Progress Toward Tuberculosis Elimination and Tuberculosis Program Performance - National Tuberculosis Indicators Project, 2016-2022.

Problem/Condition: Elimination of tuberculosis (TB) is defined as reducing TB disease incidence in the United States to less than 1 case per million persons per year. In 2022, TB incidence in the United States was 2.5 TB cases per 100,000 persons. CDC's TB program developed a set of national TB indicators to evaluate progress toward TB elimination through monitoring performance of state and city TB program activities. Examining TB indicator data enables state- and city-level TB programs to identify areas for program evaluation and improvement activities. These data also help CDC identify states and cities that might benefit from technical assistance. Period Covered: The 5-year period for which the most recent data were available for each of five indicators: 1) overall TB incidence (2018-2022), 2) TB incidence among non-U.S.-born persons (2018-2022), 3) percentage of persons with drug susceptibility results reported (2018-2022), 4) percentage of contacts to sputum acid-fast bacillus (AFB) smear-positive TB patients with newly diagnosed latent TB infection (LTBI) who completed treatment (2017-2021), and 5) percentage of patients with completion of TB therapy within 12 months (2016-2020). Description of System: The National TB Indicators Project (NTIP) is a web-based performance monitoring tool that uses national TB surveillance data reported through the National TB Surveillance System and the Aggregate Reports for TB Program Evaluation. NTIP was developed to facilitate the use of existing data to help TB program staff members prioritize activities, monitor progress, and focus program improvement efforts. The following five indicators were selected for this report because of their importance in Federal TB funding allocation and in accelerating the decline in TB cases: 1) overall TB incidence in the United States, 2) TB incidence among non-U.S.-born persons, 3) percentage of persons with drug susceptibility results reported, 4) percentage of contacts to sputum AFB smear-positive TB cases who completed treatment for LTBI, and 5) percentage of patients with completion of TB therapy within 12 months. For this report, 52 TB programs (50 states, the District of Columbia, and New York City) were categorized into terciles based on the 5-year average number of TB cases reported to National TB Surveillance System. This grouping allows comparison of TB programs that have similar numbers of TB cases and allocates a similar number of TB programs to each category. The following formula was used to calculate the relative change by TB program for each indicator: [(% from year 5 - % from year 1 ÷ % from year 1) × 100]. Results: During the 5-year period for which the most recent data were available, most TB programs had improvements in reducing overall TB incidence (71.2%) and increasing the percentage of contacts receiving a diagnosis of LTBI who completed LTBI treatment (55.8%); the majority of programs (51.0%) also had improvements in reducing incidence among non-U.S.-born persons. The average percentage of persons with drug susceptibility results reported in most jurisdictions (28 of 52, [53.9%]) met or exceeded the 5-year national average of 97% (2018-2022). The percentage of contacts to sputum acid-fast bacillus (AFB) smear-positive TB patients with newly diagnosed latent TB infection (LTBI) who completed treatment increased in 29 of 52 (55.8%) jurisdictions from 2017 to 2021, signifying that, for most jurisdictions, steps have been taken to enhance performance in this area. The average percentage of patients with completion of TB therapy within 12 months was at or above the national average of 89.7% in approximately two-thirds (32 of 52 [61.5%]) of jurisdictions. Interpretation: This report is the first to describe a 5-year relative change for TB program performance. These results suggest that TB programs are making improvements in activities that help identify persons with TB and LTBI and ensure patients complete treatment in a timely manner. Public Health Action: Use of NTIP data from individual TB programs enables a more detailed examination of trends in program performance and identification of areas for program improvement. Assessing indicator trends by TB program provides an opportunity to gain a better understanding of program performance in comparison to other programs. It can also facilitate communication between programs regarding successes and challenges in program improvement. This information is valuable for TB programs to allocate resources effectively and provide additional context on TB control for public health policymakers.

Racial and Ethnic Disaggregation of Tuberculosis Incidence and Risk Factors Among American Indian and Alaska Native Persons-United States, 2001-2020.

Objectives. To examine impacts of racial and ethnic disaggregation on the characterization of tuberculosis (TB) epidemiology among American Indian and Alaska Native (AI/AN) persons in the United States. Methods. Using data reported to the National Tuberculosis Surveillance System during 2001 to 2020, we compared annual age-adjusted TB incidence and the frequency of TB risk factors among 3 AI/AN analytic groups: non-Hispanic AI/AN alone persons, multiracial/Hispanic AI/AN persons, and all AI/AN persons (aggregate of the first 2 groups). Results. During 2009 to 2020, annual TB incidence (cases per 100 000 persons) among non-Hispanic AI/AN alone persons (range = 3.87-8.56) was on average 1.9 times higher than among all AI/AN persons (range = 1.89-4.70). Compared with non-Hispanic AI/AN alone patients with TB, multiracial/Hispanic AI/AN patients were significantly more likely to be HIV positive (prevalence ratio [PR] = 2.05) and to have been diagnosed while a resident of a correctional facility (PR = 1.71), and significantly less likely to have experienced homelessness (PR = 0.53) or died during TB treatment (PR = 0.47). Conclusions. Racial and ethnic disaggregation revealed significant differences in TB epidemiology among AI/AN analytic groups. Exclusion of multiracial/Hispanic AI/AN persons from AI/AN analytic groups can substantively affect estimates of racial and ethnic health disparities. (Am J Public Health. 2024;114(2):226-236. https://doi.org/10.2105/AJPH.2023.307498).

Tuberculosis Infection among Non-US-Born Persons and Persons ≥60 Years of Age, United States, 2019-2020.

We examined tuberculosis (TB) infection results for the United States from the 2019-2020 National Health and Nutrition Examination Survey. Over this period, 10% of non-US-born persons and 7% of those >60 years of age tested positive for TB infection. These results provide up-to-date information on TB infection among study subpopulations.

Recommendations for Use of Video Directly Observed Therapy During Tuberculosis Treatment - United States, 2023.

U.S. clinical practice guidelines recommend directly observed therapy (DOT) as the standard of care for tuberculosis (TB) treatment (1). DOT, during which a health care worker observes a patient ingesting the TB medications, has typically been conducted in person. Video DOT (vDOT) uses video-enabled devices to facilitate remote interactions between patients and health care workers to promote medication adherence and clinical monitoring. Published systematic reviews, a published meta-analysis, and a literature search through 2022 demonstrate that vDOT is associated with a higher proportion of medication doses being observed and similar proportions of cases with treatment completion and microbiologic resolution when compared with in-person DOT (2-5). Based on this evidence, CDC has updated the recommendation for DOT during TB treatment to include vDOT as an equivalent alternative to in-person DOT. vDOT can assist health department TB programs meet the U.S. standard of care for patients undergoing TB treatment, while using resources efficiently.

Estimated Latent Tuberculosis Infection Prevalence and Tuberculosis Reactivation Rates Among Non-U.S.-Born Residents in the United States, from the 2011-2012 National Health and Nutrition Examination Survey.

Increased testing and treatment of latent tuberculosis infection (LTBI) among US-residents who were born (or lived) in countries with high rates of TB can hasten progress toward TB elimination. We calculated LTBI prevalence using QuantiFERON®-TB Gold In-Tube results from the 2011 to 2012 National Health and Nutrition Examination Survey (NHANES). LTBI prevalence was highest for persons born in India (31.7%, 95% confidence interval [21.2, 44.5]). Non-Hispanic white persons had the lowest LTBI prevalence (6.3% [1.9, 18.9]). TB reactivation rate, defined as the number of TB cases not associated with recent transmission per 100 person-years of life with LTBI, was highest for persons born in Vietnam [0.183 (0.117, 0.303)]. Reactivation rates were lower among persons who had resided in the United States for ≥ 10 years than among those who had resided for < 10 years. Results among high risk populations can guide LTBI targeted testing and treatment among non-U.S.-born residents.

Estimates of Testing for Latent Tuberculosis Infection and Cost, United States, 2013.

OBJECTIVES: Tracking trends in the testing of latent tuberculosis infection (LTBI) can help measure tuberculosis elimination efforts in the United States. The objectives of this study were to estimate (1) the annual number of persons tested for LTBI and the number of LTBI tests conducted, by type of test and by public, private, and military sectors, and (2) the cost of LTBI testing in the United States. METHODS: We searched the biomedical literature for published data on private-sector and military LTBI testing in 2013, and we used back-calculation to estimate public-sector LTBI testing. To estimate costs, we applied Medicare-allowable reimbursements in 2013 by test type. RESULTS: We estimated an average (low-high) 13.3 million (11.3-15.4 million) persons tested for LTBI and 15.3 million (12.9-17.7 million) LTBI tests, of which 13.2 million (11.1-15.3 million) were tuberculin skin tests and 2.1 million (1.8-2.4 million) were interferon-γ release assays (IGRAs). Eighty percent of persons tested were in the public sector, 18% were in the private sector, and 2% were in the military. Costs of LTBI tests and of chest radiography totaled $314 million (range, $256 million to $403 million). CONCLUSIONS: To achieve tuberculosis elimination, millions more persons will need to be tested in all sectors. By targeting testing to only those at high risk of tuberculosis and by using more specific IGRA tests, the incidence of tuberculosis in the United States can be reduced and resources can be more efficiently used.

Isoniazid-Rifapentine for Latent Tuberculosis Infection: A Systematic Review and Meta-analysis.

CONTEXT: Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment. EVIDENCE ACQUISITION: Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017. EVIDENCE SYNTHESIS: The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11). CONCLUSIONS: The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.

Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection.

Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years.

Development of a Surveillance Definition for United States-Mexico Binational Cases of Tuberculosis.

OBJECTIVES: Consistently collected binational surveillance data are important in advocating for resources to manage and treat binational cases of tuberculosis (TB). The objective of this study was to develop a surveillance definition for binational (United States-Mexico) cases of TB to assess the burden on US TB program resources. METHODS: We collaborated with state and local TB program staff members in the United States to identify characteristics associated with binational cases of TB. We collected data on all cases of TB from 9 pilot sites in 5 states (Arizona, California, Colorado, New Mexico, and Texas) during January 1-June 30, 2014, that had at least 1 binational characteristic (eg, "crossed border while on TB treatment" and "received treatment in another country, coordinated by an established, US-funded, binational TB program"). A workgroup of US state, local, and federal partners reviewed results and used them to develop a practical surveillance definition. RESULTS: The pilot sites reported 87 cases of TB with at least 1 binational characteristic during the project period. The workgroup drafted a proposed surveillance definition to include 2 binational characteristics: "crossed border while on TB treatment" (34 of 87 cases, 39%) and "received treatment in another country, coordinated by an established, US-funded, binational TB program" (26 of 87 cases, 30%). Applying the new proposed definition, 39 of 87 pilot cases of TB (45%) met the definition of binational. CONCLUSION: Input from partners who were responsible for the care and treatment of patients who cross the United States-Mexico border was crucial in defining a binational case of TB.

Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012.

BACKGROUND: Reexamining the prevalence of persons infected with tuberculosis (TB) is important to determine trends over time. In 2011-2012 a TB component was included in the National Health and Nutrition Examination Survey (NHANES) to estimate the reservoir of persons infected with TB. METHODS: Civilian, noninstitutionalized U.S. population survey participants aged 6 years and older were interviewed regarding their TB history and eligibility for the tuberculin skin test (TST) and interferon gamma release assay (IGRA) blood test. Once eligibility was confirmed, both tests were conducted. Prevalence and numbers of TST positive (10 mm or greater), IGRA positive, and both TST and IGRA positive were calculated by adjusting for the complex survey design after applying corrections for item nonresponse and digit preference in TST induration measurements. To examine TST positivity over time, data from NHANES 1999-2000 were reanalyzed using the same statistical methods. The TST was performed using Tubersol, a commercially available purified protein derivative (PPD), rather than PPD-S, which was the antigen used in NHANES 1999-2000. Prior patient history of TB vaccination was not collected in this study nor were patients examined for the presence of a Bacillus of Calmette and Guerin (BCG) vaccine scar. RESULTS: For NHANES 2011-2012, TST and IGRA results were available for 6,128 (78.4%) and 7,107 (90.9%) eligible participants, respectively. There was no significant difference between the percentage of the U.S. population that was TST positive in 2011-2012 (4.7% [95% CI 3.4-6.3]; 13,276,000 persons) compared with 1999-2000 (4.3%; 3.5-5.3). In 2011-2012 the percentage that was IGRA positive was 5.0% (4.2-5.8) and double TST and IGRA positivity was 2.1% (1.5-2.8). The point estimate of IGRA positivity prevalence in foreign-born persons (15.9%; 13.5-18.7) was lower than for TST (20.5%; 16.1-25.8) in 2011-2012. The point estimate of IGRA positivity prevalence in U.S.-born persons (2.8%; 2.0-3.8) was higher than for TST (1.5%; 0.9-2.6). CONCLUSIONS: No statistically significant decline in the overall estimated prevalence of TST positivity was detected from 1999-2000 to 2011-2012. The prevalence of TB infection, whether measured by TST or IGRA, remains lower among persons born in the United States compared with foreign-born persons.

The US National Tuberculosis Surveillance System: A Descriptive Assessment of the Completeness and Consistency of Data Reported from 2008 to 2012.

BACKGROUND: In 2009, the Tuberculosis (TB) Information Management System transitioned into the National TB Surveillance System to allow use of 4 different types of electronic reporting schemes: state-built, commercial, and 2 schemes developed by the Centers for Disease Control and Prevention. Simultaneously, the reporting form was revised to include additional data fields. OBJECTIVE: Describe data completeness for the years 2008-2012 and determine the impact of surveillance changes. METHODS: Data were categorized into subgroups and assessed for completeness (eg, the percentage of patients dead at diagnosis who had a date of death reported) and consistency (eg, the percentage of patients alive at diagnosis who erroneously had a date of death reported). Reporting jurisdictions were grouped to examine differences by reporting scheme. RESULTS: Each year less than 1% of reported cases had missing information for country of origin, race, or ethnicity. Patients reported as dead at diagnosis had death date (a new data field) missing for 3.6% in 2009 and 4.4% in 2012. From 2010 to 2012, 313 cases (1%) reported as alive at diagnosis had a death date and all of these were reported through state-built or commercial systems. The completeness of reporting for guardian country of birth for pediatric patients (a new data field) ranged from 84% in 2009 to 88.2% in 2011. CONCLUSIONS: Despite major changes, completeness has remained high for most data elements in TB surveillance. However, some data fields introduced in 2009 remain incomplete; continued training is needed to improve national TB surveillance data.

Predicting U.S. tuberculosis case counts through 2020.

In 2010, foreign-born persons accounted for 60% of all tuberculosis (TB) cases in the United States. Understanding which national groups make up the highest proportion of TB cases will assist TB control programs in concentrating limited resources where they can provide the greatest impact on preventing transmission of TB disease. The objective of our study was to predict through 2020 the numbers of U.S. TB cases among U.S.-born, foreign-born and foreign-born persons from selected countries of birth. TB case counts reported through the National Tuberculosis Surveillance System from 2000-2010 were log-transformed, and linear regression was performed to calculate predicted annual case counts and 95% prediction intervals for 2011-2020. Data were analyzed in 2011 before 2011 case counts were known. Decreases were predicted between 2010 observed and 2020 predicted counts for total TB cases (11,182 to 8,117 [95% prediction interval 7,262-9,073]) as well as TB cases among foreign-born persons from Mexico (1,541 to 1,420 [1,066-1,892]), the Philippines (740 to 724 [569-922]), India (578 to 553 [455-672]), Vietnam (532 to 429 [367-502]) and China (364 to 328 [249-433]). TB cases among persons who are U.S.-born and foreign-born were predicted to decline 47% (4,393 to 2,338 [2,113-2,586]) and 6% (6,720 to 6,343 [5,382-7,476]), respectively. Assuming rates of declines observed from 2000-2010 continue until 2020, a widening gap between the numbers of U.S.-born and foreign-born TB cases was predicted. TB case count predictions will help TB control programs identify needs for cultural competency, such as languages and interpreters needed for translating materials or engaging in appropriate community outreach.

Unexpected decline in tuberculosis cases coincident with economic recession - United States, 2009.

BACKGROUND: Since 1953, through the cooperation of state and local health departments, the U.S. Centers for Disease Control and Prevention (CDC) has collected information on incident cases of tuberculosis (TB) disease in the United States. In 2009, TB case rates declined -11.4%, compared to an average annual -3.8% decline since 2000. The unexpectedly large decline raised concerns that TB cases may have gone unreported. To address the unexpected decline, we examined trends from multiple sources on TB treatment initiation, medication sales, and laboratory and genotyping data on culture-positive TB. METHODS: We analyzed 142,174 incident TB cases reported to the U. S. National Tuberculosis Surveillance System (NTSS) during January 1, 2000-December 31, 2009; TB control program data from 59 public health reporting areas; self-reported data from 50 CDC-funded public health laboratories; monthly electronic prescription claims for new TB therapy prescriptions; and complete genotyping results available for NTSS cases. Accounting for prior trends using regression and time-series analyses, we calculated the deviation between observed and expected TB cases in 2009 according to patient and clinical characteristics, and assessed at what point in time the deviation occurred. RESULTS: The overall deviation in TB cases in 2009 was -7.9%, with -994 fewer cases reported than expected (P < .001). We ruled out evidence of surveillance underreporting since declines were seen in states that used new software for case reporting in 2009 as well as states that did not, and we found no cases unreported to CDC in our examination of over 5400 individual line-listed reports in 11 areas. TB cases decreased substantially among both foreign-born and U.S.-born persons. The unexpected decline began in late 2008 or early 2009, and may have begun to reverse in late 2009. The decline was greater in terms of case counts among foreign-born than U.S.-born persons; among the foreign-born, the declines were greatest in terms of percentage deviation from expected among persons who had been in the United States less than 2 years. Among U.S.-born persons, the declines in percentage deviation from expected were greatest among homeless persons and substance users. Independent information systems (NTSS, TB prescription claims, and public health laboratories) reported similar patterns of declines. Genotyping data did not suggest sudden decreases in recent transmission. CONCLUSIONS: Our assessments show that the decline in reported TB was not an artifact of changes in surveillance methods; rather, similar declines were found through multiple data sources. While the steady decline of TB cases before 2009 suggests ongoing improvement in TB control, we were not able to identify any substantial change in TB control activities or TB transmission that would account for the abrupt decline in 2009. It is possible that other multiple causes coincident with economic recession in the United States, including decreased immigration and delayed access to medical care, could be related to TB declines. Our findings underscore important needs in addressing health disparities as we move towards TB elimination in the United States.

The unusual UBZ domain of Saccharomyces cerevisiae polymerase η.

Recent research has revealed the presence of ubiquitin-binding domains in the Y family polymerases. The ubiquitin-binding zinc finger (UBZ) domain of human polymerase η is vital for its regulation, localization, and function. Here, we elucidate structural and functional features of the non-canonical UBZ motif of Saccharomyces cerevisiae pol η. Characterization of pol η mutants confirms the importance of the UBZ motif and implies that its function is independent of zinc binding. Intriguingly, we demonstrate that zinc does bind to and affect the structure of the purified UBZ domain, but is not required for its ubiquitin-binding activity. Our finding that this unusual zinc finger is able to interact with ubiquitin even in its apo form adds support to the model that ubiquitin binding is the primary and functionally important activity of the UBZ domain in S. cerevisiae polymerase η. Putative ubiquitin-binding domains, primarily UBZs, are identified in the majority of known pol η homologs. We discuss the implications of our observations for zinc finger structure and pol η regulation.

Recipes for foodborne outbreaks: a scheme for categorizing and grouping implicated foods.

BACKGROUND: To better understand the sources of foodborne illness, we propose a scheme for categorizing foods implicated in investigations of outbreaks of foodborne diseases. Because nearly 2000 foods have been reported as causing outbreaks in the United States, foods must be grouped for meaningful analyses. METHODS: We defined a hierarchy of 17 mutually exclusive food commodities. We defined the following three commodity groups from which nearly all food is derived: aquatic animals, land animals, and plants. We defined three commodities in aquatic animals, six in land animals, and eight in plants. We considered each food as a set of ingredients composed of one or more commodities. We defined a simple food as one made of ingredients that are all in one commodity and a complex food as one containing ingredients in more than one commodity. We determined likely ingredients using a panel of epidemiologists and a web-based search process. RESULTS: We assigned 1709 (95%) of the 1794 foods implicated in outbreaks of foodborne diseases reported to Centers for Disease Control and Prevention from 1973 to 2006. Of those, 987 (57%) were simple foods and 722 (43%) were complex foods. DISCUSSION: This categorization may serve as an input for modeling the attribution of human illness to specific food commodities and could be used by policy makers, health officials, regulatory agencies, and consumer groups to evaluate the contribution of various food commodities to illness.

Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance.

DNA repair and DNA damage tolerance machineries are crucial to overcome the vast array of DNA damage that a cell encounters during its lifetime. In this review, we summarize the current state of knowledge about the eukaryotic DNA damage tolerance pathway translesion synthesis (TLS), a process in which specialized DNA polymerases replicate across from DNA lesions. TLS aids in resistance to DNA damage, presumably by restarting stalled replication forks or filling in gaps that remain in the genome due to the presence of DNA lesions. One consequence of this process is the potential risk of introducing mutations. Given the role of these translesion polymerases in mutagenesis, we discuss the significant regulatory mechanisms that control the five known eukaryotic translesion polymerases: Rev1, Pol zeta, Pol kappa, Pol eta, and Pol iota.

Comparative analysis of in vivo interactions between Rev1 protein and other Y-family DNA polymerases in animals and yeasts.

Eukaryotes are endowed with multiple specialized DNA polymerases, some (if not all) of which are believed to play important roles in the tolerance of base damage during DNA replication. Among these DNA polymerases, Rev1 protein (a deoxycytidyl transferase) from vertebrates interacts with several other specialized polymerases via a highly conserved C-terminal region. The present studies assessed whether these interactions are retained in more experimentally tractable model systems, including yeasts, flies, and the nematode C. elegans. We observed a physical interaction between Rev1 protein and other Y-family polymerases in the fruit fly Drosophila melanogaster. However, despite the fact that the C-terminal region of Drosophila and yeast Rev1 are conserved from vertebrates to a similar extent, such interactions were not observed in Saccharomyces cerevisiae or Schizosaccharomyces pombe. With respect to regions in specialized DNA polymerases that are required for interaction with Rev1, we find predicted disorder to be an underlying structural commonality. The results of this study suggest that special consideration should be exercised when making mechanistic extrapolations regarding translesion DNA synthesis from one eukaryotic system to another.

Surveillance for foodborne-disease outbreaks--United States, 1998-2002.

PROBLEM/CONDITION: Since 1973, CDC has maintained a collaborative surveillance program for collection and periodic reporting of data on the occurrence and causes of foodborne-disease outbreaks (FBDOs) in the United States. REPORTING PERIOD COVERED: 1998-2002. DESCRIPTION OF SYSTEM: The Foodborne Disease Outbreak Surveillance System reviews data on FBDOs, defined as the occurrence of two or more cases of a similar illness resulting from the ingestion of a common food. State and local public health departments have primary responsibility for identifying and investigating FBDOs. State, local, and territorial health departments use a standard form to report these outbreaks to CDC. In 1998, CDC implemented enhanced surveillance for FBDOs by increasing communication with state, local, and territorial health departments and revising the outbreak report form. Since 2001, reports of FBDOs are submitted through a web application on the Internet called the electronic Foodborne Outbreak Reporting System (eFORS). RESULTS: During 1998-2002, a total of 6,647 outbreaks of foodborne disease were reported (1,314 in 1998, 1,343 in 1999, 1,417 in 2000, 1,243 in 2001, and 1,330 in 2002). These outbreaks caused a reported 128,370 persons to become ill. Among 2,167 (33%) outbreaks for which the etiology was determined, bacterial pathogens caused the largest percentage of outbreaks (55%) and the largest percentage of cases (55%). Among bacterial pathogens, Salmonella serotype Enteritidis accounted for the largest number of outbreaks and outbreak-related cases; Listeria monocytogenes accounted for the majority of deaths of any pathogen. Viral pathogens, predominantly norovirus, caused 33% of outbreaks and 41% of cases; the proportion of outbreaks attributed to viral agents increased from 16% in 1998 to 42% in 2002. Chemical agents caused 10% of outbreaks and 2% of cases, and parasites caused 1% of outbreaks and 1% of cases. INTERPRETATION: Following implementation of measures to enhance outbreak surveillance, the annual number of FBDOs reported to CDC increased during this period compared with previous years. Viral pathogens accounted for an increased proportion of outbreaks each year during this reporting period and a higher proportion of outbreaks of known etiology during this reporting period than preceding reporting periods, probably reflecting the increased availability of improved viral diagnostic tests. S. Enteritidis continued to be a major cause of illness and L. monocytogenes was a major cause of death. In addition, multistate outbreaks caused by contaminated produce and outbreaks caused by Escherichia coli O157:H7 remained prominent. PUBLIC HEALTH ACTIONS: Methods to detect FBDOs are improving, and several changes to improve the ease and timeliness of reporting FBDO data have been implemented (e.g., a revised form to simplify FBDO reporting by state health departments and improved electronic reporting methods). State and local health departments continue to investigate and report FBDOs as part of efforts to better understand and define the epidemiology of foodborne disease in the United States. At the regional and national levels, surveillance data provide an indication of the etiologic agents, vehicles of transmission, and contributing factors associated with FBDOs and help direct public health actions to reduce illness and death caused by FBDOs.

Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination.

To design therapies for demyelinating diseases such as multiple sclerosis, it will be important to understand the mechanisms that control oligodendrocyte progenitor cell (OPC) numbers in the adult central nervous system (CNS). During development, OPC numbers are limited by the supply of platelet-derived growth factor-A (PDGF-A). Here, we examine the role of PDGF-A in regulating OPC numbers in normal and demyelinated adult CNS using transgenic mice that overexpress PDGF-A in astrocytes under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-PDGF-A mice). In adult GFAP-PDGF-A mice, there was a marked increase in OPC density, particularly in white matter tracts, indicating that the PDGF-A supply controls OPC numbers in the adult CNS as well as during development. To discover whether increasing PDGF expression increases the number of OPCs following demyelination and whether this enhances the efficiency of remyelination, we induced demyelination in GFAP-PDGF-A transgenic mice by intraspinal injection of lysolecithin or dietary administration of cuprizone. In both demyelinating models, OPC density within lesions was significantly increased compared to wild-type mice. However, morphological analysis of lysolecithin lesions did not reveal any difference in the time course or extent of remyelination between GFAP-PDGF-A and wild-type mice. We conclude that the availability of OPCs is not rate limiting for remyelination of focal demyelinated lesions in the mouse. Nevertheless, our experiments show that it is possible to increase OPC population density in demyelinated areas by artificially increasing the supply of PDGF.

Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS.

Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival of oligodendrocytes, the myelinating cells of the CNS. Enhanced remyelination has been demonstrated in vivo following systemic delivery of human recombinant GGF-2 (rhGGF-2) in experimental autoimmune encephalomyelitis (EAE). However, it is uncertain whether this is the result of direct effects of rhGGF-2 on cells of the oligodendrocyte lineage or due to modulation of the immune or inflammatory response. If this enhanced remyelination was due to direct effects of rhGGF-2 on cells of the oligodendrocyte lineage then one would expect rhGGF-2 to induce a similar proremyelinating response in nonimmune, gliotoxin models of demyelination. Using a gliotoxin model of demyelination we were therefore able to ascertain the in vivo effect of rhGGF-2 following local CNS delivery in a model that is not confounded by the concurrent presence of an immune-mediated process. No significant alteration in the rate or character of remyelination was evident following local delivery as compared to controls, and indeed nor following systemic delivery in the gliotoxin model. The results of this study therefore indicate that both direct infusion and systemic delivery of rhGGF-2 do not alter remyelination in a nonimmune, gliotoxin model of demyelination. This suggests that the proremyelinating effects of systemically delivered rhGGF-2 in EAE are unlikely to be due to direct effects on the oligodendrocyte lineage, but may be mediated by rhGGF-2 inducing an environment more favourable to remyelination, possibly through modulation of the immune response.