The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD) which is involved in the catalysis of uracil and thymine as well as 5-fluorouracil (5-FU), which is used to treat solid tumors. Patients with decreased DPD activity are at risk of serious, sometimes fatal, adverse drug reactions to this important cancer drug. Pharmacogenetic testing for DPYD is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for clinical DPYD testing. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention (CDC) based Genetic Testing Reference Materials Coordination Program (GeT-RM), in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 33 DNA samples derived from Coriell cell lines for DPYD. Samples were distributed to four volunteer laboratories for genetic testing using a variety of commercially available and laboratory-developed tests. Sanger sequencing was utilized by one laboratory and publicly available whole genome sequence (WGS) data from the 1000 Genomes Project was utilized by another to inform genotype. Thirty-three distinct DPYD variants were identified among the 33 samples characterized. These publicly available and well-characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing.

BACKGROUND: The nutritional status of children with cystic fibrosis (CF), as assessed by their body mass index percentile (BMIp), is a critical determinant of long-term health outcomes. While the intestinal microbiome plays an important role in nutrition, little is known regarding the relationship of the microbiome and BMIp in children with CF. METHODS: Pediatric patients (< 18 years old) with CF and healthy comparison patients (HCs) were enrolled in the study and stool samples obtained. BMIp was categorized as Green Zone (BMIp > 50th), Yellow Zone (BMIp 25th-49th) and Red Zone (BMIp < 25th). Intestinal microbiome assessment was performed via 16S rRNA gene sequencing; microbial richness, diversity, and differential species abundance were assessed. RESULTS: Stool samples were collected from 107 children with CF and 50 age-matched HCs. Compared to HCs, children with CF were found to have lower bacterial richness, alpha-diversity, and a different microbial composition. When evaluating them by their BMIp color zone, richness and alpha-diversity were lowest in those in the Red Zone. In addition, an unclassified amplicon sequence variant (ASV) of Blautia, a known butyrate-producing anaerobe, was of lowest abundance in children in the Red Zone. CONCLUSION: Children with CF have a dysbiotic intestinal microbiome with specific changes that accompany changes in BMIp. Longitudinal assessments of the microbiome and its metabolic activities over time are needed to better understand how improvements in the microbiome may improve nutrition and enhance long-term survival in children with CF.

Pharmacogenetic testing for CYP3A4 is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for many of the CYP3A4 variants included in clinical tests. To address this need, the Division of Laboratory Systems, CDC-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 30 DNA samples derived from Coriell cell lines for CYP3A4. Samples were distributed to five volunteer laboratories for genotyping using a variety of commercially available and laboratory-developed tests. Sanger and next-generation sequencing were also utilized by some of the laboratories. Whole-genome sequencing data from the 1000 Genomes Projects were utilized to inform genotype. Twenty CYP3A4 alleles were identified in the 30 samples characterized for CYP3A4: CYP3A4∗4, CYP3A4∗5, CYP3A4∗6, CYP3A4∗7, CYP3A4∗8, CYP3A4∗9, CYP3A4∗10, CYP3A4∗11, CYP3A4∗12, CYP3A4∗15, CYP3A4∗16, CYP3A4∗18, CYP3A4∗19, CYP3A4∗20, CYP3A4∗21, CYP3A4∗22, CYP3A4∗23, CYP3A4∗24, CYP3A4∗35, and a novel allele, CYP3A4∗38. Nineteen additional samples with preexisting data for CYP3A4 or CYP3A5 were re-analyzed to generate comprehensive reference material panels for these genes. These publicly available and well-characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing.

INTRODUCTION: Focusing on subpopulations that express the intention to receive a COVID-19 vaccination but are unvaccinated may improve the yield of COVID-19 vaccination efforts. METHODS: A nationally representative sample of 789,658 U.S. adults aged 18 years participated in the National Immunization Survey Adult COVID Module from May 2021 to April 2022. The survey assessed respondents' COVID-19 vaccination status and intent by demographic characteristics (age, urbanicity, educational attainment, region, insurance, income, and race/ethnicity). This study compared composition and within-group estimates of those who responded that they definitely or probably will get vaccinated or are unsure (moveable middle) from the first and last month of data collection. RESULTS: Because vaccination uptake increased over the study period, the moveable middle declined among persons aged 18 years. Adults aged 18-39 years and suburban residents comprised most of the moveable middle in April 2022. Groups with the largest moveable middles in April 2022 included persons with no insurance (10%), those aged 18-29 years (8%), and those with incomes below poverty (8%), followed by non-Hispanic Native Hawaiian or other Pacific Islander (7%), non-Hispanic multiple or other race (6%), non-Hispanic American Indian or Alaska Native persons (6%), non-Hispanic Black or African American persons (6%), those with below high school education (6%), those with high school education (5%), and those aged 30-39 years (5%). CONCLUSIONS: A sizable percentage of adults open to receiving COVID-19 vaccination remain in several demographic groups. Emphasizing engagement of persons who are unvaccinated in some racial/ethnic groups, aged 18-39 years, without health insurance, or with lower income may reach more persons open to vaccination.

INTRODUCTION: COVID-19 vaccines are safe, effective, and widely available, but many adults in the U.S. have not been vaccinated for COVID-19. This study examined the associations between behavioral and social drivers of vaccination with COVID-19 vaccine uptake in the U.S. adults and their prevalence by region. METHODS: A nationally representative sample of U.S. adults participated in a cross-sectional telephone survey in August-November 2021; the analysis was conducted in January 2022. Survey questions assessed self-reported COVID-19 vaccine initiation, demographics, and behavioral and social drivers of vaccination. RESULTS: Among the 255,763 respondents, 76% received their first dose of COVID-19 vaccine. Vaccine uptake was higher among respondents aged ≥75 years (94%), females (78%), and Asian non-Hispanic people (94%). The drivers of vaccination most strongly associated with uptake included higher anticipated regret from nonvaccination, risk perception, and confidence in vaccine safety and importance, followed by work- or school-related vaccination requirements, social norms, and provider recommendation (all p<0.05). The direction of association with uptake varied by reported level of difficulty in accessing vaccines. The prevalence of all of these behavioral and social drivers of vaccination was highest in the Northeast region and lowest in the Midwest and South. CONCLUSIONS: This nationally representative survey found that COVID-19 vaccine uptake was most strongly associated with greater anticipated regret, risk perception, and confidence in vaccine safety and importance, followed by vaccination requirements and social norms. Interventions that leverage these social and behavioral drivers of vaccination have the potential to increase COVID-19 vaccine uptake and could be considered for other vaccine introductions.

INTRODUCTION: Little is known about how the drivers of COVID-19 vaccination vary across the U.S. To inform vaccination outreach efforts, this study explores geographic variation in correlates of COVID-19 nonvaccination among adults. METHODS: Participants were a nationally representative sample of U.S. adults identified through random-digit dialing for the National Immunization Survey-Adult COVID Module. Analyses examined the geographic and temporal landscape of constructs in the Behavioral and Social Drivers of Vaccination Framework among unvaccinated respondents from May 2021 to December 2021 (n=531,798) and sociodemographic and geographic disparities and Behavioral and Social Drivers of Vaccination predictors of COVID-19 nonvaccination from October 2021 to December 2021 (n=187,756). RESULTS: National coverage with at least 1 dose of COVID-19 vaccine was 79.3% by December 2021, with substantial geographic heterogeneity. Regions with the largest proportion of unvaccinated persons who would probably get a COVID-19 vaccine or were unsure resided in the Southeast and Midwest (Health and Human Services Regions 4 and 5). Both regions had similar temporal trends regarding concerns about COVID-19 and confidence in vaccine importance, although the Southeast had especially low confidence in vaccine safety in December 2021, lowest in Florida (5.5%) and highest in North Carolina (18.0%). The strongest Behavioral and Social Drivers of Vaccination correlate of not receiving a COVID-19 vaccination was lower confidence in COVID-19 vaccine importance (adjusted prevalence ratio=5.19, 95% CI=4.93, 5.47; strongest in the Northeast, Southwest, and Mountain West and weakest in the Southeast and Midwest). Other Behavioral and Social Drivers of Vaccination correlates also varied by region. CONCLUSIONS: Contributors to nonvaccination showed substantial geographic heterogeneity. Strategies to improve COVID-19 vaccination uptake may need to be tailored regionally.

Pharmacogenetic testing is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials (RMs) are currently available for many of the TPMT and NUDT15 variants included in clinical tests. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention (CDC) based Genetic Testing Reference Material Coordination Program (GeT-RM), in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 19 DNA samples derived from Coriell cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using a variety of commercially available and laboratory developed tests and/or Sanger sequencing. Of the 12 samples characterized for TPMT, newly identified variants include TPMT*2, *6, *12, *16, *21, *24, *32, *33, *40; for the 7 NUDT15 reference material samples, newly identified variants are NUDT15*2, *3, *4, *5, *6, and *9. In addition, a novel haplotype, TPMT*46, was identified in this study. Pre-existing data on an additional 11 Coriell samples, as well as some supplemental testing, was utilized to create comprehensive reference material panels for TPMT and NUDT15. These publicly available and well characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing.

OBJECTIVES: Diabetes may delay milk letdown, and perceiving milk production as insufficient can lead to breastfeeding cessation. We evaluated whether prepregnancy or gestational diabetes is associated with cessation of breastfeeding by 1 week postpartum. METHODS: We analyzed 2016-2018 data from 42 sites in the Pregnancy Risk Assessment Monitoring System, a population-based survey of women with a recent live birth. Participants were surveyed 2-6 months after childbirth. We used logistic regression models to evaluate the relationship between prepregnancy or gestational diabetes only and breastfeeding <1 week postpartum among women who had initiated breastfeeding. RESULTS: Among 82 050 women who initiated breastfeeding, 4.5% reported breastfeeding <1 week postpartum. Overall, 11.7% of women reported any history of diabetes in the 3 months before becoming pregnant; 3.3% reported prepregnancy diabetes, and 8.4% reported gestational diabetes only. In both unadjusted and adjusted models, the prevalence of breastfeeding <1 week postpartum did not differ significantly among women with prepregnancy diabetes or gestational diabetes only compared with women without any history of diabetes. The prevalence of breastfeeding <1 week postpartum was 4.4% among women without any history of diabetes, 5.6% among women with prepregnancy diabetes (adjusted prevalence ratio [aPR] = 1.15; 95% CI, 0.91-1.46), and 4.5% among women with gestational diabetes only (aPR = 1.01; 95% CI, 0.84-1.20). CONCLUSIONS: We found no association between a history of diabetes prepregnancy or gestational diabetes only and breastfeeding <1 week postpartum in a large, population-based survey of postpartum women who initiated breastfeeding. Regardless of their diabetes status, women who want to breastfeed might benefit from interventions that support their ability to continue breastfeeding.

Pharmacogenetic tests typically target selected sequence variants to identify haplotypes that are often defined by star (*) allele nomenclature. Due to their design, these targeted genotyping assays are unable to detect novel variants that may change the function of the gene product and thereby affect phenotype prediction and patient care. In the current study, 137 DNA samples that were previously characterized by the Genetic Testing Reference Material (GeT-RM) Program using a variety of targeted genotyping methods were recharacterized using targeted and whole genome sequencing analysis. Sequence data were analyzed using three genotype calling tools to identify star allele diplotypes for CYP2C8, CYP2C9 and CYP2C19. The genotype calls from next-generation sequencing (NGS) correlated well to those previously reported, except when novel alleles were present in a sample. Six novel alleles and 38 novel suballeles were identified in the three genes due to identification of variants not covered by targeted genotyping assays. In addition, several ambiguous genotype calls from a previous study were resolved using the NGS and/or long read NGS data. Diplotype calls were mostly consistent between the calling algorithms, although several discrepancies were noted. This study highlights the utility of NGS for pharmacogenetic testing and demonstrates that there are many novel alleles that are yet to be discovered, even in highly characterized genes such as CYP2C9 and CYP2C19.

We conducted a cross-sectional study of pregnant women with acute respiratory illness during delivery hospitalizations in influenza season to describe clinical testing for respiratory viruses and infection prevention practices. Women had nasal swabs tested for influenza and other respiratory viruses. Among 91 enrolled women, 22 (24%) had clinical testing for influenza. Based on clinical and study testing combined, 41/91 (45%) women had samples positive for respiratory viruses. The most common virus was influenza (17/91, 19%); 53% (9/17) of influenza virus infections were identified through study testing alone. Only 16% of women were on droplet precautions. Peripartum respiratory infections may be underrecognized.

BACKGROUND: The cotton rat (genus Sigmodon) is an essential small animal model for the study of human infectious disease and viral therapeutic development. However, the impact of the host microbiome on infection outcomes has not been explored in this model, partly due to the lack of a comprehensive characterization of microbial communities across different cotton rat species. Understanding the dynamics of their microbiome could significantly help to better understand its role when modeling viral infections in this animal model. RESULTS: We examined the bacterial communities of the gut and three external sites (skin, ear, and nose) of two inbred species of cotton rats commonly used in research (S. hispidus and S. fulviventer) by using 16S rRNA gene sequencing, constituting the first comprehensive characterization of the cotton rat microbiome. We showed that S. fulviventer maintained higher alpha diversity and richness than S. hispidus at external sites (skin, ear, nose), but there were no differentially abundant genera. However, S. fulviventer and S. hispidus had distinct fecal microbiomes composed of several significantly differentially abundant genera. Whole metagenomic shotgun sequencing of fecal samples identified species-level differences between S. hispidus and S. fulviventer, as well as different metabolic pathway functions as a result of differential host microbiome contributions. Furthermore, the microbiome composition of the external sites showed significant sex-based differences while fecal communities were not largely different. CONCLUSIONS: Our study shows that host genetic background potentially exerts homeostatic pressures, resulting in distinct microbiomes for two different inbred cotton rat species. Because of the numerous studies that have uncovered strong relationships between host microbiome, viral infection outcomes, and immune responses, our findings represent a strong contribution for understanding the impact of different microbial communities on viral pathogenesis. Furthermore, we provide novel cotton rat microbiome data as a springboard to uncover the full therapeutic potential of the microbiome against viral infections.

Pharmacogenetic (PGx) testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials (RMs) are currently available for the complex rearrangements and rare variants that occur in the CYP2D6 gene. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention based Genetic Testing Reference Material Coordination Program (GeT-RM), in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Cell Repositories, has characterized 179 DNA samples derived from Coriell cell lines. Testing included the re-characterization of 137 genomic DNAs that were genotyped in previous GeT-RM studies and 42 additional samples that had not been previously characterized. DNA samples were distributed to volunteer testing laboratories for genotyping using a variety of commercially available and laboratory developed tests. These publicly available samples will support the quality assurance and quality control programs of clinical laboratories performing CYP2D6 testing.

Dogs harbor numerous zoonotic pathogens, many of which are controlled through vaccination programs. The delivery of these programs can be difficult where resources are limited. We developed a dynamic model to estimate vaccination coverage and cost-per-dog vaccinated. The model considers the main factors that affect vaccination programs: dog demographics, effectiveness of strategies, efficacy of interventions and cost. The model was evaluated on data from 18 vaccination programs representing eight countries. Sensitivity analysis was performed for dog confinement and vaccination strategies. The average difference between modelled vaccination coverage and field data was 3.8% (2.3%-5.3%). Central point vaccination was the most cost-effective vaccination strategy when &gt;88% of the dog population was confined. More active methods of vaccination, such as door-to-door or capture-vaccinate-release, achieved higher vaccination coverage in free-roaming dog populations but were more costly. This open-access tool can aid in planning more efficient vaccination campaigns in countries with limited resources.

Haiti, a Caribbean country of 10.5 million people, is estimated to have the highest burden of canine-mediated human rabies deaths in the Western Hemisphere, and one of the highest rates of human rabies deaths in the world. Haiti is also the poorest country in the Western Hemisphere and has numerous economic and health priorities that compete for rabies-control resources. As a result, primary rabies-control actions, including canine vaccination programs, surveillance systems for human and animal rabies, and appropriate postbite treatment, have not been fully implemented at a national scale. After the 2010 earthquake that further hindered the development of public health program infrastructure and services, the U.S. Centers for Disease Control and Prevention worked with the Ministry of Public Health and Population and key health development partners (including the Pan-American Health Organization) to provide technical expertise and funding for general disease surveillance systems, laboratory capacity, and selected disease control programs; including rabies. In 2011, a cross-ministerial rabies consortium was convened with participation from multiple international rabies experts to develop a strategy for successful rabies control in Haiti. The consortium focused on seven pillars: 1) enhancement of laboratory diagnostic capacity, 2) development of comprehensive animal surveillance system, 3) development of comprehensive human rabies surveillance system, 4) educational outreach, 5) sustainable human rabies biologics supply, 6) achievement of sustained canine vaccination rates of ≥ 70%, and 7) finalization of a national rabies control strategy. From 2010 until 2015, Haiti has seen improvements in the program infrastructure for canine rabies control. The greatest improvements were seen in the area of animal rabies surveillance, in support of which an internationally recognized rabies laboratory was developed thereby leading to an 18-fold increase in the detection of rabid animals. Canine rabies vaccination practices also improved, from a 2010 level of approximately 12% to a 2015 dog population coverage level estimated to be 45%. Rabies vaccine coverage is still below the goal of 70%, however, the positive trend is encouraging. Gaps exist in the capacity to conduct national surveillance for human rabies cases and access to human rabies vaccine is lacking in many parts of the country. However, control has improved over the past 5 years as a result of the efforts of Haiti's health and agriculture sectors with assistance from multiple international organizations. Haiti is well situated to eliminate canine-mediated human rabies deaths in the near future and should serve as a great example to many developing countries struggling with similar barriers and limitations.

An estimated 59 000 persons die annually of infection with the rabies virus worldwide, and dog bites are responsible for 95% of these deaths. Haiti has the highest rate of animal and human rabies in the Western Hemisphere. This study describes the status of animal welfare, animal vaccination, human bite treatment, and canine morbidity and mortality in Haiti in order to identify barriers to rabies prevention and control. An epidemiologic survey was used for data collection among dog owners during government-sponsored vaccination clinics at fourteen randomly selected sites from July 2014 to April 2015. A total of 2005 surveys were collected and data were analysed using parametric methods. Over 50% of owned dogs were allowed to roam freely, a factor associated with rabies transmission. More than 80% of dog owners reported experiencing barriers to accessing rabies vaccination for their dogs. Nearly one-third of the dog population evaluated in this study died in the year preceding the survey (32%) and 18% of these deaths were clinically consistent with rabies. Dog bites were commonly reported, with more than 3% of the study population bitten within the year preceding the survey. The incidence of canine rabies in Haiti is high and is exacerbated by low access to veterinary care, free-roaming dog populations and substandard animal welfare practices. Programmes to better understand the dog ecology and development of methods to improve access to vaccines are needed. Rabies deaths are at historical lows in the Western Hemisphere, but Haiti and the remaining canine rabies endemic countries still present a significant challenge to the goal of rabies elimination in the region.

SUMMARY: Many diseases and injuries can impair joint mobility. Normal reference values are needed to determine extent of impairment to assess and monitor joint motion. There is very little published data describing normal joint range of motion (ROM) for healthy men and women across a wide span of ages. We enrolled male and female subjects aged between 2 and 69 years who were free from conditions that could potentially limit joint mobility for the study. Nine licensed physical therapists used universal goniometers to determine passive joint motion bilaterally of elbow flexion, extension, supination and pronation, shoulder flexion, hip flexion and extension, knee flexion and extension, and ankle dorsiflexion and plantarflexion. Descriptive statistics were calculated for male and female subjects in four age groups: 2-8, 9-19, 20-44 and 45-69 years. Joint ROM measurements were obtained on a total of 674 (53.6% female) healthy, normal subjects aged 2-69 years. Female subjects had greater joint mobility in all age groups in nearly all joints and the gender difference was most obvious in measures of ankle plantarflexion, elbow pronation and supination. Range of motion average values for all joints decreased with advancing age for both men and women and, in most cases, were significantly different than most commonly used normative values. Our study of ROM measurements taken by trained physical therapists on a large sample of healthy individuals revealed significant gender- and age-related variation that may be an important consideration in patient assessment.

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized as waived (from routine regulatory oversight) or nonwaived based on the complexity of the tests; tests of moderate and high complexity are nonwaived tests. Laboratories that perform molecular genetic testing are subject to the general CLIA quality systems requirements for nonwaived testing and the CLIA personnel requirements for tests of high complexity. Although many laboratories that perform molecular genetic testing comply with applicable regulatory requirements and adhere to professional practice guidelines,specific guidelines for quality assurance are needed to ensure the quality of test performance. To enhance the oversight of genetic testing under the CLIA framework,CDC and the Centers for Medicare & Medicaid Services (CMS) have taken practical steps to address the quality management concerns in molecular genetic testing,including working with the Clinical Laboratory Improvement Advisory Committee (CLIAC). This report provides CLIAC recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. The recommended practices address the total testing process (including the preanalytic,analytic,and postanalytic phases),laboratory responsibilities regarding authorized persons,confidentiality of patient information,personnel competency,considerations before introducing molecular genetic testing or offering new molecular genetic tests,and the quality management system approach to molecular genetic testing. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care. Improvements in the quality and use of genetic laboratory services should improve the quality of health care and health outcomes for patients and families of patients.