among a simulated population of 19.45 million people, virus introduction from external sources was associated with the emergence of the spring and summer epidemic in 2021. There was a tradeoff between the intensity of the spring and summer epidemic in 2021 and the intensity of the epidemic in the subsequent winter. Among children 1 year of age, the estimated incidence of RSV hospitalizations was 707 per 100 000 children per year in the 2021 and 2022 RSV season, compared with 355 per 100 000 children per year in a typical RSV season., Conclusions and Relevance: This simulation modeling study found that virus introduction from external sources was associated with the spring and summer epidemics in 2021. These findings suggest that pediatric departments should be alert to large RSV outbreaks in the coming seasons, the intensity of which could depend on the size of the spring and summer epidemic in that location. Enhanced surveillance is recommended for both prophylaxis administration and hospital capacity management.

The ability to effectively lead an interdisciplinary translational team is a crucial component of team science success. Most KL2 Clinical Scholars have been members of scientific teams, but few have been team science leaders. There is a dearth of literature and outcome measures of effective Team Science Leadership in clinical and translational research. We focused our curriculum to emphasize Team Science Leadership, developed a list of Team Science Leadership competencies for translational investigators using a modified Delphi method, and incorporated the competencies into a quantitative evaluation survey. The survey is completed on entry and annually thereafter by the Scholar; the Scholar's primary mentor and senior staff who educate and interact with the Scholar rate the Scholar at the end of each year. The program leaders and mentor review the results with each Scholar. The survey scales had high internal consistency and good factor structure. Overall ratings by mentors and senior staff were generally high, but ratings by Scholars tended to be lower, offering opportunities for discussion and career planning. Scholars rated the process favorably. A Team Science Leadership curriculum and periodic survey of attained competencies can inform individual career development and guide team science curriculum development., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Background: Vaccine receipt among mid-adults remains low, with only one quarter of adults being up to date for all recommended vaccines. It is important to understand the myriad factors that influence vaccine receipt among mid-adult women to address these low rates., Methods: We conducted a cross-sectional analysis of data from women ages 24-45 years collected as part of an ongoing case-control study of the effectiveness of HPV vaccine. We examined associations between demographic characteristics and healthcare utilization and receipt of individual vaccines and combinations of multiple vaccines using logistic regression analyses for three routinely recommended vaccines: tetanus, influenza and HPV., Results: Among the 309 women enrolled in the study, only 19 (6.2%) were up to date for all three recommended vaccines and 41 (13.3%) had not received any of the recommended vaccines. A greater number of health care visits in the past year was associated with receipt of influenza (aOR = 6.37, 95% CI = 2.53, 16.1) and tetanus (aOR = 2.17, 95% CI = 1.14, 4.12) vaccines. White women were more likely to have received HPV vaccine (aOR = 2.39, 95% CI = 1.07, 5.36)., Conclusions: Uptake of recommended vaccines is low among young and mid-adult women. There is a need for greater understanding of the underlying factors influencing vaccine receipt in this population.

Introduction: In 2006, the first human papillomavirus (HPV) vaccine was approved by the Food and Drug Administration in the USA based on pre-licensure clinical trials that found it to be highly efficacious at preventing persistent infection and precancerous, high-grade cervical lesions (HGCLs) caused by viral types the vaccine protects against. However, the real-world effectiveness of HPV vaccines as used in clinical practice may be quite different from the efficacy found in pre-licensure clinical trials. More than 10 years have passed since the introduction of the vaccine programme. It is critical to determine if the full benefits of HPV are being realised in real-world settings., Methods and Analysis: The objectives of this study were to estimate the effectiveness of HPV vaccines as used in real-world clinical settings and to determine the degree to which the vaccine's effectiveness varies based on age at the time of immunisation and the number of doses received. The study will be a population-based, matched case-control study. Cases will be women with newly diagnosed HGCL associated with HPV types 16 and 18. Matched controls will be women with a normal Pap test result, matched individually to cases in a 2:1 ratio by age, a practice and date of testing. Medical records will be reviewed to determine dates of receipt of the HPV vaccine for all participants. We will use multivariate conditional logistic regression to control for potential confounders., Ethics and Dissemination: This protocol presents minimal risk to the subjects. This protocol has received approval from the Institutional Review Board of Yale University (HIC: 1502015308), and a Health Insurance Portability and Accountability Act (HIPAA) Waiver of Authorisation has been granted to allow investigators to recruit subjects for the study. Findings will be disseminated through peer-reviewed, open-access scientific journals and conference presentations., Competing Interests: Competing interests: Dr Niccolai has served as Scientific Advisor for Merck. Dr Sheth receives Gardasil 9 from Merck at no cost for research and has served as a consultant for Merck. All other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a matched case-control study to assess the effectiveness of Lyme vaccine (LYMErix) as it was used in clinical practice. We found ≥3 doses to be 71% effective against Lyme disease. This is the first study to show that the Lyme vaccine is effective in a real-world setting., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Emergency care for children is provided predominantly in community emergency departments (CEDs), where abusive injuries frequently go unrecognized. Increasing access to regional child abuse experts may improve detection of abuse in CEDs. In three CEDs, we intervened to increase involvement of a regional hospital child protection team (CPT) for injuries associated with abuse in children < 12 months old. We aimed to increase CPT consultations about these infants from the 3% baseline to an average of 50% over 12 months., Methods: We interviewed CED providers to identify barriers and facilitators to recognizing and reporting abuse. Providers described difficulties differentiating abusive from nonabusive injuries and felt that a second opinion would help. Using a plan-do-study-act approach, beginning in April 2018, we tested, refined, and implemented interventions to increase the frequency of CPT consultation, including leadership and champion engagement, provider training, clinical pathway implementation, and an audit and feedback process. Data were collected for 15 months before and 17 months after initiation of interventions. We used a statistical process control chart to track CPT consultations about children < 1 year old with high-risk injuries, use of skeletal surveys (SSs), and reports to child protective services (CPS)., Results: Evidence of special cause was identified beginning in June 2018, with a shift of 8 points to one side of the center line. For the subsequent 8-month period, the CPT was consulted for a mean of 47.5% of children with high-risk injuries; this was sustained for an additional 7 months. The average percentage of infants with high-risk injuries who received a SS increased from 6.7% to 18.9% and who were reported to CPS increased from 10.7% to 32.6%., Conclusion: Targeted interventions in CEDs increased the frequency of CPT consultation, SS use, and reports to CPS for infants with high-risk injuries. Such interventions may improve recognition of physical abuse., (© 2020 by the Society for Academic Emergency Medicine.)

Objectives: We aimed to develop and test a tool to engage parents of febrile infants ≤ 60 days of age evaluated in the emergency department (ED). The tool was designed to improve communication for all parents and to support shared decision-making (SDM) about whether to perform a lumbar puncture (LP) for infants 29 to 60 days of age., Methods: We conducted a multiphase development and testing process: 1) individual, semistructured interviews with parents and clinicians (pediatric and general emergency medicine [EM] physicians and pediatric EM nurses) to learn their preferences for a communication and SDM tool; 2) design of a "storyboard" of the tool with design impression testing; 3) development of a software application (i.e., app) prototype, called e-Care; and 4) usability testing of e-Care, using qualitative assessment and the system usability scale (SUS)., Results: We interviewed 27 parents and 23 clinicians. Interviews revealed several themes, including that a communication tool should augment but not replace verbal communication; a Web-based format was preferred; and information about infections and testing, including the rationales for specific tests, would be valuable. We then developed separate versions of e-Care for infants ≤ 28 days and 29 to 60 days of age, in both English and Spanish. The e-Care app includes four sections: 1) homepage; 2) why testing is done; 3) what tests are done; and 4) what happens after testing, including a table for parents of infants 29 to 60 days of age to compare the risks/benefits of LP in preparation for an SDM conversation. Parents and clinicians reported that e-Care was understandable and helpful. The mean SUS score was 90.3 (95% confidence interval = 84 to 96.6), representing "excellent" usability., Conclusions: The e-Care app is a useable and understandable tool to support communication and SDM with parents of febrile infants ≤ 60 days of age in the ED., (© 2020 by the Society for Academic Emergency Medicine.)

Background: Accurate identification of new diagnoses of human papillomavirus-associated cancers and precancers is an important step toward the development of strategies that optimize the use of human papillomavirus vaccines. The diagnosis of human papillomavirus cancers hinges on a histopathologic report, which is typically stored in electronic medical records as free-form, or unstructured, narrative text. Previous efforts to perform surveillance for human papillomavirus cancers have relied on the manual review of pathology reports to extract diagnostic information, a process that is both labor- and resource-intensive. Natural language processing can be used to automate the structuring and extraction of clinical data from unstructured narrative text in medical records and may provide a practical and effective method for identifying patients with vaccine-preventable human papillomavirus disease for surveillance and research., Objective: This study's objective was to develop and assess the accuracy of a natural language processing algorithm for the identification of individuals with cancer or precancer of the cervix and anus., Methods: A pipeline-based natural language processing algorithm was developed, which incorporated machine learning and rule-based methods to extract diagnostic elements from the narrative pathology reports. To test the algorithm's classification accuracy, we used a split-validation study design. Full-length cervical and anal pathology reports were randomly selected from 4 clinical pathology laboratories. Two study team members, blinded to the classifications produced by the natural language processing algorithm, manually and independently reviewed all reports and classified them at the document level according to 2 domains (diagnosis and human papillomavirus testing results). Using the manual review as the gold standard, the algorithm's performance was evaluated using standard measurements of accuracy, recall, precision, and F-measure., Results: The natural language processing algorithm's performance was validated on 949 pathology reports. The algorithm demonstrated accurate identification of abnormal cytology, histology, and positive human papillomavirus tests with accuracies greater than 0.91. Precision was lowest for anal histology reports (0.87, 95% CI 0.59-0.98) and highest for cervical cytology (0.98, 95% CI 0.95-0.99). The natural language processing algorithm missed 2 out of the 15 abnormal anal histology reports, which led to a relatively low recall (0.68, 95% CI 0.43-0.87)., Conclusions: This study outlines the development and validation of a freely available and easily implementable natural language processing algorithm that can automate the extraction and classification of clinical data from cervical and anal cytology and histology., (©Carlos R Oliveira, Patrick Niccolai, Anette Michelle Ortiz, Sangini S Sheth, Eugene D Shapiro, Linda M Niccolai, Cynthia A Brandt. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 03.11.2020.)

Purpose: To assess the trends and sociodemographic disparities of anal cancer. Methods: For this time series, billing claims were reviewed for all encounters between 2007 and 2011 in the Yale New Haven Health System. Results: There were 80 new cases identified. Decreasing trends were seen in women and increasing trend in men (-30.1% and 27.3%). Diagnoses were more common in areas with the highest proportion of racial minorities (incidence rate ratio [IRR]=1.75; p ≤0.01) and poverty (IRR=1.72; p =0.04). Conclusions: Anal cancer continues to rise in men during the postvaccine era. Communities with the highest proportion of poverty and racial/ethnic minority groups bear the highest burden of disease., Competing Interests: Dr. L.M.N. reports previous work as a Scientific Advisor for Merck. All other authors declare no conflicts of interest., (© Carlos R. Oliveira et al., 2020; Published by Mary Ann Liebert, Inc.)

Background: Ascertaining history of prior immunization with human papillomavirus (HPV) vaccine can be challenging and resource-intensive. Computer-assisted self-interviewing instruments have the potential to address some of the challenges of self-reporting, and may also reduce the time, costs, and efforts associated with ascertaining immunization status., Objective: This study assesses both the feasibility and the accuracy of a computer-assisted self-interviewing instrument to ascertain a patient's history of immunization with the HPV vaccine., Methods: We developed both a survey and a Web-based data collection system using computer-assisted self-interviewing to ascertain self-reported HPV vaccine immunization history. We implemented the instrument in a sample of adult women enrolled in an ongoing study of the HPV vaccine. Vaccine records from prior sources of care were reviewed to verify reported immunization history., Results: Among the 312 participants who provided HPV vaccine immunization history by self-report, almost all (99%) were able to do so using the computer-assisted self-interviewing instrument. The median survey completion time was 10 minutes (IQR 7-17). The accuracy of self-report was 84%, sensitivity was 89%, specificity was 80%, and the negative predictive value was 92%., Conclusions: We found that it is feasible to collect a history of immunization with the HPV vaccine using a computer-assisted self-interviewing instrument. This approach is likely to be acceptable to adult women and is reasonably accurate in a clinical research setting., (©Carlos R Oliveira, Lital Avni-Singer, Geovanna Badaro, Erin L Sullivan, Sangini S Sheth, Eugene D Shapiro, Linda M Niccolai. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 22.01.2020.)

Background: Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss. By law, newborns in Connecticut who fail newborn hearing screening are tested for infection with CMV. This targeted screening is controversial, because most children with congenital CMV infection are asymptomatic, and CMV-related hearing loss can have a delayed onset. Our hospital uses a saliva polymerase chain reaction (PCR) assay (confirmed by a urine PCR assay) to detect CMV. Here, we report the results of the first year of our screening program., Methods: We reviewed the medical records of newborns in the Yale New Haven Health System who failed the newborn hearing screening test between January 1 and December 31, 2016., Results: Of 10964 newborns, 171 failed newborn hearing screening, and 3 of these newborns had positive saliva CMV PCR test results. Of these 3 newborns, 2 had positive results on the confirmatory test (for 1 of them the confirmatory test was not performed until the infant was 10 weeks old), and 1 had a negative result on the confirmatory test. Three additional newborns with congenital CMV infection were tested because of clinical indications (1 for ventriculomegaly on prenatal ultrasound and 2 for CMV infection of the mother). Results of audiology follow-up were available for 149 (87.1%) of the 171 newborns who failed newborn hearing screening; 127 (85.2%) had normal results., Conclusion: Our targeted screening program for congenital CMV infection had a low yield. Consideration should be given to other strategies for identifying children at risk of hearing loss as a result of congenital CMV infection., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination., Objectives: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome., Methods: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria., Results: Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%)., Conclusions: Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.

Objective: To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed "radiologically isolated syndrome" or RIS)., Methods: Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS., Results: We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%-60%) in a median of 2.0 years (interquartile range [IQR] 1.0-4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%-76%) in a median of 1.1 years (IQR 0.5-1.9 years). The presence of ≥2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4-86.2, p = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4-43.6, p = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex., Conclusions: We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.

When a new vaccine is introduced, it is critical to monitor trends in disease rates to ensure that the vaccine is effective and to quantify its impact. However, estimates from observational studies can be confounded by unrelated changes in healthcare utilization, changes in the underlying health of the population, or changes in reporting. Other diseases are often used to detect and adjust for these changes, but choosing an appropriate control disease a priori is a major challenge. The "synthetic controls" (causal impact) method, which was originally developed for website analytics and social sciences, provides an appealing solution. With this approach, potential comparison time series are combined into a composite and are used to generate a counterfactual estimate, which can be compared with the time series of interest after the intervention. We sought to estimate changes in hospitalizations for all-cause pneumonia associated with the introduction of pneumococcal conjugate vaccines (PCVs) in five countries in the Americas. Using synthetic controls, we found a substantial decline in hospitalizations for all-cause pneumonia in infants in all five countries (average of 20%), whereas estimates for young and middle-aged adults varied by country and were potentially influenced by the 2009 influenza pandemic. In contrast to previous reports, we did not detect a decline in all-cause pneumonia in older adults in any country. Synthetic controls promise to increase the accuracy of studies of vaccine impact and to increase comparability of results between populations compared with alternative approaches.

Background: Our understanding of the epidemiology of influenza is limited in tropical regions, which in turn has hampered identifying optimal region-specific policy to diminish disease burden. Influenza-like illness (ILI) is a clinical diagnosis that can be used as a surrogate for influenza. This study aimed to define the incidence and seasonality of ILI and to assess its association with climatic variables and school calendar in an urban community in the tropical region of Salvador, Brazil., Methods: Between 2009 and 2013, we conducted enhanced community-based surveillance for acute febrile illnesses (AFI) among patients ≥ 5 years of age in a slum community emergency unit in Salvador, Brazil. ILI was defined as a measured temperature of ≥ 37.8 °C or reported fever in a patient with cough or sore throat for ≤ 7 days, and negative test results for dengue and leptospirosis. Seasonality was analyzed with a harmonic regression model. Negative binomial regression models were used to correlate ILI incidence with rainfall, temperature, relative humidity and the number of days per month that schools were in session while controlling for seasonality., Results: There were 2,651 (45.6% of 5,817 AFI patients) ILI cases with a mean annual incidence of 60 cases/1,000 population (95% CI 58-62). Risk of ILI was highest among 5-9 year olds with an annual incidence of 105 cases/1,000 population in 2009. ILI had a clear seasonal pattern with peaks between the 35-40th week of the year. ILI peaks were higher and earlier in 5-9 year olds compared with > 19 year olds. No association was seen between ILI and precipitation, relative humidity or temperature. There was a significant association between the incidence of ILI in children 5-9 years of age and number of scheduled school days per month., Conclusions: We identified a significant burden of ILI with distinct seasonality in the Brazilian tropics and highest rates among young school-age children. Seasonal peaks of ILI in children 5-9 years of age were positively associated with the number of school days, indicating that children may play a role in the timing of seasonal influenza transmission.

Whether or not Borrelia burgdorferi can persist after conventional treatment with antimicrobials has been a very controversial issue. Two recent studies took different approaches to try to answer this question. In one, investigators showed that, in each of 22 instances in 17 patients with two consecutive episodes of culture-proved erythema migrans, the strains of B. burgdorferi were different based on their genotypes. This indicated that the repeat episodes were due to new infections rather than recrudescence of the original infection. In another study, in which persistence of B. burgdorferi was assessed by using xenodiagnosis, no viable B. burgdorferi were cultured from ticks fed on any of the patients. There continues to be no evidence that viable B. burgdorferi persist in humans after conventional treatment with antimicrobials.

Background: Because of ongoing outbreaks of varicella, a second dose of varicella vaccine was added to the routine immunization schedule for children in June 2006 by the Centers for Disease Control and Prevention., Methods: We assessed the effectiveness of 2 doses of varicella vaccine in a case-control study by identifying children ≥4 years of age with varicella confirmed by polymerase chain reaction assay and up to 2 controls matched by age and pediatric practice. Effectiveness was calculated using exact conditional logistic regression., Results: From July 2006 to January 2010, of the 71 case subjects and 140 matched controls enrolled, no cases (0%) vs 22 controls (15.7%) had received 2 doses of varicella vaccine, 66 cases (93.0%) vs 117 controls (83.6%) had received 1 dose, and 5 cases (7.0%) vs 1 control (0.7%) did not receive varicella vaccine (P < .001). The effectiveness of 2 doses of the vaccine was 98.3% (95% confidence level [CI]: 83.5%-100%; P < .001). The matched odds ratio for 2 doses vs 1 dose of the vaccine was 0.053 (95% CI: 0.002-0.320; P < .001)., Conclusion: The effectiveness of 2 doses of varicella vaccine in the first 2.5 years after recommendation of a routine second dose of the vaccine for children is excellent. Odds of developing varicella were 95% lower for children who received 2 doses compared with 1 dose of varicella vaccine.

Background: Infants aged <12 months are at high risk of hospitalization for influenza. Influenza vaccine is recommended for pregnant women and for most children; however, no vaccine is approved for infants aged <6 months. Effective approaches are needed to protect this vulnerable population. Vaccination of women during pregnancy may protect the infant through transfer of antibodies from the mother. Few studies have examined the effectiveness of this strategy, and those studies produced mixed results., Methods: In a matched case-control study, case patients were infants aged <12 months admitted to a large urban hospital in the northeastern United States because of laboratory-confirmed influenza from 2000 to 2009. For each case, we enrolled 1 or 2 control subjects who were infants who tested negative for influenza and matched cases by date of birth and date of hospitalization (within 4 weeks). Vaccine effectiveness was calculated on the basis of matched odds ratios and was adjusted for confounding., Results: The mothers of 2 (2.2%) of 91 case subjects and 31 (19.9%) of 156 control subjects aged <6 months, and 1 (4.6%) of 22 case subjects and 2 (5.6%) of 36 control subjects aged ≥6 months, had received influenza vaccine during pregnancy. The effectiveness of influenza vaccine given to mothers during pregnancy in preventing hospitalization among their infants, adjusted for potential confounders, was 91.5% (95% confidence interval [CI], 61.7%-98.1%; P = .001) for infants aged <6 months. The unadjusted effectiveness was 90.7% (95% CI, 59.9%-97.8%; P = .001)., Conclusions: Influenza vaccine given to pregnant women is 91.5% effective in preventing hospitalization of their infants for influenza in the first 6 months of life.

Although varicella vaccine is given to clinically stable human immunodeficiency virus (HIV)-infected children, its effectiveness is unknown. We assessed its effectiveness by reviewing the medical records of closely monitored HIV-infected children, including those receiving highly active antiretroviral therapy (HAART) between 1989 and 2007. Varicella immunization and development of varicella or herpes zoster were noted. Effectiveness was calculated by subtracting from 1 the rate ratios for the incidence rates of varicella or herpes zoster in vaccinated versus unvaccinated children. The effectiveness of the vaccine was 82% (95% confidence interval [CI], 24%-99%; P = .01) against varicella and was 100% (95% CI, 67%-100%; P < .001) against herpes zoster. When the analysis was controlled for receipt of HAART, vaccination remained highly protective against herpes zoster.

KI virus was detected in respiratory secretions of 8/367 (2.2%) symptomatic and 0/96 asymptomatic children (p = 0.215). WU virus was detected in 26/367 (7.1%) symptomatic and 6/96 (6.3%) asymptomatic children (p = 1.00). These human polyomaviruses may not independently cause respiratory tract disease in young children.

A program of routine varicella vaccination of children 12-18 months of age, begun in the United States in 1995, has been very successful in reducing the incidence of varicella. Varicella-zoster virus (VZV), in both wild-type and live attenuated forms, is notable for its ability to produce latent infection of sensory neurons from which it can later reactivate to cause herpes zoster (HZ). Therefore, the effects of vaccination on this secondary VZV-related disease are important to consider; in practice, however, such studies are complicated by the typically long delay between acquisition of the virus and its reactivation. Studies of immunocompromised children have shown that vaccination is relatively protective against HZ in this highly vulnerable group. We now present long-term follow-up data on a group of individuals who received varicella vaccine as healthy young adults 10-26 years ago and who have been followed prospectively by means of active surveillance. Among some 2000 person-years of follow-up, 2 cases of HZ have occurred, for a rate of 1.00 case/1000 person-years. Overall, the incidence of HZ in this cohort, therefore, is similar to published data for the US population in the prevaccine era.

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

Background: Human bocavirus (HBoV) is a newly identified human parvovirus that was originally identified in the respiratory secretions of children with respiratory tract disease. To further investigate the epidemiological profile and clinical characteristics of HBoV infection, we screened infants and children <2 years of age (hereafter referred to as "children") for HBoV., Methods: Children for whom respiratory specimens submitted to a diagnostic laboratory tested negative for respiratory syncytial virus, parainfluenza viruses (types 1-3), influenza A and B viruses, and adenovirus, as well as asymptomatic children, underwent screening for HBoV by use of polymerase chain reaction (PCR). Respiratory specimens were obtained from the children from 1 January 2004 through 31 December 2004., Results: Twenty-two (5.2%) of the 425 children who had a respiratory specimen submitted to the diagnostic laboratory and 0 of the 96 asymptomatic children were found to be positive for HBoV by PCR (P=.02). Fever, rhinorrhea, cough, and wheezing were observed in > or =50% of the HBoV-positive children. Of the 17 children who had chest radiography performed, 12 (70.6%) had abnormal findings. HBoV appeared to have a seasonal distribution. Nucleotide polymorphisms were detected in the viral capsid protein (VP) 1/VP2 genes. Two distinct HBoV genotypes circulated during the study period., Conclusions: HBoV is circulating in the United States and is associated with both upper and lower respiratory tract disease in infants and young children.

Kawasaki disease is a systemic vasculitis of childhood; its etiology is unknown. We identified evidence of a novel human coronavirus, designated "New Haven coronavirus" (HCoV-NH), in respiratory secretions from a 6-month-old infant with classic Kawasaki disease. To further investigate the possible association between HCoV-NH infection and Kawasaki disease, we conducted a case-control study. Specimens of respiratory secretions from 8 (72.7%) of 11 children with Kawasaki disease and from 1 (4.5%) of 22 control subjects (children without Kawasaki disease matched by age and the time the specimens were obtained) tested positive for HCoV-NH by reverse-transcriptase polymerase chain reaction (Mantel-Haenszel matched odds ratio, 16.0 [95% confidence interval, 3.4-74.4]; P=.0015). These data suggest that HCoV-NH infection is associated with Kawasaki disease.

Electronic Health Records (EHRs) are designed for patient-centered care and not for cross-patient analyses. Thus to ensure that measurements of quality of care derived from data extracted from EHRs are meaningful, they must be validated.1 We present preliminary data regarding validation of measurements of quality of care in a pediatric clinic.

From February to April 2003, we performed an e-mail-based survey to assess responses of physicians at Yale University to being offered smallpox vaccine. Of 58 respondents, 3 (5%) had been or intended to be vaccinated. Reasons cited for declining vaccination included: belief that benefits did not outweigh risks (55%), belief that the vaccination program was unnecessary (18%), desire to wait and see what side effects occurred in vaccinees (11%), and worries about compensation or liability (7%). Most (94%) considered risks to themselves, family, or patients in their decision. Only 3% thought a smallpox attack in the next 5 years was likely or very likely. Physicians did not accept the smallpox vaccine because they did not believe the potential benefits were sufficient.

Lyme disease, which is caused by Borrelia burgdorferi and transmitted in the United States primarily by Ixodes scapularis (the deer tick), is the most common vector borne disease in the United States. Its most frequent manifestation, a characteristic, expanding annular rash (erythema migrans), sometimes accompanied by myalgia, arthralgia, and malaise, occurs in nearly 90% of persons with symptomatic infection. Other manifestations of Lyme disease include seventh cranial nerve palsy, aseptic meningitis, and arthritis. Extensive coverage in the press about the serious effects of Lyme disease has led to widespread anxiety about this illness that is far out of proportion to the actual morbidity that it causes. This problem is exacerbated by the frequent use of serological tests to eliminate the possible diagnosis of Lyme disease in persons with only nonspecific symptoms (such as arthralgia or fatigue) who have a very low probability that Lyme disease is the cause of their symptoms. Consequently, misdiagnosis is frequent and is the most common cause of failure of treatment. The prognosis for most persons with Lyme disease is excellent.

Pneumococcal antibody levels surrounding systemic pneumococcal illness (SPI) were measured in children infected with human immunodeficiency virus (HIV). Archived serum samples were collected from 28 HIV-infected children who had 34 cases of SPI, caused by pneumococcal groups 4, 6, 9, 14, 19, and 23. Serum samples collected within 23 weeks before and 13 weeks after the SPI were assayed by ELISA for antipneumococcal polysaccharide (PnPs) IgG antibody to 6 representative pneumococcal serotypes. There was a wide range (0. 16-30.80 microg/mL) of pre-SPI anti-PnPs antibody levels to the presumed infecting serotypes, with a geometric mean level of 0.83 microg/mL (n=34). Seventy-six percent of the antibody values were <2.0 microg/mL, and 95% were <5.0 microg/mL. Homologous seroresponses (>/=4-fold rise in anti-PnPs antibody) were detected in only 4 (27%) of 15 paired serum samples. Heterologous, noninfecting group seroresponses were detected frequently (72%) in the paired serum samples from these 4 homologous group seroresponders.

In a prospective cohort study of 267 children born to mothers infected with HIV-1 in New Haven, Connecticut, an abrupt decline in the risk of mother-to-child transmission occurred in 1990 and persisted at least through December, 1993. A retrospective, observational study was undertaken to identify factors that might be responsible for this decline. Three variables were assessed: the use of orally administered zidovudine during pregnancy, the CD4+ T-lymphocyte count of the mother, and the mode of delivery. The risk of transmission was 18.6% (36/194; 95% CI: 14.1-24.8%) in infants of all women not treated with zidovudine compared with 5.5% (3/55; 95% CI: 1.1-15.1%) in infants of all women who were treated (odds ratio: 0.25; p = 0.02). In a subgroup of women with known CD4+ cell counts, the risk of transmission was 21.1% (20/95; 95% CI: 13.4-30.6%) in untreated women compared with 5.5% (3/55) in those who received zidovudine (odds ratio: 0.22; p = 0.01). In women with CD4+ T-cell counts < 200/microl, the differences remained significant (39.1% in those not treated vs. 4.2% in those treated; p < 0.004). There was an inverse relationship between CD4+ cell count and risk of transmission: among untreated mothers whose T-lymphocyte counts were > or = 500, 200-499, or < 200/microl, HIV-1 was transmitted to the offspring of 8.2, 30.4, and 39.1% of offspring, respectively (p < 0.002 by the exact trend test). There was no significant association between mode of delivery and vertical transmission of HIV. We conclude that treatment with orally administered zidovudine alone (500 mg/day) in the course of routine prenatal care is associated with a significant reduction in the risk of vertical transmission.

Using the results of Epstein-Barr virus-specific immunofluorescence serology as the "gold standard," we found that the sensitivities of the five rapid test kits varied from 78 to 84% and specificities varied from 89 to 100%. Enzyme-linked immunosorbent assay-determined specific Epstein-Barr virus antibody profiles had a sensitivity and specificity of 98.6 and 95.5%, respectively.

We conducted a matched case-control study to identify risk factors for first febrile seizures, with special emphasis on characteristics of the acute illness episode. Cases were identified through hospital emergency departments; controls were identified through outpatient clinics and emergency departments. Sixty-nine children with first febrile seizures and no history of previous unprovoked seizures were matched for age (+/- 6 months), site of routine pediatric care, and date of visit (+/- 2 weeks) with 1 or 2 febrile controls who had no history of previous febrile or unprovoked seizures. Medical records for the index visit were reviewed, and parents were interviewed by telephone. Illness characteristics examined included height of temperature, type of underlying illness, contact with a physician during the illness but before the index visit, and use of acetaminophen or decongestants. Family history of febrile and of unprovoked seizures, sociodemographic characteristics, daycare use, and selected pre- and perinatal variables were also studied. On multivariable analysis, significant independent risk factors were height of temperature, history of febrile seizures in a first- or in a higher degree relative. Gastroenteritis as the underlying illness had a significant inverse (i.e., protective) association with febrile seizures. Maternal smoking during pregnancy was a marginally significant predictor of febrile seizures.

To determine the risk of acquiring Lyme disease or babesiosis from blood transfusion, serum was collected before and 6 weeks after patients received multiple transfusions during cardiothoracic surgery and antibodies to Borrelia burgdorferi and Babesia microti were measured. Of 155 subjects, 149 received 601 total units of packed red blood cells (PRBC) and 48 received 371 total units of platelets. No patient developed clinical or serologic evidence of Lyme disease; 1 (who received 5 units of PRBC) developed clinical and serologic evidence of babesiosis. The risk of acquiring Lyme disease from a transfused unit of PRBC was 0 (95% confidence interval [CI], 0-0.5%) and from a transfused unit of platelets was 0 (95% CI, 0-0.8%); the same risks for babesiosis were 0.17% (95% CI, 0.004%-0.9%) and 0 (95% CI, 0-0.8%), respectively. The risk of acquiring either Lyme disease or babesiosis from a blood transfusion in Connecticut is very low.