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PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant therapy (NAT). Pathologic complete response (pCR) has become a prognostic marker for overall and disease-free survival. The aim of this study was to determine if dynamic contrast-enhanced (DCE)-MRI after 2 and/or 4 cycles of NAT can identify patients with a high likelihood of achieving pCR, triaging them to standard of care (SOC), or, when appropriate, to de-escalation trials. Conversely, we aimed to identify chemoresistant tumors that are unlikely to achieve pCR and may benefit from escalated targeted trials. METHOD AND MATERIALS 309 patients with stage I-III TNBC underwent DCE-MRI (temporal resolution: 9-12 sec) at baseline (BL), 2 cycles (C2), and 4 cycles (C4) of SOC doxorubicin/cyclophosphamide (AC) NAT as part of a prospective IRB-approved study (NCT02276443). Tumor volumes of the index lesion were calculated using 3 axis measurements during the early phase of the DCE-MRI (60s). Percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. Patients were randomly assigned to a training or a validation cohort in a 1:1 ratio. pCR was assessed at surgery after completion of SOC NAT. Correlation between pCR and TVR was evaluated using ROC analysis. RESULTS Of 309 TNBC patients, 136 (44%) achieved pCR. Following 2 cycles of NAT, TVR >80% was predictive of pCR (chemosensitivity), while TVR ≤ 55% was predictive of non-pCR (chemoresistance) with PPV 80%, NPV 89%, AUC 0.811 (0.73~0.893, p< 0.0001) in the training cohort, and PPV 82%, NPV 85%, AUC 0.815 (CI:0.736~0.894, p< 0.0001) in the validation cohort. Following 4 cycles of NAT, TVR >90% was predictive of pCR, while TVR ≤80% was predictive of non-pCR with PPV 80%, NPV 84%, AUC 0.827 (0.756~0.898, p< 0.0001) in the training cohort and with PPV 73%, NPV 82%, AUC 0.785 (CI:0.709~0.862, p< 0.001) in the validation cohort. Using this model, the pCR status was correctly classified in 50% of TNBC patients using C2 DCE-MRI in the training cohort, and 54% in the validation cohort. Only 8% were misclassified in the training cohort, and 10% in the validation cohort. Using C4 DCE-MRI, the pCR status of 61% and 57% of TNBC was correctly classified in the validation and the testing cohorts, respectively. 12% were misclassified in the validation cohort, and 21% in the testing cohort. CONCLUSION DCE-MRI after 2 and 4 cycles of AC-based NAT correctly predicted the pCR status of 54% and 57% of TNBC patients, respectively, as either excellent responders or nonresponders with high AUC 0.811 and 0.827. This may allow patients to be triaged to SOC NAT with option of de-escalation or early targeted therapies for non-responders. Citation Format: Mary S. Guirguis, Beatriz Adrada, Miral Patel, Frances Perez, Rosalind Candelaria, Wei Yang, Jia Sun, Rania M. Mohamed, Medine Boge, H. T. Carisa Le-Petross, Jessica Leung, Gary J. Whitman, Deanna L. Lane, Marion E. Scoggins, Tanya Moseley, Benjamin Musall, Jason White, Sanaz Pashapoor, Peng Wei, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Mark Pagel, Lei Huo, Kelly K. Hunt, Elizabeth Ravenberg, Alastair M. Thompson, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Stacy Moulder, Clinton Yam, Jingfei Ma, Gaiane Rauch. DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-15.

In 2018, CDC recommended a highly efficacious adjuvanted recombinant zoster vaccine (RZV) as a 2-dose series for prevention of herpes zoster (HZ) for immunocompetent persons age ≥ 50 years, with the 2nd dose recommended 2-6 months after the 1st dose. We estimated second-dose RZV series completion in the U.S. among 50-64-year-olds using two administrative databases. Second-dose RZV series completion was ∼70% within 6-months and 80% within 12-months of first dose. Among those who received only 1 RZV dose with at least 12 months of follow-up time, 96% had a missed opportunity for a second-dose vaccination, defined as a provider or pharmacy visit, among whom 36% had a visit for influenza or pneumococcal vaccination within 2-12 months of their first-dose of RZV. We found that RZV series completion rates in 50-64-year-olds was high. Availability of RZV at pharmacies has potentially helped increase series completion, but missed opportunities remain.

Tracking vaccination coverage is a critical component of monitoring a vaccine program. Three different surveillance systems were used to examine trends in varicella vaccination coverage during the United States vaccination program: National Immunization Survey–Child, National Immunization Survey–Teen, and immunization information systems (IISs). The relationship of these trends to school requirements and disease decline was also examined. Among children aged 19–35 months, ≥1 dose of varicella vaccine increased from 16.0% in 1996 to 89.2% by the end of the 1-dose program in 2006, stabilizing around at least 90.0% thereafter. The uptake of the second dose was rapid after the 2007 recommendation. Two-dose coverage among children aged 7 years at 6 high-performing IIS sites increased from 2.6%–5.5% in 2006 to 86.0%–100.0% in 2020. Among adolescents aged 13–17 years, ≥2-dose coverage increased from 4.1% in 2006 to 91.9% in 2020. The proportion of adolescents with history of varicella disease declined from 69.9% in 2006 to 8.4% in 2020. In 2006, 92% of states and the District of Columbia (DC) had 1-dose daycare or school entry requirements; 88% of states and DC had 2-dose school entry requirements in the 2020–2021 school year. The successes in attaining and maintaining high vaccine coverage were paramount in the dramatic reduction of the varicella burden in the United States over the 25 years of the vaccination program, but opportunities remain to further increase coverage and decrease varicella morbidity and mortality.

Congenital cytomegalovirus (cCMV) is not a nationally notifiable condition, and little is known about how U.S. health departments (HDs) currently conduct cCMV surveillance.We surveyed U.S. HDs that conduct cCMV surveillance or screening activities identified through a web-based assessment. Meetings were held with each HD to enhance our understanding of survey responses.Ten states are systematically collecting cCMV case data to track cCMV cases during early infancy and to provide resources and services to families. Cases are ascertained using cCMV diagnostic codes, reported diagnosis, or laboratory results. Data elements collected for each case include demographics (all 10 states), clinical signs (8 states), laboratory data (4 states), treatment (4 states), and long-term outcomes (1 state). Annual number of cases reported by HDs ranged from 3 to 47 cases/year in seven states, which was much lower than the expected number of cCMV cases. All 10 HDs have the ability to analyze data collected and four disseminate findings. Major challenges of surveillance reported by HDs were lack of standardized case definitions, personnel constraints, and limited funding.A comprehensive account of cCMV disease burden is severely limited by low case ascertainment and paucity of data on long-term outcomes. A standardized public health case definition for cCMV would improve consistency in measuring disease prevalence across jurisdictions and over time. Surveillance for cCMV has the potential to increase disease awareness and inform strategies to prevent cCMV-associated disabilities.

Background Protection against herpes zoster (HZ) is primarily conferred by cell-mediated immunity (CMI). However, anti-VZV-glycoprotein (anti-gp) antibody responses to Zoster Vaccine Live (ZVL) correlate with protection, suggesting a potential protective role for antibody. Detailed studies of antibody responses to the Recombinant Zoster Vaccine (RZV) are lacking. Methods We compared ELISA-measured anti-gp and anti-glycoprotein E (anti-gE) antibodies and avidity in 159 participants randomized to RZV (n = 80) or ZVL (n = 79) recipients over 5 years post-vaccination and identified predictors of antibody persistence. Results The comparison between vaccine groups showed higher anti-gE and anti-gp antibody levels after RZV than ZVL over the 5-year study duration. RZV recipients also had higher anti-gE avidity for 5 years and higher anti-gp avidity in the first year post-vaccination. Compared with pre-vaccination, RZV recipients maintained higher levels of anti-gE antibodies and avidity for 5 years, whereas ZVL recipients only maintained higher anti-gE avidity. Anti-gp antibody levels and avidity decreased to pre-vaccination levels or below after 1-year post-vaccination in both groups. Independent predictors of persistence of antibody levels and avidity were the following: vaccine type, pre-vaccination and peak antibody levels and avidity, pre-vaccination and peak CMI, and age. Sex or prior ZVL administration did not affect persistence. Conclusion Antibody responses and avidity were higher and more persistent in RZV than ZVL recipients. The effect of age on antibody persistence in RZV recipients is novel.

Among 342 US infants with congenital cytomegalovirus treated with antivirals, 114 (33%) received ganciclovir (with or without valganciclovir) and 228 (67%) received valganciclovir only, for a median of 8 and 171 days, starting at a median of 15 and 45 days of life, respectively, with neutropenia diagnosed in 25% and 17%.

On August 29, 2021, the United States government oversaw the emergent establishment of Operation Allies Welcome (OAW), led by the U.S. Department of Homeland Security (DHS) and implemented by the U.S. Department of Defense (DoD) and U.S. Department of State (DoS), to safely resettle U.S. citizens and Afghan nationals from Afghanistan to the United States. Evacuees were temporarily housed at several overseas locations in Europe and Asia* before being transported via military and charter flights through two U.S. international airports, and onward to eight U.S. military bases

Background and Purpose: There is currently lack of recognized imaging criteria for prediction of treatment response to NAST in breast cancer patients. And early identification of treatment response to neoadjuvant systemic therapy (NAST) in Triple Negative Breast Cancer (TNBC) patients is important for appropriate treatment selection and response monitoring. A novel MRI sequence, Magnetic Resonance Image Compilation (MagIC) is capable of simultaneous quantitation of several tissue water properties including longitudinal (T1), transverse (T2) relaxation times, and proton density (PD). In this study we evaluated the ability of a radiomic model extracted from a novel MagIC sequence acquired early during NAST to predict pathologic complete response to NAST in TNBC. Materials and Methods: This IRB approved prospective ARTEMIS trial (NCT02276443) included 184 women (122 training dataset, 62 testing dataset) diagnosed with stage I-III TNBC. All patients were scanned with MagIC on a 3T MRI scanner at baseline (184 patients), and after 4 cycles (156 Patients) of NAST. T1, T2 and PD maps were generated from the source images using SyMRI (SyntheticMR, Linkoping, Sweden). Histopathology at surgery was used to determine pathologic complete response (pCR) which was defined as absence of the invasive cancer in the breast and axillary lymph nodes. 3D contouring of the tumors was performed using an in-house toolbox. 310 (10 first-order, 300 GLCM) textural features were extracted from each map, with total of 930 features/patient. Radiomic features were compared between pCR and non-pCR using Wilcoxon Rank Sum test and Fisher’s exact test. To build a multivariate, predictive model, logistic regression with elastic net regularization was performed for texture feature selection. The tuning parameter was optimized using 5-fold cross-validation based on the average area under curve (AUC) of each fold of a cross-validation using training data. Then the testing data were used to compare model’s performance by AUC. Results: Univariate analysis found 23 PD, 17 T1 and 10 T2 radiomic features at C4 time point to be able to predict pCR status with AUC >70% in both training and testing cohort. The top performing radiomic features were Entropy, Variance, Homogeneity and Energy (Tables1-2). Multivariate radiomics models from C4-PD, and C4-T1 maps showed best performance during both cross validation and independent testing. The radiomic signature of C4-T1 map that included 27features had best performance, with an AUC of 0.77, 0.70 (95% CI: 0.571-0.868) in training and testing cohort respectively. C4-PD map radiomic signature that included 6features was able to predict the pCR status with AUC of 0.73, 0.72 (95% CI: 0.571-0.868) in training and testing cohort respectively. Conclusion: Our data found that MagIC-based radiomics signature could potentially predict pathologic complete response in TNBC early during NAST. This data shows the potential application of MagIC radiomic model for improvement of response assessment in TNBC. Table 1.Best performing radiomic features from PD map after 4 cycles of NAST in TNBC patients.FeatureTraining CohortTraining CohortTraining CohortTesting CohortTesting CohortTesting CohortNAUC95% CINAUC95% CIP-valuePD-mapAngular Variance of Sum entropy1060.73820.6437-0.8328500.73240.5895-0.8752 Table 2.Best performing radiomic features from T1-T2 maps after 4 cycles of NAST in TNBC patients.FeatureTraining CohortTraining CohortTraining CohortTesting CohortTesting CohortTesting CohortNAUC95% CINAUC95% CIP-valueT1-mapAngular Variance of Sum entropy1060.76530.6762-0.8544500.70510.5524-0.8579 Citation Format: Nabil Elshafeey, Ken-Pin Hwang, Beatriz Elena Adrada, Rosalind Pitpitan Candelaria, Medine Boge, Rania M Mahmoud, Huiqin Chen, Jia Sun, Wei Yang, Aikaterini Kotrotsou, Benjamin C Musall, Jong Bum Son, Gary J Whitman, Jessica Leung, Huong Le-Petross, Lumarie Santiago, Deanna Lynn Lane, Marion Elizabeth Scoggins, David Allen Spak, Mary Saber Guirguis, Miral Mahesh Patel, Frances Perez, Abeer H Abdelhafez, Jason B White, Lei Huo, Elizabeth Ravenberg, Wei Peng, Alastair Thompson, Senthil Damodaran, Debu Tripathy, Stacey L Moulder, Clinton Yam, Mark David Pagel, Jingfei Ma, Gaiane Margishvili Rauch. Radiomics model based on magnetic resonance image compilation (MagIC) as early predictor of pathologic complete response to neoadjuvant systemic therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-06.

Background: TNBC constitutes an aggressive and heterogeneous group of tumors with variable response to neoadjuvant therapy (NAT) that currently lacks clinically available profiling strategies for prediction. We aimed to develop an integrated model based on imaging, pathological and clinical data capable to predict NAT response in TNBC early during therapy. METHOD AND MATERIALS:125 Stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433) who had DCE-MRI at baseline (BL) and post 2 cycles (C2) of NAT, and had surgery were included in this analysis. Tumor volume was calculated using 3D measurements at BL and C2 time points DCE-MRI. Percent tumor volume reduction (TVR) between BL and C2 was calculated. Demographic, clinical, and pathological data (age, T and N stage, histology, androgen receptor expression, Ki-67, stromal tumor infiltrating lymphocytes level (sTIL), and PD-L1 expression), and treatment response at surgery (pCR vs non-pCR) were documented. Recursive partitioning was used to identify TVR cutoff value. Multivariate logistic regression and ROC analysis were used to assess associations and build and evaluate predictive models. RESULTS: 61 (49%) TNBC pts showed pCR at surgery, and 64 (51%) non-pCR. Recursive partitioning analysis identified ≥ 55% TVR as the optimal cutoff values for pCR prediction at C2. TVR, N stage and sTIL were significantly associated with pCR in the multivariate analyses (p Citation Format: Gaiane Margishvili Rauch, Rosalind P. Candelaria, Mary Saber Guirguis, Medine Boge, Rania M. M. Mohamed, Nabil Elshafeey, Jia Sun, Gary J Whitman, Jessica Leung, Huong C Le-Petross, Lumarie Santiago, Deanna Lane, Marion Scoggins, David Spak, Miral M Patel, Frances Perez, Jason B. White, Elizabeth Ravenberg, Wei Peng, Debu Tripathy, Vicente Valero, Jennifer Litton, Lei Huo, Clinton Yam, Alastair Thompson, Jingfei Ma, Stacy L. Moulder, Wei Yang, Beatriz E. Adrada. Integrated model for early prediction of neoadjuvant systemic therapy response in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-07.

Epidemiologic data regarding the risk of Guillain-Barré syndrome (GBS) following herpes zoster (HZ) are limited. We conducted a self-controlled case series analysis using two large national data sources to evaluate the risk of GBS following HZ among U.S. adults. We analyzed medical claims from the IBM® MarketScan® Commercial Claims and Encounters (persons 18-64 years during 2010-2018) and Centers for Medicare and Medicaid Services Medicare (persons ≥65 years during 2014-2018) databases. HZ cases were defined as persons with an outpatient claim with a primary or secondary ICD-9 or ICD-10 diagnostic code for HZ. GBS cases were defined as persons with an inpatient claim with a principle diagnostic code for GBS and an associated procedural code. We compared the rates of GBS following HZ in the 1-42-day risk window versus primary (100-365-day) or secondary (43-99-day) control windows. We identified 489,516 persons 18-64 years of age and 650,229 persons ≥65 years of age with HZ, among whom 11 and 41, respectively, developed GBS 1-365 days following HZ. The risk of GBS following HZ was increased during the risk window as compared to the primary control window for both groups, with a rate ratio of 6.3 (95% CI, 1.8-21.9) for those 18-64 years and 4.1 (95% CI, 1.9-8.7) for those ≥65 years. This study provides new and methodologically rigorous epidemiologic support for an association between HZ and GBS, and useful context regarding the benefits versus potential risks of zoster vaccination.

Background Measles elimination (interruption of endemic measles virus transmission) in the United States was declared in 2000; however, the number of cases and outbreaks have increased in recent years. We characterized the epidemiology of measles outbreaks and measles transmission patterns after elimination to identify potential gaps in the US measles control program. Methods We analyzed national measles notification data from 1 January 2001 to 31 December 2019. We defined measles infection clusters as single cases (isolated cases not linked to additional cases), 2-case clusters, or outbreaks with ≥3 linked cases. We calculated the effective reproduction number (R) to assess changes in transmissibility and reviewed molecular epidemiology data. Results During 2001–2019, a total of 3873 measles cases, including 747 international importations, were reported in the United States; 29% of importations were associated with outbreaks. Among 871 clusters, 69% were single cases and 72% had no spread. Larger and longer clusters were reported since 2013, including 7 outbreaks with >50 cases lasting >2 months, 5 of which occurred in known underimmunized, close-knit communities. No measles lineage circulated in a single transmission chain for >12 months. Higher estimates of R were noted in recent years, although R remained below the epidemic threshold of 1. Conclusions Current epidemiology continues to support the interruption of endemic measles virus transmission in the United States. However, larger and longer outbreaks in recent postelimination years and emerging trends of increased transmission in underimmunized communities emphasize the need for targeted approaches to close existing immunity gaps and maintain measles elimination.

In July 2022, a case of paralytic poliomyelitis resulting from infection with vaccine-derived poliovirus (VDPV) type 2 (VDPV2)

To describe the impact of the US varicella vaccination program on severe varicella outcomes, we analyzed varicella hospitalizations using the National Inpatient Sample 1993–2019 and varicella deaths using the National Center for Health Statistics data 1990–2019. Over 25 years of vaccination program (1995–2019), varicella hospitalizations, and deaths declined 94% and 97%, respectively, among persons aged 99%, respectively) was among persons aged 10 500 varicella hospitalizations and 100 varicella deaths are now prevented annually in the United States as a direct result of vaccination and reduction in varicella-zoster virus circulation.

When the US varicella vaccination program was introduced in 1995, its impacts on the epidemiology of herpes zoster (HZ) were not precisely known. We used a large claims database to examine HZ incidence in the US during 1998–2019 among persons aged ≥30 years (the prevaccine cohort, born before 1990), and aged 1–29 years (includes the postvaccine cohort, born since 1990). We defined incident HZ as the first instance of an outpatient or emergency department (ED) claim with an HZ diagnostic code. Additionally, we examined the proportion of HZ visits among all ED visits as a complementary method to assess for healthcare-seeking artifacts in the findings. In persons aged ≥30 years (prevaccine cohort), we observed age-specific increases in HZ incidence during the earlier study years, with decelerations in later years, starting in 2007 with oldest age groups. Similar patterns were seen when we examined HZ visits as a proportion of all ED visits. For persons aged 1–29 years, age-specific HZ incidence increased early in the study period for the oldest age groups who were born prevaccine, but later declined in a stepwise pattern once each age group was comprised of persons born in the postvaccine period. Our results, corroborated with previously published studies, do not support prior modeling predictions that the varicella vaccination program would increase HZ incidence among adult cohorts who previously experienced varicella. Our findings also suggest that continued declines in age-specific HZ incidence as varicella-vaccinated cohorts age are likely.

We describe the changing epidemiology of varicella outbreaks informed by past and current active and passive surveillance in the United States by reviewing data published during 1995–2015 and analyzing new data from 2016 to 2019. Varicella outbreaks were defined as ≥5 varicella cases within 1 setting and ≥1 incubation period. During the 1-dose varicella vaccination program (1995‒2006), the number of varicella outbreaks declined by 80% (2003–2006 vs 1995–1998) in 1 active surveillance area where vaccination coverage reached 90.5% in 2006. During the 2-dose program, in 7 states with consistent reporting to the Centers for Disease Control and Prevention, the number of outbreaks declined by 82% (2016–2019 vs 2005–2006). Over the entire program (1995–2019), outbreak size and duration declined from a median of 15 cases/outbreak and 45 days duration to 7 cases and 30 days duration. The proportion of outbreaks with

Background . The Vaccine Adverse Event Reporting System (VAERS) is the United States national passive vaccine safety surveillance system. We updated the data on the safety of single-antigen varicella vaccine (VAR) and assessed the safety of combination measles, mumps, rubella, and varicella vaccine (MMRV) licensed in the United States using VAERS data. Methods US VAERS reports received after administration of VAR and MMRV during 2006–2020 were identified. Reports were analyzed by vaccine type, age, seriousness, most common adverse events (AEs), and concomitant vaccines. We reviewed medical records of selected reports of AEs of special interest and conducted empirical Bayesian data mining to identify disproportionally reported AEs. Results During 2006–2020, approximately 132.8 million VAR doses were distributed; 40 684 reports were received in VAERS (30.6/100 000 doses distributed), with 4.1% classified as serious (1.3/100 000 doses distributed). Approximately 35.5 million MMRV doses were distributed; 13 325 reports were received (37.6/100 000 doses distributed) with 3.3% classified as serious (1.3/100 000 doses distributed). The most common adverse health events after both VAR and MMRV were injection site reactions (31% and 27%), rash (28% and 20%), and fever (12% and 14%), respectively. Vaccination errors accounted for 23% of reports after VAR administration and 41% after MMRV administration, but ≥95% of them did not describe an adverse health event. AEs associated with evidence of vaccine strain varicella-zoster virus (vVZV) infection included meningitis, encephalitis, herpes zoster, and 6 deaths (all in immunocompromised persons with contraindications for vaccination). No new or unexpected AE was disproportionally reported. Conclusions No new or unexpected safety findings were detected for VAR and MMRV given as recommended, reinforcing the favorable safety profiles of these vaccines. Providers should obtain specimens for viral testing and strain-typing for serious AEs if they consider vVZV as the possible causative agent.

Surveillance is critical for monitoring vaccine impact. Varicella surveillance challenges predated varicella vaccine US licensure in 1995. Several interim steps were needed before case-based surveillance could be established in most states, and both active and passive surveillance was needed to document the vaccination program’s impact on varicella incidence. By the end of the 1-dose program in 2005, incidence had declined 90% in the active surveillance areas, with significant declines occurring in all age groups within 5 years of program implementation. Additional declines occurred during the 2-dose program leading to >97% decline in incidence over the 25 years of program implementation through 2019, based on data from 4 states with continuous passive reporting. Surveillance showed that declines were highest among children and adolescents covered by the routine vaccination recommendations but occurred in all age groups. Although surveillance systems changed and were adapted to reflect evolving epidemiology, data consistently demonstrated decreasing varicella incidence following the vaccination program implementation. The vaccination program dramatically decreased virus circulation and increased community protection. Continued and improved varicella surveillance is needed to accurately monitor disease epidemiology and further guide prevention efforts.

ObjectiveU.S. healthcare utilization declined during the COVID-19 pandemic, potentially leading to spurious drops in disease incidence recorded in administrative healthcare datasets used for public health surveillance. We used time series modeling to characterize the magnitude and duration of the COVID-19 pandemic’s impact on claims-based monthly incidence of 12 symptomatic conditions among Medicare beneficiaries aged ≥65 years.MethodsTime series of observed monthly incidence of each condition were generated using Medicare claims data from January 2016–May 2021. Incidence time series were decomposed through seasonal and trend decomposition using Loess, resulting in seasonal, trend, and remainder components. We fit a non-linear mixed effects model to remainder time series components and used it to estimate underlying incidence and number of unrecorded cases of each condition during the pandemic period.ResultsObserved incidence of all 12 conditions declined steeply in March 2020 with nadirs in April 2020, generally followed by return to pre-pandemic trends. The relative magnitude of the decrease varied by condition, but month of onset and duration did not. Estimated unrecorded cases during March 2020–May 2021 ranged from 9,543 (95% confidence interval [CI]: 854–15,703) for herpes zoster to 236,244 (95% CI: 188,583–292,369) for cataracts.ConclusionsDue to reduced healthcare utilization during the COVID-19 pandemic, claims-based data underestimate incidence of non-COVID-19 conditions. Time series modeling can be used to quantify this underestimation, facilitating longitudinal analyses of disease incidence pre- and post-pandemic.

OBJECTIVE: To critically review researchers’ use of diagnosis codes to identify congenital cytomegalovirus (cCMV) infection or disease in healthcare administrative databases. Understanding the limitations of cCMV ascertainment in those databases can inform cCMV surveillance and health services research. METHODS: We identified published studies that used diagnosis codes for cCMV or CMV in hospital discharge or health insurance claims and encounters records for infants to assess prevalence, use of services, or healthcare costs. We reviewed estimates of prevalence and of charges, costs, or expenditures associated with cCMV diagnosis codes. RESULTS: Five studies assessed hospitalizations with cCMV diagnosis codes recorded in hospital discharge databases, from the United States (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Six other studies analyzed claims or encounters data from the United States (n = 5) or Japan (n = 1) to identify infants with cCMV codes. Prevalence estimates of recognized cCMV ranged from 0.6 to 3.8 per 10,000 infants. Economic analyses reported a wide range of per-hospitalization or per-infant cost estimates, which lacked standardization or comparability. CONCLUSIONS: The administrative prevalence of cCMV cases reported in published analyses of administrative data from North America, Western Europe, Japan, and Australia (0.6–3.8 per 10,000 infants) is an order of magnitude lower than the estimates of the true birth prevalence of 3–7 per 1,000 newborns based on universal newborn screening pilot studies conducted in the same regions. Nonetheless, in the absence of systematic surveillance for cCMV, administrative data might be useful for assessing trends in testing and clinical diagnosis. To the extent that cCMV cases recorded in administrative databases are not representative of the full spectrum of cCMV infection or disease, per-child cost estimates generated from those data may not be generalizable. On the other hand, claims data may be useful for estimating patterns of healthcare use and expenditures associated with combinations of diagnoses for cCMV and known complications of cCMV.

We examined the incidence of toxic shock syndrome in the United States during 2006–2018 among persons

Background: The MERIT cohort (Mammography, Early Detection, Risk Assessment, and Imaging Technologies, 2017-present) has enrolled women receiving annual screening mammograms (MG) at MD Anderson with a primary goal to integrate clinical data and imaging data with blood biomarker profiles to determine risk of developing breast and other cancers. Here we report interim results for breast cancers among post-menopausal women in the cohort categorized based on breast density and BMI and differences between participants who underwent MRI/MG screening vs standard annual MG screening. Methods: The study annually collects comprehensive health measurements, questionnaire information, imaging data, and blood specimens. Plasma is processed and frozen within 4 hours of collection (draw-to-freezer, >500,000 aliquots to date) for biomarker research. Part of the cohort also has MRI screening every 6 months alternating with standard mammography (MRI/MG). BI-RADS breast density was determined by radiologist scoring using the baseline mammogram. Self-reported post-menopausal status (12 months without a menstrual period) was used to classify participants. When not available, those participants older than 50 years were classified as post-menopausal. Results: 4,392 of the 6,222 eligible subjects from MERIT were post-menopausal and included in the analyses. The average follow up was 2.4 mammograms per participant. MRI/MG screening was used for 385 (8.8%) participants who were more likely to be younger (59.6 vs 62.1 years, P< 0.01), have lower BMI (27.9 vs 28.6, P = 0.02) and dense breasts (64% vs 50%, P< 0.01). The rates of breast cancer were overall higher for those screened by MRI/MG vs standard MG (13.9 vs 6.9 cases per 1,000 mammograms). A total of 79 breast cancers (7.6 cases per 1,000 mammograms) were diagnosed with the highest rate of breast cancers in high BMI participants with dense breasts (see table). A blood-based biomarker profile for risk of breast cancer with high BMI was developed using matched pre-diagnostic plasma by mass spectrometry metabolomic analyses. Conclusions: The MERIT cohort has a higher-than-average rate of breast cancers, in part explained by a high-risk MRI/MG screening group. High BMI and dense breasts were generally associated with higher rates of breast cancer. The differences in the rates of breast cancer incidence for the high BMI group between non dense and dense breasts is likely understated for the standard mammogram group because of the lower sensitivity of mammography in dense breasts. Interestingly, the rates of breast cancers in the low BMI/non dense breast group were almost equally high as the low BMI/dense breast group, likely a result of reduced sensitivity of mammography for dense breasts. For future work, we will integrate the blood biomarker profiles with the breast density and BMI information to develop a more personalized risk model. MERIT Cohort Breast Cancers Rates of diagnosed breast cancers per 1,000 mammograms for post-menopausal women (N = 79 breast cancers)*‡P Citation Format: Jessica Leung, Olena Weaver, Samir Hanash, Jennifer Dennison. The MERIT Cohort: An MD Anderson Initiative to Integrate Blood and Imaging Biomarkers to Personalize Breast Cancer Risk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-03-01.

PURPOSE Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer. Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) predicts better survival. Early prediction of the treatment response can potentially triage non-responding patients to alternative protocol treatments, spare them of the unneeded toxicity, and improve pCR. We evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on the dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI) MRI images obtained early during NAST to predict pCR. MATERIALS AND METHODS This IRB-approved prospective study (NCT02276443) included 182 patients with biopsy proven stage I-III TNBC who had multiparametric MRIs at baseline (BL), post 2 cycles (C2), and post 4 cycles (C4) of NAST before surgery. Tumors and peritumoral regions of 5 mm and 10 mm in thickness were segmented on the 2.5 minutes DCE subtraction images and on the b=800 DWI images. Ten histogram-based first order texture features including mean, minimum, maximum, standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentile, and 300 radiomic Grey Level Co-occurrence matrix (GLCM) features along with their absolute and relative differences between the 3 imaging time points were extracted from the tumors and from the peritumoral regions with an in-house Matlab toolbox. Treatment response at surgery (pCR vs non-pCR) was documented. The samples were divided into training and testing datasets by a 2:1 ratio. Area under the receiver operating characteristics curve (AUC ROC) was calculated for univariate analysis in predicting pCR. Logistic regression with elastic net regularization was performed for texture feature selection. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. RESULTS Of 182 TNBC patients, 88 (48%) had pCR and 94 (52%) did not achieve pCR. Eight multivariate models combining radiomic features from both DCE and DWI tumoral and peritumoral regions had AUC > 0.8 (0.807-0.831) with p-value < 0.001 in both training and testing sets. The highest AUC=0.831 was obtained from a model consisting of 15 radiomic features: tumor DWI (5 GLCM features) at C2, peritumoral region on DCE (skewness) at C2, tumor DCE (1st, 5th percentile) at C4, tumor DWI (3 GLCM features) at C4, peritumoral region DWI (1 GLCM feature) at C4, and the relative difference between C4/C2 on DCE (5th, 95th percentile and mean). CONCLUSION Multi-parametric MRI-based radiomics models from the tumor and the peritumoral regions showed high accuracy as potential early predictors of NAST response in TNBC patients. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-06.

Background and Purpose Triple negative breast cancer (TNBC) is a biologically aggressive tumor and a refractory subtype of breast cancer due to the lack of therapeutic targets, such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. In this study, we investigated the accuracy of radiomic models based on the dynamic contrast enhanced (DCE) MRI images obtained after the completion of NAST as discriminators of treatment response in TNBC patients. Materials and Methods This IRB-approved prospective study (ARTEMIS trial, NCT02276443) included 181 patients with biopsy proven stage I-III TNBC who Had MRIs after completion of NAST and before surgery. Patients were classified as pathologic complete response (pCR) and non-pCR at the surgery. Tumors were segmented on the 2.5 minutes DCE subtraction images. Regions with necrosis or clip artifacts were excluded from the contour. If tumors were not visible, the tumor bed was contoured. Whole-tumor histogram-based first order texture features (p=10) including mean, minimum, maximum, Standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentiles, and radiomic (p=300) Grey Level Co-occurrence matrix (GLCM) features were extracted with an in-house Matlab toolbox. The samples were split into training and testing data sets by a 2:1 ratio. For univariate analysis area under the receiver operating characteristics curve (AUC ROC) was performed for pCR status prediction. For texture feature selection logistic regression with elastic net regularization was performed. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. A P-value less than 0.05 was considered statistically significant. Results Of the total 181 patients, 88 (49%) had pCR and 93 (51%) had non-pCR. Univariate analysis identified 7 statistically significant first order imaging features (Minimum, Maximum, Mean, 1st Percentile, 5th Percentile, 95th Percentile, and 99th Percentile) with AUC >= 0.7 (p< 0.001), in both training and testing data sets. Percentile 5 showed highest AUC = 0.78 (p< 0.001). Two multivariate models were statistically significant at cross-validation with AUC>=0.7. The first model combined 2 first order data (Percentile 1 and Percentile 5) with AUC = 0.73 (p< 0.001). The second model combined 8 first order features (Percentile 1, 5, 95, 99, Mean, Minimum, Maximum, and Skewness) and 24 GLCM features with AUC = 0.7 (p=0.003). Conclusion DCE-MRI radiomic features from tumor and tumor bed regions in TNBC may be helpful imaging biomarkers for predicting treatment response after NAST. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Huiqin Chen, Jia Sun, Peng Wei, Jennifer K. Litton, Vicente Valero, Clinton Yam, Mark Pagel, Jingfei Ma, Gaiane Rauch. A Pre-operative Dynamic Contrast Enhanced MRI-Based Radiomics Models as Predictors of Treatment Response after Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-35.

Background and Purpose Early prediction of neoadjuvant systemic therapy (NAST) response in triple negative breast cancer (TNBC) patients could potentially aid in the selection of alternative therapies and avoid unnecessary toxicity in patients unlikely to achieve pathologic complete response (pCR) with NAST. In this study, we investigated the radiomic features of the peritumoral and the tumoral regions from dynamic contrast enhanced (DCE) MRI acquired at different time points of NAST for early treatment response prediction in TNBC. Methods and Materials This study included 182 biopsy-confirmed stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433). All patients underwent DCE-MRI on a GE 3T MRI scanner at baseline (BL), after two (C2) and four (C4) cycles of doxorubicin/cyclophosphamide based chemotherapy and before surgery. The peritumoral and the tumoral regions were segmented manually by two fellowship-trained radiologists using early phase (2.5 min) DCE-MRI subtraction images. Ten first order radiomic features, 300 grey-level-co-occurrence matrix (GLCM) features along with their absolute and relative differences (C4/BL, C2/BL, C4/C2) between the 3 imaging time points were extracted from the peritumoral and the tumoral regions. Patients were randomly divided into training and testing sets in a 2:1 ratio. For univariate analysis, area under the receiver operating characteristics curve (AUC ROC) was measured to determine the features most predictive of pCR/non-pCR. Wilcoxon Rank Sum test was used to test the statistical significance of predictive performance. In multivariate analysis, radiomic models were established using logistic regression with elastic net regularization followed by 5-fold cross validation for performance assessment. Results Eighty-eight (48%) patients had pCR (59 training, 29 testing) and 94 (52%) patients had non-pCR (63 training, 31 testing). Twenty-five radiomic features (4 from peritumoral C4, 5 from tumoral C4, 4 from peritumoral C4/BL, 6 from tumoral C4/BL, 2 from peritumoral C4/C2 and 4 from tumoral C4/C2) were statistically significant with AUC ≥ 0.75 in both the training and the testing sets at the univariate analysis. The significant features at C4 had AUCs of 0.75-0.79 for the training set and 0.76-0.81 for the testing set. Changes measured between C4 and BL or C2 showed AUC of 0.76-0.84 in the training and 0.75-0.81 in the testing datasets. Eleven multivariate regression models comprised of radiomic features at BL, C2, C4 and their changes (C4/BL, C4/C2 and C2/BL) showed an AUC of 0.80-0.84 for cross validation and an AUC of 0.80-0.82 for independent testing. Conclusions Radiomic models using longitudinal DCE MRI parameters of peritumoral and tumoral regions during NAST have the potential to predict pCR in TNBC patients undergoing NAST. Citation Format: Bikash Panthi, Rania M. Mohamed, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-34.

The Center for Global Early Detection at MD Anderson has initiated two longitudinal early detection studies: LEAP (Lung Cancer Early Detection and Prevention, 2013-2019) for lung cancer screening and MERIT (Mammography Early Detection Risk Assessment and Imaging Technologies, 2017-ongoing) for breast cancer screening. Both cohorts enrolled subjects based on US standard-of-care guidelines at the time of enrollment for low-dose CT screening and mammography, respectively. The cohorts collected detailed health data from questionnaires, imaging data, and blood specimens at the time of screening. In addition to information on the screened-detected cancers, follow-up information was collected on any other types of cancers that are diagnosed after enrollment. Here, we evaluate the incidence of other cancers without available screening to assess the potential impact of multi-cancer early detection studies for these two types of screening populations. The two studies enrolled approximately 9,300 subjects (N = 2853 for LEAP; N = 6,400 for MERIT) with median follow up times of 2.99 years (IQR: 1.09-4.08) for LEAP and 2.05 years (IQR: 0.09-3.01) for MERIT. Currently, there are more than 800,000 aliquots of banked biospecimens from both cohorts. The incidence of lung cancer for the LEAP cohort undergoing low-dose CT screening was 0.91% per year. Cancers other than lung cancer were also diagnosed after enrollment including prostate, breast, bladder, head, and neck, colorectal, lymphoma, endocrine, gynecologic, and kidney cancers. Overall, the incidence of other cancers in LEAP was high for those cancers without available screening - 0.49% per year excluding breast, prostate, and colorectal cancers. The incidence of breast cancer for women in LEAP was lower than expected, 0.17% per year, likely a result of underscreening by mammography. For the MERIT cohort, the incidence of breast cancer was 0.89% per year. Cancers other than breast were diagnosed in MERIT after enrollment including gynecologic, melanoma, lung, colorectal, endocrine, bladder, and gastrointestinal cancers. The incidence of other cancers in MERIT was 0.55% per year, excluding colorectal cancer. We conclude that the incidence of cancers without a current screening modality in LEAP and MERIT is sufficiently high (0.49-0.55% per year) to justify the application of multi-cancer screening. Even for cancers with standard-of-care screening, a multi-cancer blood-based biomarker test could be useful given the possibility of underscreening, as we observed for breast cancer in the LEAP cohort. Citation Format: Jennifer Dennison, Ehsan Irajizad, Edwin Ostrin, Myrna Godoy, Olena Weaver, Jessica Leung, Samir Hanash. Application of multi-cancer early detection to lung and breast cancer screening populations. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P057.

BACKGROUND Kawasaki disease (KD) is a febrile illness of unknown etiology. Patients with Kawasaki disease shock syndrome (KDSS) may present with clinical signs of poor perfusion and systolic hypotension in addition to typical KD features. The United States Centers for Disease Control and Prevention analyzes and interprets large hospitalization databases as a mechanism for conducting national KD surveillance. METHODS The Kids' Inpatient Database (KID), the National (Nationwide) Inpatient Sample (NIS), and the IBM MarketScan Commercial (MSC) and MarketScan Medicaid (MSM) databases were analyzed to determine KD-associated hospitalization rates and trends from 2006 to the most recent year of available data. KD and potential KDSS hospitalizations were defined using International Classification of Disease-Clinical Modification codes. RESULTS For the most recent year, the KD-associated hospitalization rates for children

Persons with immune-mediated inflammatory diseases (IMIDs) are at an increased risk of herpes zoster (HZ). In 2018, the Centers for Disease Control and Prevention recommended a highly efficacious vaccine, recombinant zoster vaccine (RZV), for prevention of HZ in immunocompetent patients ≥50 years of age. This study was undertaken to estimate RZV vaccination among adults ages ≥50 years with IMIDs during 2018-2019 and to examine possible vaccine-related flares following RZV.We identified a cohort of IMID patients using medical claims data from the IBM MarketScan (ages 50-64 years) and Centers for Medicare and Medicaid Services Medicare (ages ≥65 years) databases. Presumed flares were defined as hospitalization/emergency department visit for their respective IMIDs, or steroid treatment with a short-acting oral glucocorticoid or parenteral glucocorticoid injection. We conducted a self-controlled case series (SCCS) analysis to examine a temporal association between RZV and flares.Among enrollees with IMIDs, 14.8% of 55,654 MarketScan enrollees and 43.2% of 160,545 Medicare enrollees received ≥1 dose of RZV in 2018-2019. Two-dose series completion rates were 76.6% in MarketScan enrollees and 85.4% in Medicare enrollees. In the SCCS analysis, 10% and 13% developed flares in the control window, compared to 9% and 11-12% in the risk window following 1 or 2 doses of RZV among MarketScan and Medicare enrollees, respectively. We found no statistically significant increase in flares following RZV administration for any IMID in either age group following RZV dose 1 or dose 2.We did not find an increase in presumed flares following RZV vaccination. Among adults ages ≥50 years with IMIDs, a substantial proportion received RZV compared to general zoster coverage estimates, and series completion rates were high.

Given the availability of an effective and safe vaccine, the World Health Organization (WHO) declared that global measles eradication is achievable, and measles elimination goals have since been established as interim steps toward eradication. As part of a strategy to maintain elimination, the Pan American Health Organization (PAHO) and WHO stipulate a minimum annual reporting rate of discarded non-measles cases of ≥2 per 100,000 population, in order to ensure sensitive surveillance and adequate investigative effort. With its effective vaccination program, the United States in 2000 was among the first countries to verify elimination, although subsequently, it has not routinely reported discarded rates. We estimated MLI investigation rates among insured individuals during 2010–2017, using data from the MarketScan® databases. We defined “MLI investigations” as measles serologic testing within 5 days following diagnostic codes for measles-compatible symptoms and conditions. We provide a rationale for pre-specifying three subgroups for analysis: children aged ≤15 years; males aged 16–22 years excluding data from summer months; and males aged ≥23 years. MLI investigation rates ranged from 6.6─26.4 per 100,000, remaining stable over time except during the 2015 measles outbreaks when rates increased, particularly among young children. In addition to high vaccine uptake, measles elimination requires ongoing vigilance by clinicians and high-quality, case-based surveillance. Estimated rates of MLI investigations in this U.S. population suggesting that the quality of measles surveillance is sufficiently sensitive to detect endemic measles circulation if it were to be occurring.

The varicella-zoster virus (VZV) genome, as with all other human herpesviruses, comprises both unique and repeated regions. In addition, the genome includes six sequences of tandemly repeating short elements termed reiteration regions, designated R1 to R5. The R4 element is duplicated, with one copy each in the terminal repeat short (TRs) and the internal repeat short (IRs) regions. The reiteration regions (R) are an understudied feature of the VZV genome even though three of them (R1, R2 and R3) reside inside the coding regions of important viral genes. R1 is located in ORF11, a tegument protein and the homoolog to herpes simplex virus UL47. R2 is located in ORF 14, which encodes glycoprotein C. R3 is located in ORF22, a component of the viral tegument and the largest gene product encoded by the virus. It is the homolog to herpes simplex virus UL36. R4A is located in the IRs and is duplicated, usually in inverted orientation, as R4B in the TRs. R5 is located in a non-coding region between ORF60 and 61. We developed primers to amplify and Sanger sequence all six reiteration regions, including primers that independently amplify the two copies of R4. We sequenced the reiteration regions from more than 80 genomes for viruses selected from the Kaiser Permanente Herpes Zoster Study, each of which was sampled from patients with well-characterized cases of herpes zoster. Samples were selected to provide a broad representation of VZV clades. The remainder of these genomes were sequenced using the Illumina MiSeq platform.

Background Sensorineural hearing loss (SNHL) is well described in children with congenital cytomegalovirus (CMV) infection, but limited data are available on middle ear effusion (MEE) occurrence in this population. We assessed the prevalence of MEE and the degree of transient hearing change associated with MEE among children with congenital CMV infection. Methods Children with congenital CMV infection enrolled in a longitudinal study received hearing and tympanometric testing during scheduled follow-up visits annually up to 6 years of age. We used a generalized linear mixed-effect logistic regression model to compare the odds of MEE, defined as type B tympanogram (normal ear canal volume with little tympanic membrane movement) among patients categorized as symptomatic or asymptomatic based on the presence of congenital CMV-associated signs in the newborn period. Results Forty-four (61%) of 72 symptomatic and 24 (28%) of 87 asymptomatic patients had ≥1 visit with MEE. After controlling for the number of visits, symptomatic patients had significantly higher odds of MEE (odds ratio: 2.09; 95% confidence interval: 1.39-3.14) than asymptomatic patients. Transient hearing decrease associated with a type B tympanogram ranged from 10 to 40 dB, as measured by audiometric air-bone gap in 11 patients. Conclusions Among children with congenital CMV, MEE can result in transient hearing decrease, which can reduce the efficacy of a hearing aid in those with SNHL. It is warranted that children with congenital CMV infection and SNHL receive routine audiologic and tympanometric testing to better manage hearing aid amplification levels.

During January 1-October 1, 2019, a total of 1,249 measles cases and 22 measles outbreaks were reported in the United States. This represents the most U.S. cases reported in a single year since 1992 (1), and the second highest number of reported outbreaks annually since measles was declared eliminated* in the United States in 2000 (2). Measles is an acute febrile rash illness with an attack rate of approximately 90% in susceptible household contacts (3). Domestic outbreaks can occur when travelers contract measles outside the United States and subsequently transmit infection to unvaccinated persons they expose in the United States. Among the 1,249 measles cases reported in 2019, 1,163 (93%) were associated with the 22 outbreaks, 1,107 (89%) were in patients who were unvaccinated or had an unknown vaccination status, and 119 (10%) measles patients were hospitalized. Closely related outbreaks in New York City (NYC) and New York State (NYS; excluding NYC), with ongoing transmission for nearly 1 year in large and close-knit Orthodox Jewish communities, accounted for 934 (75%) cases during 2019 and threatened the elimination status of measles in the United States. Robust responses in NYC and NYS were effective in controlling transmission before the 1-year mark; however, continued vigilance for additional cases within these communities is essential to determine whether elimination has been sustained. Collaboration between public health authorities and undervaccinated communities is important for preventing outbreaks and limiting transmission. The combination of maintenance of high national vaccination coverage with measles, mumps, and rubella vaccine (MMR) and rapid implementation of measles control measures remains the cornerstone for preventing widespread measles transmission (4).

During January 1-October 1, 2019, a total of 1,249 measles cases and 22 measles outbreaks were reported in the United States. This represents the most U.S. cases reported in a single year since 1992 (1), and the second highest number of reported outbreaks annually since measles was declared eliminated* in the United States in 2000 (2). Measles is an acute febrile rash illness with an attack rate of approximately 90% in susceptible household contacts (3). Domestic outbreaks can occur when travelers contract measles outside the United States and subsequently transmit infection to unvaccinated persons they expose in the United States. Among the 1,249 measles cases reported in 2019, 1,163 (93%) were associated with the 22 outbreaks, 1,107 (89%) were in patients who were unvaccinated or had an unknown vaccination status, and 119 (10%) measles patients were hospitalized. Closely related outbreaks in New York City (NYC) and New York State (NYS; excluding NYC), with ongoing transmission for nearly 1 year in large and close-knit Orthodox Jewish communities, accounted for 934 (75%) cases during 2019 and threatened the elimination status of measles in the United States. Robust responses in NYC and NYS were effective in controlling transmission before the 1-year mark; however, continued vigilance for additional cases within these communities is essential to determine whether elimination has been sustained. Collaboration between public health authorities and undervaccinated communities is important for preventing outbreaks and limiting transmission. The combination of maintenance of high national vaccination coverage with measles, mumps, and rubella vaccine (MMR) and rapid implementation of measles control measures remains the cornerstone for preventing widespread measles transmission (4).

Two herpes zoster (HZ) vaccines licensed in the United States are recommended by the Advisory Committee on Immunization Practices (ACIP): (i) live-attenuated vaccine (ZVL) using vOka strain varicella-zoster virus (VZV) and (ii) recombinant adjuvanted vaccine (RZV) containing recombinant varicella-zoster virus (VZV) glycoprotein E (gE). Two phase 3 clinical trials of RZV led the Advisory Committee on Immunization Practices (ACIP) to recommend it with preferred status. VZV T cell-mediated immunity (CMI), but not humoral immunity, is considered essential for protection against HZ. Published studies of humoral immunity focused on VZV-specific IgG concentration. To complement reports comparing the CMI responses to these vaccines, we compared humoral responses in ZVL and RZV recipients, emphasizing functional qualities (avidity and neutralization). Baseline avidities to a VZV glycoprotein mixture (gp) were near the upper limit of detection, but avidity to gE was much lower. Small increases in gp avidity were observed for both RZV and ZVL vaccination (19 and 12 avidity index units [AIU], respectively). RZV boosted both gE avidity and VZV neutralizing antibody significantly more than ZVL (mean gE avidity boost, 47 AIU versus 22 AIU; mean neutralizing antibody boost, 22-fold versus 8-fold). Increases in neutralizing antibodies strongly correlated with gE avidity increases (r = 0.5) and moderately with gp avidity increases (r = 0.23). After 1 year, 81% of RZV recipients and only 18% of ZVL recipients retained >50% of their peak avidity boosts. These results are consistent with the CMI responses to these vaccines: RZV responses are skewed to long-term memory, whereas ZVL preferentially induces transient effector responses. IMPORTANCE These observations further distinguish the immunogenicity and duration of the immune response of the two vaccines. In addition, measurements of functional humoral immunity (IgG avidity and neutralizing antibody) in response to zoster immunization, alone or combined with other immune markers, might contribute to practical in vitro correlates of protection. Combined with previous observations of the cell-mediated response to these vaccines, this study suggests that vaccine development will benefit from more expansive and granular assessments of acquired immunity during early phase 1 immunogenicity trials.

This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient Mϕs, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-κB ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1−/−) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in Mϕs induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.

CONTEXT Since 2007, 2 doses of varicella vaccine have been routinely recommended, with a catch-up second dose recommended for those who received only 1 prior dose. OBJECTIVE To examine varicella vaccination coverage with 2 or more doses and the proportions of adolescents with evidence of immunity to varicella (≥2 doses of vaccine or varicella history) during 2007-2014. To assess timing of second-dose receipt, factors associated with 2 or more vaccine doses, and missed second-dose opportunities during 2014. DESIGN, SETTING, AND PARTICIPANTS We used data from the 2007-2014 National Immunization Survey-Teen (NIS-Teen), which collects information on adolescents aged 13 to 17 years in the United States. RESULTS From 2007 to 2014, varicella vaccination coverage with 2 or more doses increased from 8.3% to 66.9% in 13- to 15-year-olds and from 3.6% to 56.7% in 16- to 17-year-olds. The proportions with evidence of immunity also increased from 68.0% to 84.1% (13- to 15-year-olds) and 78.6% to 83.4% (16- to 17-year-olds). In 2014, 13.4% of 13- to 15-year-olds and 3.2% of 16- to 17-year-olds had received their second dose at 4 to 6 years of age. Factors most significantly associated with lower coverage with 2 or more doses were not having an 11- to 12-year well-child visit, not receiving an adolescent vaccine, and residence in a state with no 2-dose immunization school entry requirement. Seventy-seven percent of 1-dose vaccinated adolescents had 1 or more missed opportunities to receive their second dose; if were they not missed, 2-dose coverage would have increased from 79.5% to 94.8%. CONCLUSIONS Levels of varicella vaccination coverage with 2 or more doses and the proportion of adolescents with evidence of immunity increased from 2007 to 2014, though 16% lacked evidence of immunity in 2014. Although catch-up campaigns have succeeded, missed vaccination opportunities persist.