Publications by authors named "Carlos R Oliveira"

41 Publications

Effectiveness of HPV vaccine by age at vaccination and number of doses: protocol for a population-based matched case-control study.

BMJ Open 2021 Apr 19;11(4):e043093. Epub 2021 Apr 19.

Epidemiology of Microbial Diseases, Yale University School of Public Health, New Haven, Connecticut, USA.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-043093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057558PMC
April 2021

The clinical epidemiology of coronavirus disease 2019 in children and adolescents mirrors the widening gap in healthcare disparities.

Curr Opin Pediatr 2021 06;33(3):281-285

Department of Pediatrics, Section of Infectious Diseases and Global Health, Yale University School of Medicine.

Purpose Of Review: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has exacerbated the longstanding racial/ethnic health disparities in the USA, with a disproportionately negative effect on children of color. This review summarizes recently published studies that describe the clinical epidemiology and racial/ethnic disparities associated with SARS-CoV-2 in children.

Recent Findings: Children with SARS-CoV-2 infections manifest with a wide spectrum of disease. Most are either asymptomatic or mildly symptomatic with fever, gastrointestinal, and/or upper respiratory disease. Some children can progress to develop severe lower respiratory disease or a hyper-inflammatory, Kawasaki-like syndrome leading to cardiovascular shock. Although SARS-CoV-2-related deaths in children are rare, more children died within the first nine months of the pandemic than have died during any influenza season over the last decade.Black and Hispanic children represent less than 41% of the US population but account for three out of every four SARS-CoV-2-related hospitalizations and deaths in the USA. The drivers of these disparities in children are complex and likely a combination of societal, biological, and behavioral influences.

Summary: This pandemic brought to light longstanding health disparities in historically marginalized populations, and minority children have suffered tremendously. It provides an opportunity to understand how a virus hijacked deep-rooted inequities, address these inequities, and work to prevent this outcome in future pandemics/epidemics.
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http://dx.doi.org/10.1097/MOP.0000000000001018DOI Listing
June 2021

Inpatient Immunization With HPV Vaccine: A Qualitative Study With Postpartum Women.

Womens Health Issues 2021 Mar 11. Epub 2021 Mar 11.

Department of Obstetrics, Gynecology, & Reproductive Sciences, School of Medicine, Yale University, New Haven, Connecticut. Electronic address:

Introduction: Rates of immunization with human papillomavirus (HPV) vaccine among adolescent and young adult females remain suboptimal. There is a continued need to focus on catch-up immunization. Some hospitals in the United States have implemented inpatient postpartum HPV immunization programs (IPP-HPV) as part of a strategy to improve rates of catch-up immunization. Patients' perspectives are critical to facilitating broad adoption of IPP-HPV. The objectives of this study were to understand the experiences and perspectives of postpartum women recommended to receive HPV vaccine before hospital discharge and to identify facilitators of and barriers to program implementation.

Methods: We conducted in-depth semistructured interviews with postpartum women eligible for IPP-HPV. We used purposive sampling to ensure representation across race, ethnicity, and language. Interviews were analyzed using an iterative thematic approach.

Results: The median age of participants (n = 24) was 22 years (range, 15-26 years), and six had declined the inpatient dose of HPV vaccine. Overall, women viewed IPP-HPV favorably. Facilitators of program implementation included viewing HPV vaccine as prevention, normalization of the vaccine, convenience of IPP-HPV, and the experience of a patient-centered approach. Barriers included the peripartum environment and associated stress, vaccine hesitancy, and a lack of both awareness of and knowledge about HPV vaccine.

Conclusions: IPP-HPV immunization is a strategy well-received by women for improving rates of catch-up immunization. The implementation of such programs may be optimized by increasing awareness that the vaccine is available and recommended for postpartum women, and by using a patient-centered approach that is sensitive to the needs of postpartum patients.
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http://dx.doi.org/10.1016/j.whi.2021.02.002DOI Listing
March 2021

Monitoring HPV vaccine impact on cervical disease: Status and future directions for the era of cervical cancer elimination.

Prev Med 2021 Mar 4;144:106363. Epub 2021 Mar 4.

Yale School of Public Health, Department of Epidemiology of Microbial Diseases, USA. Electronic address:

Post-licensure monitoring of the impact of HPV vaccines is critical to track the progress being made toward cervical cancer elimination and to identify areas where further progress can accelerate the achievement of this important public health goal. Over the past decade, a large body of evidence has revealed convincing benefits of HPV vaccination in preventing cervical infections and precancers at the individual-level (i.e., direct effectiveness) as well as in reducing the population-level burden of disease (i.e., overall effectiveness). At this time, effectiveness of the vaccines on preventing cervical cancer is just beginning to emerge given that there is a prolonged latency period for invasive disease. As we enter the era of cervical cancer elimination, these early and promising results may be expected in other countries in the near future. Thus, monitoring the direct and overall effectiveness for cervical cancer is an urgent research priority. In this article, we summarize what is known about the effectiveness of HPV vaccines on precancerous outcomes, and we highlight considerations for continuing these important public health activities going forward to monitor progress toward cervical cancer elimination.
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http://dx.doi.org/10.1016/j.ypmed.2020.106363DOI Listing
March 2021

Angiotensin II modulates the murine hematopoietic stem cell and progenitors cocultured with stromal S17 cells.

Cell Biol Int 2021 Mar 6. Epub 2021 Mar 6.

Departamento de Farmacologia, Escola Paulista de Medicina, Instituto Nacional de Farmacologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.

Although the existence of the renin-angiotensin system (RAS) in the bone marrow is clear, the exact role of this system in hematopoiesis has not yet been fully characterized. Here the direct role of angiotensin II (AngII) in hematopoietic stem cells (HSCs), common myeloid progenitors (CMPs), granulocyte/monocyte progenitors (GMPs), and megakaryocytes/erythroid progenitors (MEPs), using a system of coculture with stromal S17 cells. Flow cytometry analysis showed that AngII increases the percentage of HSC and GMP, while reducing CMP with no effect on MEP. According to these data, AngII increased the total number of mature Gr-1 /Mac-1 cells without changes in Terr119 cells. AngII does not induce cell death in the population of LSK cells. In these populations, treatment with AngII decreases the expression of Ki67 protein with no changes in the Notch1 expression, suggesting a role for AngII on the quiescence of immature cells. In addition, exposure to AngII from murine bone marrow cells increased the number of CFU-GM and BFU-E in a clonogenic assay. In conclusion, our data showed that AngII is involved in the regulation of hematopoiesis with a special role in HSC, suggesting that AngII should be evaluated in coculture systems, especially in cases that require the expansion of these cells in vitro, still a significant challenge for therapeutic applications in humans.
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http://dx.doi.org/10.1002/cbin.11584DOI Listing
March 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Testing in Children in a Large Regional US Health System During the Coronavirus Disease 2019 Pandemic.

Pediatr Infect Dis J 2021 03;40(3):175-181

Department of Infection Prevention, Yale New Haven Hospital.

Background: The objective was to evaluate patterns of pediatric coronavirus disease 2019 testing in a large health system throughout the pandemic, before and after school reopening.

Methods: This was a cross-sectional time-series study of clinical virology results from children tested for severe acute respiratory syndrome coronavirus 2 in Southern Connecticut and areas of New York and Rhode Island. Data collected include demographics, hospital admission, changes in percent positive tests over time, detection intervals in persistently positive children and cycle threshold values. The setting was the Yale New Haven Health System has 6 hospitals at 4 Connecticut locations, 1 hospital in Rhode Island and ambulatory locations in Connecticut, Rhode Island and New York. Participants included twenty-three-thousand one-hundred thirty-seven children ≤ 18 years of age, tested for coronavirus disease 2019 at an ambulatory testing site, the emergency department or on an inpatient unit within the Yale New Haven Health System.

Results: Among all tests, 3.2% were positive. Older children consistently made up the larger portion of positive pediatric cases, regardless of community prevalence. Increased pediatric cases later in the pandemic when prevalence in adults was relatively low correlates with a higher number of tests performed in children and not with an increased positivity rate. No significant changes in trends of positivity were detected after the reopening of schools. Symptomatic and asymptomatic children had similar cycle threshold values regardless of age, and a subset of children demonstrated persistent viral detection, some for as long as 6 weeks.

Conclusion: An increase in pediatric cases documented in the late summer was predominately due to increased access to testing for children. The percent positivity in children did not change in the first 3 weeks after school opened. A subset of children has detectable severe acute respiratory syndrome coronavirus 2 RNA in the upper respiratory tract for weeks after the initial infection.
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http://dx.doi.org/10.1097/INF.0000000000003024DOI Listing
March 2021

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of COVID-19 in Children and Adolescents.

J Pediatric Infect Dis Soc 2021 Jan 3. Epub 2021 Jan 3.

Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, New York, New York, USA.

Background: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for two novel virus-neutralizing monoclonal antibody therapies, bamlanivimab, and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate COVID-19 in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.

Methods: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.

Results: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.

Conclusions: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence, and ensure implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.
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http://dx.doi.org/10.1093/jpids/piaa175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799019PMC
January 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth.

J Pediatr 2021 03 14;230:23-31.e10. Epub 2020 Nov 14.

Department of Pediatrics, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY.

Objective: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity.

Study Design: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut.

Results: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 10 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity.

Conclusions: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666535PMC
March 2021

Evaluation of an Inpatient Postpartum Human Papillomavirus Immunization Program.

Obstet Gynecol 2020 11;136(5):1006-1015

Department of Obstetrics, Gynecology & Reproductive Sciences and the Department of Pediatrics, Yale School of Medicine, and the Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut.

Objective: To evaluate the result of an inpatient postpartum human papillomavirus (HPV) immunization pilot program in a diverse, low-income patient population from an urban, hospital-based obstetrics and gynecology clinic.

Methods: In this cohort study, we present results from the first 2 years of the inpatient postpartum HPV immunization program, in which vaccine-eligible postpartum women were identified and immunized during their hospital stays. The program was implemented after educational outreach with prenatal and postpartum clinicians and nurses. Associations between receipt of the HPV vaccine as an inpatient and the characteristics of patients, and the likelihood of and missed opportunities for receiving a subsequent dose of the HPV vaccine as an outpatient were determined using logistic regression, time-to-event analyses, chi-squared tests and t-tests.

Results: From April 11, 2017, to April 10, 2019, 394 (59.2%) of 666 postpartum women were eligible for the inpatient postpartum HPV immunization program. The majority (265/394, 67.3%) received the immunization pilot program HPV dose; 36 of those 265 (13.6%) completed the series with that dose. Among women due for additional doses after hospital discharge, those who received the inpatient dose were more likely to receive a subsequent outpatient dose (138/229) than were those who did not receive an inpatient dose (39/129; hazard ratio 2.51, 95% CI 1.76-3.58). On average, there were 30.7 fewer (95% CI 5.8-55.6, P<.02) missed opportunities for subsequent outpatient doses for every 100 eligible visits among women who received the inpatient dose, compared with women who did not. By the end of the study, the proportion of women who had completed the vaccine series was higher among women who received the inpatient dose (95/265, 35.8%) than in those who did not (12 out 129, 9.3%; odds ratio 5.45, 95% CI 2.86-10.38).

Conclusion: The inpatient postpartum HPV immunization program was associated with increased rates of immunization and addressed a previously missed opportunity. Inpatient immunization programs can serve as a critical way to address gaps in vaccine uptake.
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http://dx.doi.org/10.1097/AOG.0000000000004097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584732PMC
November 2020

Disparities in the Epidemiology of Anal Cancer: A Cross-Sectional Time Series.

Health Equity 2020 16;4(1):382-385. Epub 2020 Sep 16.

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.

To assess the trends and sociodemographic disparities of anal cancer. For this time series, billing claims were reviewed for all encounters between 2007 and 2011 in the Yale New Haven Health System. 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; ≤0.01) and poverty (IRR=1.72; =0.04). 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.
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http://dx.doi.org/10.1089/heq.2020.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501948PMC
September 2020

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

J Pediatric Infect Dis Soc 2021 Feb;10(1):34-48

Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, New York, New York, USA.

Background: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.

Methods: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.

Results: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.

Conclusions: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.
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http://dx.doi.org/10.1093/jpids/piaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543452PMC
February 2021

Ethical and Public Health Implications of Targeted Screening for Congenital Cytomegalovirus.

Pediatrics 2020 07;146(1)

Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.

Congenital cytomegalovirus (cCMV) is the most common congenital infection and is associated with sensorineural hearing loss, developmental delays, and visual impairment. The clinical presentation of cCMV is variable, and the majority (80%-90%) of newborns will never manifest any clinical symptoms. Given the clinical heterogeneity of cCMV infection, it is challenging to identify which newborns may benefit from testing. Recently, certain states have implemented a targeted screening program in which newborns who fail the newborn hearing screen are tested for cCMV. Clinicians and legislative bodies have been propelled into debates about the ethical and moral permissibility of a targeted cCMV screening approach. Those who oppose this screening approach describe undue burden on patients, families, and the health care system because the majority of newborns who fail the newborn hearing screen and have cCMV will not go on to have any sequelae related to cCMV, including hearing loss. However, those who support this screening approach cite the importance of early detection and ongoing surveillance for hearing loss and developmental delays in this high-risk group of newborns. This debate will be considered by experts in the field.
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http://dx.doi.org/10.1542/peds.2020-0617DOI Listing
July 2020

Natural Language Processing for Surveillance of Cervical and Anal Cancer and Precancer: Algorithm Development and Split-Validation Study.

JMIR Med Inform 2020 Nov 3;8(11):e20826. Epub 2020 Nov 3.

Departments of Emergency Medicine, Biostatistics, and Health Informatics, Yale Schools of Medicine and Public Health, New Haven, CT, United States.

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.
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http://dx.doi.org/10.2196/20826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671846PMC
November 2020

Feasibility and Accuracy of a Computer-Assisted Self-Interviewing Instrument to Ascertain Prior Immunization With Human Papillomavirus Vaccine by Self-Report: Cross-Sectional Analysis.

JMIR Med Inform 2020 Jan 22;8(1):e16487. Epub 2020 Jan 22.

Department of Epidemiology of Microbial Diseases, Yale University School of Public Health, New Haven, CT, United States.

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.
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http://dx.doi.org/10.2196/16487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003116PMC
January 2020

Trends in Anogenital Wart Diagnoses in Connecticut, 2013-2017.

JAMA Netw Open 2020 01 3;3(1):e1920168. Epub 2020 Jan 3.

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamanetworkopen.2019.20168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042856PMC
January 2020

Lyme Arthritis and Clinical Judgment.

Pediatrics 2020 01 13;145(1). Epub 2019 Dec 13.

Department of Pediatrics, Yale School of Medicine and

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http://dx.doi.org/10.1542/peds.2019-1998DOI Listing
January 2020

One-step fiber post cementation and core build-up in endodontically treated tooth: A clinical case report.

J Esthet Restor Dent 2020 Jan 23;32(1):5-11. Epub 2019 Nov 23.

Department of Dental Materials and Prosthodontics, Araraquara Dental School, Sao Paulo State University (UNESP), Araraquara, São Paulo, Brazil.

Objective: This clinical case report addresses the step-by-step of the application of a core-and-post system that uses a single resin composite material to fiber post cementation and core build-up in a maxillary left central incisor.

Clinical Considerations: The literature reports several materials and methods for the restoration of endodontically treated teeth with coronal destruction that require an intra-radicular fiber post for the core build-up. The present case report describes a core-and-post or "monoblock" technique. A dual resin composite (Core-X Flow; Dentsply DeTrey) highly filled material and cement was used for luting the fiber post (Blue X-Post) and build-up the core structure in an easy application.

Conclusions: The "core-and-post" technique that uses a single material system protocol minimizes the material interfaces, steps of procedures, and chair-time in comparison to conventional techniques.

Clinical Significance: The use of different materials for post cementation and core build-up requires more steps, which increases the chair-time and number of interfaces among the materials. Since the "monoblock" technique uses only one material, it can streamline the clinical procedures, thus, saving time and materials. Moreover, techniques based on core-and-post systems are easily applied, versatile, and esthetics, and can be applicable to posterior and anterior teeth.
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http://dx.doi.org/10.1111/jerd.12551DOI Listing
January 2020

Compliance with cervical cancer screening guidelines in young female patients: rates and trends of screening in New Haven County, CT.

Am J Obstet Gynecol 2019 11 4;221(5):530-532. Epub 2019 Jul 4.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1016/j.ajog.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829042PMC
November 2019

Medicinal properties of Angelica archangelica root extract: Cytotoxicity in breast cancer cells and its protective effects against in vivo tumor development.

J Integr Med 2019 Mar 8;17(2):132-140. Epub 2019 Feb 8.

Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04044-020, Brazil. Electronic address:

Objective: Although Angelica archangelica is a medicinal and aromatic plant with a long history of use for both medicinal and food purposes, there are no studies regarding the antineoplastic activity of its root. This study aimed to evaluate the cytotoxicity and antitumor effects of the crude extract of A. archangelica root (CEAA) on breast cancer.

Methods: The cytotoxicity of CEAA against breast adenocarcinoma cells (4T1 and MCF-7) was evaluated by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Morphological and biochemical changes were detected by Hoechst 33342/propidium iodide (PI) and annexin V/PI staining. Cytosolic calcium mobilization was evaluated in cells staining with FURA-4NW. Immunoblotting was used to determine the effect of CEAA on anti- and pro-apoptotic proteins (Bcl-2 and Bax, respectively). The 4T1 cell-challenged mice were used for in vivo assay.

Results: Using ultra-high-performance liquid chromatography-mass spectrometry analysis, angelicin, a constituent of the roots and leaves of A. archangelica, was found to be the major constituent of the CEAA evaluated in this study (73 µg/mL). The CEAA was cytotoxic for both breast cancer cell lines studied but not for human fibroblasts. Treatment of 4T1 cells with the CEAA increased Bax protein levels accompanied by decreased Bcl-2 expression, in the presence of cleaved caspase-3 and cytosolic calcium mobilization, suggesting mitochondrial involvement in breast cancer cell death induced by the CEAA in this cell line. No changes on the Bcl-2/Bax ratio were observed in CEAA-treated MCF7 cells. Gavage administration of the CEAA (500 mg/kg) to 4T1 cell-challenged mice significantly decreased tumor growth when compared with untreated animals.

Conclusion: Altogether, our data show the antitumor potential of the CEAA against breast cancer cells in vitro and in vivo. Further research is necessary to better elucidate the pharmacological application of the CEAA in breast cancer therapy.
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http://dx.doi.org/10.1016/j.joim.2019.02.001DOI Listing
March 2019

Human Papillomavirus Vaccination and Anogenital Warts: A Systematic Review of Impact and Effectiveness in the United States.

Sex Transm Dis 2019 04;46(4):213-220

Pediatrics, Yale School of Medicine, New Haven, CT.

Background: Assessing the impact and effectiveness of HPV vaccines on anogenital warts in the United States can provide early indication of the success of vaccination programs as well as identify potential areas for improvement.

Methods: Articles were identified from the PubMed, Medline, and Embase databases. Exclusion criteria were applied, and remaining studies were then classified as impact or effectiveness studies.

Results: Eight eligible studies published through March 2018 were included. Population-based impact studies examining trends in diagnoses reported consistent declines in females ages 25 years and younger after 2006 when routine female vaccination began in the United States. Declines in males ages 25 years and younger were also seen; however, these declines were lower than those in females and more evident after routine male vaccination began in 2011. Among females and males older than 25 years, little to no change has been seen in the trends of anogenital warts since 2006. Studies that included the pre-vaccine era (before 2006) reported increasing trends during this period. After vaccine introduction, a reversal in these trends was observed. Effectiveness studies that included individual-level vaccination histories consistently demonstrated a lower risk of anogenital warts for those receiving at least one dose of the vaccine compared to those unvaccinated.

Conclusions: These findings suggest that the degree of HPV vaccine impact has varied substantially by age and sex. Achieving the full prevention potential of HPV vaccines will likely require greater coverage among both females and males. Post-licensure estimates of effectiveness demonstrate the real-world benefit of the vaccine.
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http://dx.doi.org/10.1097/OLQ.0000000000000948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640846PMC
April 2019

Impact of a clinical interventions bundle on uptake of HPV vaccine at an OB/GYN clinic.

Vaccine 2018 06 11;36(25):3599-3605. Epub 2018 May 11.

Department of Obstetrics, Gynecology, & Reproductive Sciences, School of Medicine, Yale University, PO Box 208063, New Haven, CT 06520-8063, United States. Electronic address:

Introduction: HPV vaccine uptake is lowest among young adults. Little is known about the most effective way to decrease missed opportunities (MO) and increase uptake of the vaccine in this vulnerable population.

Objectives: To determine the impact of a clinical intervention bundle on the rate of MO and uptake of the vaccine among young adult women.

Methods: From 2/2014 to 7/2015, an intervention bundle (designating physician and nurse champions, pre-screening patients' charts, empowering nurses to recommend immunization, providing no-cost vaccinations, placing prompts in clinic note templates, eliminating requirement for pre-vaccination pregnancy test) was implemented at an urban, hospital-based OB/GYN clinic. Medical records were reviewed for all vaccine-eligible (non-pregnant, 11-26 years) women seen between 2/2013 and 9/2016. Impact of the bundled interventions on the monthly rates of MO and vaccine uptake was estimated by analyzing immunization trends with an interrupted time-series model using counterfactual comparison groups in order to control for pre-existing trends.

Results: There were 6,463 vaccine-eligible visits during our study period. The prevalence of women who had both completed and initiated the series was significantly higher, 20.3% and 29.7% respectively, in the last month, compared to their counterfactuals (p < 0.01). In the last study month, the rate of MO was significantly lower than its counterfactual (19.73 per 100 encounters lower, p < 0.01). Hispanic women had attributable reductions in their rates of MO that were twice that of White women. Statistically significant attributable reductions were also seen among Spanish speakers, publicly insured, and uninsured women.

Conclusions: Implementation of this intervention bundle effectively reduced the monthly rate of MO and increased the prevalence of women who had initiated and completed the HPV vaccine series. The reduction of MO was most drastic among Hispanic, publicly insured and uninsured women compared to White and privately insured.
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http://dx.doi.org/10.1016/j.vaccine.2018.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314176PMC
June 2018

Missed opportunities for HPV immunization among young adult women.

Am J Obstet Gynecol 2018 03 6;218(3):326.e1-326.e7. Epub 2017 Dec 6.

Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, Yale University, New Haven.

Background: Despite the availability of a safe and efficacious vaccine against human papillomavirus, uptake of the vaccine in the United States is low. Missed clinical opportunities to recommend and to administer human papillomavirus vaccine are considered one of the most important reasons for its low uptake in adolescents; however, little is known about the frequency or characteristics of missed opportunities in the young adult (18-26 years of age) population.

Objective: The objective of the study was to assess both the rates of and the factors associated with missed opportunities for human papillomavirus immunization among young adult women who attended an urban obstetrics and gynecology clinic.

Study Design: In this cross-sectional study, medical records were reviewed for all women 18-26 years of age who were underimmunized (<3 doses) and who sought care from Feb. 1, 2013, to January 31, 2014, at an urban, hospital-based obstetrics and gynecology clinic. A missed opportunity for human papillomavirus immunization was defined as a clinic visit at which the patient was eligible to receive the vaccine and a dose was due but not administered. Multivariable logistic regression was used to test associations between sociodemographic variables and missed opportunities.

Results: There were 1670 vaccine-eligible visits by 1241 underimmunized women, with a mean of 1.3 missed opportunities/person. During the study period, 833 of the vaccine eligible women (67.1%) had at least 1 missed opportunity. Overall, the most common types of visits during which a missed opportunity occurred were postpartum visits (17%) or visits for either sexually transmitted disease screening (21%) or contraception (33%). Of the patients with a missed opportunity, 26.5% had a visit at which an injectable medication or a different vaccine was administered. Women who identified their race as black had higher adjusted odds of having a missed opportunity compared with white women (adjusted odds ratio, 1.61 [95% confidence interval, 1.08-2.41], P < .02). Women who reported a non-English- or non-Spanish-preferred language had lower adjusted odds of having a missed opportunity (adjusted odds ratio, 0.25 [95% confidence interval, 0.07-0.87], P = .03). No other patient characteristics assessed in this study were significantly associated with having a missed opportunity.

Conclusion: A majority of young-adult women in this study had missed opportunities for human papillomavirus immunization, and significant racial disparity was observed. The greatest frequency of missed opportunities occurred with visits for either contraception or for sexually transmitted disease screening.
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http://dx.doi.org/10.1016/j.ajog.2017.11.602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924702PMC
March 2018

Cafestol, a diterpene molecule found in coffee, induces leukemia cell death.

Biomed Pharmacother 2017 Aug 10;92:1045-1054. Epub 2017 Jun 10.

Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address:

To evaluate the antitumor properties of Cafestol four leukemia cell lines were used (NB4, K562, HL60 and KG1). Cafestol exhibited the highest cytotoxicity against HL60 and KG1 cells, as evidenced by the accumulation of cells in the sub-G1 fraction, mitochondrial membrane potential reduction, accumulation of cleaved caspase-3 and phosphatidylserine externalization. An increase in CD11b and CD15 differentiation markers with attenuated ROS generation was also observed in Cafestol-treated HL60 cells. These results were similar to those obtained following exposure of the same cell line to cytarabine (Ara-C), an antileukemic drug. Cafestol and Ara-C reduced the clonogenic potential of HL60 cells by 100%, but Cafestol spared murine colony forming unit- granulocyte/macrophage (CFU-GM), which retained their clonogenicity. The co-treatment of Cafestol and Ara-C reduced HL60 cell viability compared with both drugs administered alone. In conclusion, despite the distinct molecular mechanisms involved in the activity of Cafestol and Ara-C, a similar cytotoxicity towards leukemia cells was observed, which suggests a need for prophylactic-therapeutic pre-clinical studies regarding the anticancer properties of Cafestol.
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http://dx.doi.org/10.1016/j.biopha.2017.05.109DOI Listing
August 2017

Association between Carotid Intima Media Thickness and Heart Rate Variability in Adults at Increased Cardiovascular Risk.

Front Physiol 2017 26;8:248. Epub 2017 Apr 26.

Center of Innovation, Technology and Education at Anhembi Morumbi University-Laureate International UniversitiesSao Jose dos Campos, Brazil.

Atherosclerotic carotid intima-media thickness (IMT) may be associated with alterations in the sensitivity of carotid baroreceptors. The aim of this study was to investigate the association between carotid IMT and the autonomic modulation of heart rate variability (HRV). A total of 101 subjects were enrolled in this prospective observational study. The carotid IMT was determined by duplex ultrasonography. The cardiac autonomic function was determined through HRV measures during the Deep Breathing Test. Linear regression models, adjusted for demographics, comorbidities, body mass index, waist-hip-ratio, and left ventricular ejection fraction were used to evaluate the association between HRV parameters and carotid IMT. Participants had a mean age of 60.4 ± 13.4 years and an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk score (using the Pooled Cohort Equations) of 16.4 ± 17. The mean carotid media thickness was highest (0.90 ± 0.19 mm) in the first quartile of the standard deviation of all RR intervals (SDNN) (19.7 ± 5.1 ms) and progressively declined in each subsequent quartile to 0.82 ± 0.21 mm, 0.81 ± 0.16 mm, and 0.68 ± 0.19 in quartiles 2 (36.5 ± 5.9 ms), 3 (57.7 ± 6.2 ms) and 4 (100.9 ± 22.2 ms), respectively. In multivariable adjusted models, there was a statistical significant association between SDNN and carotid IMT (OR -0.002; 95%CI -0.003 to -0.001, = 0.005). The same significant association was found between carotid IMT and other measures of HRV, including coefficient of variation of RR intervals (CV) and dispersion of points along the line of identity (SD2). In a cohort of individuals at increased cardiovascular risk, carotid IMT as a marker of subclinical atherosclerosis was associated with alterations of HRV indicating an impaired cardiac autonomic control, independently of other cardiovascular risk factors.
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http://dx.doi.org/10.3389/fphys.2017.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405141PMC
April 2017

Influenza-like illness in an urban community of Salvador, Brazil: incidence, seasonality and risk factors.

BMC Infect Dis 2016 Mar 15;16:125. Epub 2016 Mar 15.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, Brazil.

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.
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http://dx.doi.org/10.1186/s12879-016-1456-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791800PMC
March 2016

Macular Star and Central Visual Loss: Two Pediatric Cases.

Clin Pediatr (Phila) 2016 May 16;55(5):496-8. Epub 2015 Aug 16.

Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1177/0009922815601033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849471PMC
May 2016

Update on persistent symptoms associated with Lyme disease.

Curr Opin Pediatr 2015 Feb;27(1):100-4

aDepartment of Pediatrics bDepartment of Epidemiology of Microbial Diseases cDepartment of Investigative Medicine, Yale University Schools of Medicine and of Public Health, Graduate School of Arts and Sciences, New Haven, Connecticut, USA.

Purpose Of Review: Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne illness in the United States. The pathogenesis, ecology, and epidemiology of Lyme disease have been well described, and antimicrobial treatment is very effective. There has been controversy about whether infection can persist and cause chronic symptoms despite treatment with antimicrobials. This review summarizes recent studies that have addressed this issue.

Recent Findings: The pathogenesis of persistent nonspecific symptoms in patients who were treated for Lyme disease is poorly understood, and the validity of results of attempts to demonstrate persistent infection with B. burgdorferi has not been established. One study attempted to use xenodiagnosis to detect B. burgdorferi in patients who have been treated for Lyme disease. Another study assessed whether repeated episodes of erythema migrans were due to the same or different strains of B. burgdorferi. A possible cause of persistent arthritis in some treated patients is slow clearance of nonviable organisms that may lead to prolonged inflammation. The results of all of these studies continue to provide evidence that viable B. burgdorferi do not persist in patients who receive conventional antimicrobial treatment for Lyme disease.

Summary: Patients with persistent symptoms possibly associated with Lyme disease often provide a challenge for clinicians. Recent studies have provided additional evidence that viable B. burgdorferi do not persist after conventional treatment with antimicrobials, indicating that ongoing symptoms in patients who received conventional treatment for Lyme disease should not be attributed to persistent active infection.

Video Abstract:
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http://dx.doi.org/10.1097/MOP.0000000000000167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417349PMC
February 2015

Complications of vaccination with bacille Calmette-Guérin.

Clin Pediatr (Phila) 2014 Aug 7;53(9):914-6. Epub 2014 May 7.

Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1177/0009922814533414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848971PMC
August 2014

Brain magnetic resonance imaging of infants with bacterial meningitis.

J Pediatr 2014 Jul 13;165(1):134-9. Epub 2014 Apr 13.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Children's Medical Center, Dallas, TX. Electronic address:

Objectives: To describe the results of brain magnetic resonance imaging (MRI) of infants with bacterial meningitis and how the findings affected clinical management.

Study Design: This retrospective study included all infants <12 months of age who were hospitalized at Children's Medical Center, Dallas and had culture-confirmed bacterial meningitis and a brain MRI from January 1, 2001 to December 1, 2011. Infants were identified by review of all positive bacterial cultures of cerebrospinal fluid (CSF) from the Children's Medical Center Microbiology Laboratory. Demographic, clinical, laboratory, and neuroimaging data were reviewed. Infants with ventriculoperitoneal shunt or whose CSF culture yielded skin commensals were excluded. A neuroradiologist blinded to clinical information reviewed all MRI studies.

Results: Of the 440 infants who had a positive CSF culture result, 111 (25%) had a pathogen isolated from CSF and were enrolled in the study. Of these, 68% (75/111) had a brain MRI performed during the hospitalization; abnormalities included leptomeningeal enhancement (57%), cerebral infarct (43%), subdural empyema (52%), cerebritis (26%), hydrocephalus (20%), and abscess (11%). By multiple logistic regression analysis, infants with late seizures and an abnormal neurologic examination were more likely to have an abnormal MRI (P < .05). MRI results led to neurosurgical intervention in 23% of infants; a positive bacterial culture of CSF obtained >48 hours after initiation of antibiotic therapy was associated with neurosurgical intervention (P = .01). Fourteen (19%) infants with bacterial meningitis had a normal brain MRI.

Conclusions: Brain MRIs were performed frequently and often were abnormal in infants with bacterial meningitis, leading to changes in clinical management.
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http://dx.doi.org/10.1016/j.jpeds.2014.02.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855593PMC
July 2014